How does smoking, an environmental factor, cause cancer, fundamentally a genetic disease?

How does smoking, an environmental factor, cause cancer, fundamentally a genetic disease?

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If cancer is fundamentally a genetic disease, how might an environmental factor such as smoking cause cancer?

Because cigarette smoke contains many carcinogens. Carcinogens can cause cancer by directly affecting the genome. Wikipedia has a list of those present in cigarette smoke, which includes classics such as lead, benzene, and formaldehyde, not to mention radioactive polonium.

There are carcinogens in smoke but they've not been shown to be the cause of cancer in smokers. Note that some smokers never develop cancer or heart disease; some have lived more than 100 years.

Just because something is classified as a carcinogen doesn't mean it causes cancer in everyone and doesn't mean a given exposure to a particular carcinogen has any effect at all. All smoking does is increase one's risk of developing cancer. That it increases risk is not a fact but the association between smoking and cancer is significant, statistically. (This means it meets certain mathematical criteria and is, therefore, not mere opinion).

Chromosomal replication is not perfect and a healthy cell can replicate only a limited number of times. Cancer is characterized (in part) by a loss of this control. When DNA mutates in a way that results in the loss of this control an otherwise-healthy cell (now a mutation) results. Smoking increases cell turnover and the increased turnover increases the likelihood this type of mutation will occur.

You can think of skin cancers in the same way. This is the reason an exposure resulting in a color change (sunburn, tanning including that from a tanning booth) increases the risk of skin cancer.

Over a typical lifetime we develop a handful of cancerous tumors. They're killed by our immune system. Symptoms of malignant cancer develop when the immune system hasn't been effective.

6.6: Mutations

  • Contributed by Suzanne Wakim & Mandeep Grewal
  • Professors (Cell Molecular Biology & Plant Science) at Butte College

Can a mutation really turn a person into a superhero? Of course not, but mutations can sometimes result in drastic changes in living things.

Figure (PageIndex<1>): Superhero

A Call For More Research On Cancer's Environmental Triggers

A stretch of the Mississippi River from New Orleans to Baton Rouge, La., that is crowded with chemical plants has been called "Cancer Alley" because of the health problems there. Giles Clarke/Getty Images hide caption

We already know how to stop many cancers before they start, scientists say. But there's a lot more work to be done.

"Around half of cancers could be prevented," said Christopher Wild in the opening session of an international scientific meeting on cancer's environmental causes held in June. Wild is the former director of the World Health Organization's International Agency for Research on Cancer.

"Cancer biology and treatment is where most of the money goes," he said, but prevention warrants greater attention. "I'm not saying that we shouldn't work to improve treatment, but we haven't balanced it properly."

Perhaps no question about cancer is more contentious than its causes. People wonder, and scientists debate, if most malignancies stem from random DNA mutations and other chance events or from exposure to carcinogens, or from behaviors that might be avoided.

At the conference in Charlotte, N.C., scientists pressed for a reassessment of the role of environmental exposures by applying modern molecular techniques to toxicology. They called for more aggressive collection of examples of human pathology and environmental samples, including water and air, so that cellular responses to chemicals can be elucidated.

The hope is that by identifying specific traces of exposures in human cancer specimens, scientists can identify environmental causes of disease that might be prevented.

"Over 80,000 chemicals are used in the United States, but only a few have been tested for carcinogenic activity," said Margaret Kripke, an immunologist and professor emeritus at MD Anderson Cancer Center, in an interview at the meeting.

"This has been a very neglected area of cancer research for the last several decades," said Kripke, the driving force behind the conference, which was put on by the American Association for Cancer Research. "Environmental toxicology was very popular in the 1950s and 1960s," she said, but genetics then began to overshadow studies of cancer's environmental causes. "Toxicology fell by the wayside."

While the incidence of tobacco-linked cancers has been falling, malignancies not associated with smoking are rising, Kripke said. Recent evidence suggests an escalating rate of lung cancer in nonsmokers. That trend implicates other environmental factors.

Around the globe, cancer's overall incidence is climbing. This year, 18 million people will be diagnosed with some form of cancer and over 9 million will die from it.

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Infections — many preventable, such as by human papillomavirus —account for 15% of new cases.

Another rising cause is obesity, along with urbanization. People generally get less physical activity and eat differently in cities, and pollution is heavier there, too. "As people move into cities, that will drive up cancer rates," Wild said.

One of the biggest obstacles to preventing cancer is that many people just don't think it's feasible. Progress "requires long-term vision and commitment," Wild said. "Funding is limited, and there's little private sector investment."

A change in the way benefits of cancer prevention are framed could help. "When I was at the IARC, one thing that struck me was the power of economic arguments over health arguments for preventing cancer," Wild said.

Cancer treatment costs can be prohibitive. But productivity lost from premature deaths in Brazil, Russia, India, China and South Africa alone runs $46.3 Abillion annually, he said. "Developing countries are not prepared to deal with the rising cancer burden."

The precise proportion of cancers arising from environmental and occupational exposure to carcinogens is uncertain. In 2009, a report by the President's Cancer Panel called prior approximations of around 6% "woefully out of date" and low. A 2015 paper by over a hundred concerned scientists cited "credible" estimates of 7% to 19%.

Scientist at the Charlotte meeting emphasized the complexity of cancer's causes and the need for toxicologists to update methods to reflect that complexity, such as by studying interactions of environmental and genetic risks, and by examining cells after a mix of exposures. "Most toxic exposures do not occur singly," said Rick Woychik, deputy director of the National Institute of Environmental Health Sciences.

Until recently, many toxicology tests were performed in rodents, because it would be unethical to deliberately evaluate possible carcinogens in people. But these animal experiments are labor-intensive and slow, he said.

New alternatives are now being tried. "We learned from pharma that with robotics and high-throughput technology you can interrogate a lot of biology quickly and at lower costs," he said.

Epidemiological research of human exposures has been stymied by the difficulty of proving cause-and-effect — that a particular substance actually causes cancer — and by shortcomings of survey data from questionnaires.

At the conference, scientists offered glimpses of new technology that is helping fill informational gaps.

Bogdan Fedeles of MIT explained how DNA serves as a lifelong "recording device." He and others use duplex sequencing to examine human samples for genetic "fingerprints of exposure."

Allan Balmain, a geneticist at University of California, San Francisco, spoke about mutational signatures in malignancies. In liver cancer, for instance, these signatures can offer causal clues—such as smoking, alcohol or aflatoxin, a product of mold that grows on some foods.

Many chemicals that cause or stimulate cancer growth are produced inside our bodies. "It's not all about the environment," Balmain said.

Others highlighted a conceptual shift in how scientists define carcinogens. Key characteristics may include a substance's capacity to stimulate growth of malignant cells, or to induce inflammation—without necessarily causing DNA damage, long seen as the necessary .

"The answer to 'What is a carcinogen?' is changing" said Ruthann Rudel, a toxicologist at the Silent Spring Institute who has published extensively on breast carcinogens. She detailed new techniques to screen breast cancer cells for changes in response to specific chemical exposures.

The public health stakes for the field are high.

Professor air pollution in St. John the Baptist Parish, La., and potential exposures to carcinogens from fracking and planned

Elaine Schattner is a physician in New York writing a book on cancer attitudes that will be published by Columbia University Press.

Cancer and the Environment: Gene-Environment Interaction (2002)

The past decade has witnessed important advances in the understanding of factors that influence cancer risk. Several environmental factors continue to surface as potentially instrumental in explaining the wide global variation in the incidence and biological behavior of various tumors. For example, discoveries that both essential and nonessential dietary nutrients can markedly influence several key biological events&mdashincluding cell cycle regulation, processes involved in replication or transcription, immunocompetence, and factors involved with apoptosis, or programmed cell death&mdashhave strengthened convictions that specific foods or components may markedly influence cancer risk.

Analyses of the incidence of cancer in twin pairs and in families are traditional methods for answering questions about the relationships between cancer etiology, genes, and the environment. Sorting out the relative roles of each in the initiation and progression of cancer can lead to clearer elucidation of how shared environmental influences can disparately affect the health of individual members of a community, that is, why some people exposed to a specific agent develop cancer when others do not.

Finally, although environmental, occupational, and recreational exposures to carcinogens contribute to cancer risk in humans, variation in incidence and progression of cancers among individuals can be attributed to interindividual variation in genetic makeup. Recent research has identified functional polymorphisms that influence an individual&rsquos cancer risk and has focused on gene products involved in activation and detoxification of carcinogens and DNA repair. Gene polymorphisms that are important in apoptosis will increasingly be recognized as clues to individual susceptibility to cancer, explaining why individuals with shared environmental exposures do not always share cancer morbidity and mortality.


There are unprecedented opportunities for using the food supply to achieve genetic potential, that is, to optimize our performance and reduce the risks of diseases, said John Milner, Department of Nutrition, Pennsylvania State University. Although 80 percent of cancers are related to environmental factors, the influence of diet in the development of cancer is somewhat uncertain. However, the general consensus is that approximately 35 to 40 percent of cancers relate to dietary habits, although the range might be quite large.

The influence of diet in the development of cancer is somewhat uncertain. However, the general consensus is that approximately 35 to 40 percent of cancers relate to dietary habits

Even though science has come a long way in understanding what factors are important in controlling cancer risks or modifying health in general, we still do not really know who is going to benefit, and under what circumstances, said Milner. In fact, we do not yet know if there are some people who would be placed at risk because of exaggerated intakes of certain types of foods or food components. The whole issue of the role of diet in health is exceedingly complex when trying to assess the relative roles of individual foods as they relate to overall cancer risk. There are some areas of agreement, however, said Milner. More than 80 percent of the studies that have been published reveal a reduction in cancer risk with an increase in fruit and vegetable consumption. However, there is considerable variability among populations, suggesting that a person&rsquos genetics may be important in determining the response. He added that we need to have a better understanding of how genes are involved in the cancer process and how individual nutrients can modify these genes and ultimately influence the probability of developing cancer.

Some of the strongest evidence linking diet and cancer comes from the epidemiological observation that increased vegetable and fruit consumption is associated with a reduction in the risk for cancers of the mouth and pharynx, esophagus, lung, stomach, colon, and rectum. Likewise considerable evidence points to a host of essential and nonessential nutrients as modifiers of cancer risk at a variety of sites. Milner noted that part of this variation in cancer risk may arise from variation in the intake of one or more essential nutrients supplied by either plant or animal food sources. Vegetables derived from various parts of plants including roots (e.g., carrots, parsnips), leaves (e.g., spinach, lettuce), flowers (e.g., artichoke, broccoli), stalks (e.g., celery, rhubarb), and seeds (e.g., corn, peas), as well as a host of fruits, provide thousands of chemically diverse phytonutrients that may contribute to these observations. Some of these phytonutrients&mdashincluding flavonoids, carotenoids, organosulfides, and

isothiocyanates&mdashhave been the focus of recent research to determine both their effects on risk and their mechanisms of action.

Despite the clear linkages that have been found between the risk of developing some types of cancers and dietary patterns, inconsistencies have been detected, which might reflect the multifactorial and complex nature of cancer, the specificity that individual dietary constituents have in modifying specific genetic pathways, and the temporal relationship between dietary intervention and phenotypic changes in tumor incidence or behavior. The chemical and biological diversity of dietary components in combination with a range of molecular targets makes pinpointing the importance of diet in various cancers a challenge, emphasized Milner. It is likely that this challenge will be augmented by advances in cell biology and epidemiology. For instance, when limonene (found in citrus fruits) is added to tumor cells it has been found to enhance several genes while suppressing others. Since several of the identified genes are involved in the pathways leading to apoptosis, it is possible that agents such as limonene could play a role in the cell signaling involved in programmed cell death. Similarly, studies with a variety of other nutrients, including selenium, isothiocyanates, and allyl sulfide, have been reported to modify at least 20 different gene products associated with cancer prevention.

In addition, knockout and transgenic animals can provide important clues about the specific site of action of dietary components. The use of these genomic technologies to evaluate the effects of nutrients offers exciting opportunities for determining which cellular change is most important in bringing about a change in the incidence or behavior of a tumor.

A reductionist approach to diet and cancer prevention may produce oversimplifications and confusion. We clearly need to know what the mechanisms are that account for specific bioactive food components but must also recognize that we eat whole foods.

Preclinical evidence suggests that diverse dietary constituents including selenium, allyl sulfur, genistein, and resveratrol can influence the same genetic pathways associated with tumor cell proliferation and apoptosis. Such common effects raise concerns about potential interactive and cumulative effects among nutrients, said Milner. In addition, compounds such as diallyl disulfide, which is found in crushed garlic, can actually suppress the growth rate of cells, and indole-3-carbinol, found in cabbage, can shift estradiol metabolism, which can affect tumor formation. The only problem, said Milner, is that we may have to consume about three-quarters of a pound of cabbage a day and several cloves of garlic to bring about a response. We know of a few examples where isolated food components and intact foods do not bring about the same biological response. Thus, a reductionist

approach to diet and cancer prevention may produce oversimplifications and confusion. We clearly need to know what the mechanisms are that account for specific bioactive food components but must also recognize that we eat whole foods.

Astonishing strides have been made in understanding how molecules and genetic pathways differ in precancerous and malignant cells and from their normal counterparts. Capitalizing on the differences in cellular signatures that are characterized by active and inactive genes and cellular products could assist in determining who should and should not benefit from intervention strategies. Clearly, added Milner, such information will help clarify the reason for discrepancies among preclinical, epidemiological, and intervention studies.

At least part of the variation in response to dietary components can probably be explained by the consumer&rsquos genetic profile. It is now becoming apparent that the prevalence of polymorphisms is variable among studied populations, and these differences could influence the response to diet. Evidence exists that genetic polymorphisms may modulate cancer risk through their influence on folate metabolism. For example, epidemiologic studies have reported that the relationship between dietary folate and colorectal cancer risk is influenced by polymorphism in methylenetetrahydrofolate reductase activity. Variation in the response to folate metabolism is not unique since other studies suggest that variation in receptors for vitamin D may also be linked to cancer risk. Considerably more information is needed about how genetic polymorphisms influence the response to dietary components and ultimately cancer risk, added Milner.

Unquestionably, cancer is intertwined with environmental factors including diet. Strategies to prevent cancer through modification of either diet or specific dietary patterns will probably not be uniformly effective for all individuals, said Milner. He stressed that a better understanding of gene&ndashnutrient interactions will be needed to determine those who might benefit most from dietary intervention and those who might be placed at risk. For example, there are data suggesting that some women who consume large amounts of fruits and vegetables may be at increased risk of giving birth to children with infantile leukemia. These women appear to have a reduced ability to remove some of the flavonoids from their system, which thus accumulate and become toxic to the developing fetus. Although in most cases there likely will be benefits from increased consumption of fruits and vegetables during pregnancy, in a small subset of the population an opposite response may occur. Future research in nutrition and cancer prevention must give top priority to studies that seek to understand the basic molecular and genetic mechanisms by which nutrients influence the various steps in carcinogenesis. &ldquoBy understanding the importance of the genetic profile, we can identify who is going to benefit and who is not going to benefit from dietary intervention,&rdquo concluded Milner.


Mounting evidence supports the concept that cancer is generally a polygenic multifactorial disease, which makes environment an important modifier in the risk of cancer, stated Kari Hemminki, Karolinska Institute. It is estimated that only 1 percent of cancers are caused by &ldquocancer syndromes&rdquo and up to 5 percent result from highly penetrant single-gene mutations thus, the majority are polygenic. Studies with various animal and in vitro models, initiation and promotion models, adenoma carcinoma models, and immortalized human cells provide evidence that polygenic mechanisms are important in cancer, at least in experimental systems.

Almost all of the known cancer syndromes are monogenic and conform to a two-stage model of development that is, they require inactivation of two copies of a tumor suppressor gene in order to initiate. These syndromes tend to be dominant Mendelian conditions, which can be assessed in family studies covering two or more generations. However, such studies provide no data on recessive Mendelian conditions and have a limited resolving power in polygenic conditions. Consequently, apart from highly penetrant single-gene mutations, the risks posed by low-penetrance single-gene mutations, polygenes, and recessive genes are poorly understood.

Hemminki described a study of data obtained from 44,000 same-sex twin pairs to assess cancer risks for co-twins of twins with cancer. There were almost 10,000 pairs in which one of the members had cancer. The analysis of environmental and inherited contributions was based on correlations between monozygotic twins who share the genome completely, that is, 100 percent concordance in their genomes. A similar concordance was carried out with dizygotic twins, the difference being the assumption that only 50 percent of the genes are common. The assumption is that the environment is affecting monozygotic and dizygotic twins similarly. Some of these different effects will then be 100 percent, or

Twin studies as tools for understanding genes, the environment, and cancer

Genetic: if monozygotic twins are more similar for a given trait than dizygotic twins

Shared Environment (e.g., diet and childhood experiences): if there is twin similarity not accounted for by genetic effects

Nonshared Environment: anything that is not hereditary and not shared between relatives, that is, sporadic causes of cancer

1. The nonshared random environmental effect was the largest factor for all cancers, accounting for 58 to 82 percent of the total variation (Table 3-1) (Lichtenstein et al., 2000). Statistically significant heritability estimates were detected for cancers of the colorectum (35 percent), breast (27 percent), and prostate (42 percent). The estimates for shared environmental effects ranged from 0 to 20 percent, but none were statistically significant.

A Swedish family cancer database, containing 10 million people, is the largest population-based data set ever used for studies on familial cancer, said Hemminki. The data are used to develop estimates for the environmental and inherited components in cancer, using the genetic relationships among family members to calculate the effects of genotype, shared environment, and nonshared environment. The database has been used in modeling cancer causation and has revealed that environmental causes explained most of the total variation for all neoplasms except thyroid cancer, for which heritable causes were largest. There also appears to be a subgroup of cancer patients who develop a second cancer to which there is a strong genetic predisposition, that often cannot be predicted by a family history. This phenomenon is typical of polygenic disease.

Hemminki reported that the twin and family data quantified nonshared environmental effects as ranging from 40 to 90 percent for different cancers. It is of interest to note that this effect was large for some cancers of identified environmental causes, such as lung and cervical cancers. In contrast, shared environment&mdashcommon family experiences and habits&mdashaccounted for 0 to 30 percent of cancer etiology. For all cancer, the genetic effect was estimated to be 26 percent however, there is evidence supporting heritability for all cancers.

Types of Mutations

There are a variety of types of mutations. Two major categories of mutations are germline mutations and somatic mutations.

  • Germline mutations occur in gametes, the sex cells, such as eggs and sperm. These mutations are especially significant because they can be transmitted to offspring and every cell in the offspring will have the mutations.
  • Somatic mutations occur in other cells of the body. These mutations may have little effect on the organism because they are confined to just one cell and its daughter cells. Somatic mutations also cannot be passed on to offspring.

Mutations also differ in the way that the genetic material is changed. Mutations may change an entire chromosome or just one or a few nucleotides.

Chromosomal Alterations

Chromosomal alterations are mutations that change chromosome structure or number. They occur when a section of a chromosome breaks off and rejoins incorrectly or does not rejoin at all. Possible ways these mutations can occur are illustrated in Figure (PageIndex<3>). Chromosomal alterations are very serious. They often result in the death of the organism in which they occur. If the organism survives, it may be affected in multiple ways. An example of a human chromosomal alteration is the mutation that causes Down Syndrome. It is a duplication mutation that leads to developmental delays and other abnormalities. It occurs when the individual inherits an extra copy of chromosome 21. It is also called trisomy ("three-chromosome") 21.

Figure (PageIndex<3>): Chromosomal Alterations. The chromosomal alterations may occur due to deletion or duplication of genes in a chromosome, inversion of a section of a chromosome, insertion of genes from one chromosome to another, or exchanges of genes between two chromosomes.

A point mutation is a change in a single nucleotide in DNA. This type of mutation is usually less serious than a chromosomal alteration. An example of a point mutation is a mutation that changes the codon UUU to the codon UCU. Point mutations can be silent, missense, or nonsense mutations, as shown in Table (PageIndex<1>). The effects of point mutations depend on how they change the genetic code.

Table (PageIndex<1>): Point Mutation Types
Type Description Example Effect
Silent mutated codon codes for the same amino acid CAA (glutamine) &rarr CAG (glutamine) none
Missense mutated codon codes for a different amino acid CAA (glutamine) &rarr CCA (proline) variable
Nonsense a mutated codon is a premature stop codon CAA (glutamine) &rarr UAA (stop) usually serious

Frameshift Mutations

A frameshift mutation is a deletion or insertion of one or more nucleotides that changes the reading frame of the base sequence. Deletions remove nucleotides, and insertions add nucleotides. Consider the following sequence of bases in RNA:

AUG-AAU-ACG-GCU = methionine-asparagine-threonine-alanine

Now assume that an insertion occurs in this sequence. Let&rsquos say an A nucleotide is inserted after the start codon AUG. Then the sequence of bases becomes:

AUG-AAA-UAC-GGC-U = methionine-lysine-tyrosine-glycine

Even though the rest of the sequence is unchanged, this insertion changes the reading frame and thus all of the codons that follow it. As this example shows, a frameshift mutation can dramatically change how the codons in mRNA are read. This can have a drastic effect on the protein product. Another example of the frameshift mutation due to the deletion of a nucleotide is illustrated in Figure (PageIndex<4>). In this example, a premature stop codon is created by the mutation.

Figure (PageIndex<4>): The image shows how the frame of the coding sequence of a gene changes when a nucleotide gets deleted due to mutation. Normal gene codes for a polypeptide met-lys-phe-gly-ile-val-pro. When a U from the third position of the third codon gets deleted, the polypeptide reduced to met-lys-leu-ala because the third and fourth codons code for different amino acids and the fifth codon converts to a stop codon.

New Studies Examine Genetic, Environmental Risk Factors Linked to Lung Cancer Among Never Smokers

NEW YORK (Precision Oncology News) – As cigarette smoking — a leading risk factor for lung cancer — is on the decline, new studies are exploring genetic and other environmental risk factors that affect whether or not someone might develop the disease.

According to the US Centers for Disease Control and Prevention, about 14 percent of US adults were smokers in 2017, down from 20.9 percent in 2005. At the same time, lung cancer among people who have never smoked is becoming proportionately higher, and never smokers now account for between 10 percent and 25 percent of lung cancer patients.

Many previous studies of lung cancer, including by The Cancer Genome Atlas project, have relied on lung cancer samples that largely came from people who had been smokers. Eighty-one percent of patients whose tumors were analyzed in the TGCA lung adenocarcinoma project were former or current smokers. Still, these studies hinted that the mutational profiles of lung tumors from smokers and non-smokers differ.

Some new studies aim to examine the mutational landscape of lung cancer among non-smokers to not only tease out what genetic alterations arise in their disease, but also to pinpoint environmental or other factors that contribute to disease risk. The findings may then be applied to identify people who are at increased risk of developing lung cancer or suggest treatment approaches for those who have already developed the disease.

"We know a few important established risk factors like radon or asbestos or passive smoking or some previous lung diseases, but we don't know what causes the large majority of these cases," Maria Teresa Landi, a senior investigator at the National Cancer Institute, said in an interview. "And there is no effective treatment for them. So, we really wanted to study them for this reason."

She and her colleagues launched Sherlock-lung, a genomic epidemiologic study of lung cancer in people who have never smoked, to try to uncover the etiology of the disease among nonsmokers. They plan to collect 2,000 to 2,500 lung cancer samples from people living in a range of geographic areas and from people of a range of ethnicities. That way, she said, the study will encompass a number of exposures and genetic backgrounds and be applicable to a wide population.

So far, Landi said they've conducted whole-genome sequencing of paired tumor and blood samples from 235 lung cancer cases and are currently sequencing another 600 cases.

While that number is small, they already can pick up differences in the mutational signature patterns seen in their nonsmokers, as compared to what has been detected in smokers.

Similarly, Fred Hutchinson Cancer Research Center's Alice Berger has teamed with researchers from the Women's Health Initiative, a long-term national study that started in the 1990s, to also study gene mutations in lung cancers from women who never smoked. (Men and women, she noted, also appear to harbor differences in their mutational profiles.)

Berger and her colleagues plan to sequence lung tumors from about 130 women, about 110 of which will be from never smokers and the rest from women who did smoke. So far, they've collected DNA from 99 lung tumors and sequenced about a third of them and have plans to finish sequencing by later this year. Berger noted they are in particular ensuring they can detect frequent translocations, as there are various gene fusions that appear to be more common among non-smokers.

Both studies also aim to delve into environmental factors that could influence lung cancer risk, such as asbestos, air pollution, or radon exposure. Smoking, Berger noted, leaves a particular mutational mark on the tumor genome, and so too could these other types of exposures.

She and her colleagues also plan to examine secondhand smoke exposure, as do NCI's Landi and her colleagues.

"We have information about if they live with people who do [smoke], [or] work in workplaces where they're exposed to smoke," Berger said. "If you work in a casino or something like that, you might have a high rate of secondhand smoke."

Through Sherlock-lung, Landi and her colleagues want to explore the links between those known environmental exposures among individuals in their study — such as radon or indoor air pollution — or endogenous mutational processes — such as DNA repair or DNA replication — to the mutational signatures they see in patients' tumors.

Once they do that, they plan to see whether those mutational signatures present in people with lung cancer who were exposed to a high level of a known environmental risk factor can be teased out among individuals with lung cancer whose environmental exposures are low or even unknown. They plan on then validating these signatures through in silico simulations.

Researchers at Johns Hopkins University and their colleagues, meanwhile, have already begun to dig into how environmental exposures influence lung cancer risk among never smokers. At the annual American Association for Cancer Research meeting in April, Hopkins' Batel Blechter presented data on lung cancer risk among non-smoking women in China. She and her colleagues were particularly interested in the influence of coal as a cooking fuel — a known lung cancer risk factor — in conjunction with genetic factors on the risk of developing lung cancer.

Using data from the Female Lung Cancer Consortium in Asia (FLCCA) study, the Hopkins team examined the women's risk of developing lung cancer based on their genetic profiles by building a polygenic risk score based on 10 SNPs from a genome-wide association study conducted among women in Asia. Women with high risk scores were, they found, more likely to develop lung cancer.

At the same time, they examined the rate of lung cancer among women who had or who never had used coal in the home to find that those who had used coal in their homes had an increased risk of lung cancer.

"We often find that gene and environment both have an effect," Hopkins' Nilanjan Chatterjee, a biostatistician and Blechter's advisor, said in an interview. "If you look at the effect of the gene, it is similar whether you have that [environmental] parameter or not."

But in this case, the Hopkins-led team found the environmental factor — here, coal use — was a stronger risk factor among women with low genetic risk for lung cancer.

While he cautioned he did not have a strong theory for why this occurred, he noted that some researchers have speculated that, in some cases, the influence of genetic factors could already make risk so high that it cannot go much higher even with the addition of some environmental factor.

"That is interesting, but we do not know what it means biologically," Chatterjee said of their finding.

Through studies like these, researchers hope to combine both genetic and environmental risk factors to gauge people's risk of developing lung cancer as well as uncover means of preventing or treating disease.

Chatterjee and his colleagues argued in a 2016 JAMA Oncology paper that such a model could help guide cancer screening efforts and the understanding of individual risk.

In that paper — which used breast cancer as an example — he and his colleagues built a model that combined the influence of about 100 genetic risk variants and epidemiological factors like BMI, smoking status, whether someone was taking hormone replacement therapy, and more to determine breast cancer risk. The addition of these environmental factors to the polygenic risk score model, Chatterjee noted, improved its performance predicting risk in the general population.

This, he added, can then help guide screening efforts. He noted that there has been back-and-forth in the US about when to, in the case of breast cancer, begin mammography screening. Current guidelines rely heavily on age, but he said that these sorts of risk models could identify people who, though they are young, may be at higher risk of disease and who might benefit from earlier screening. At the same time, it could be used to identify people who are older, but are at lower risk of disease, and for whom screening could possibly start later in life.

"You can see that if you use this type of risk model, you will probably recommend screening it in a different way for many people," Chatterjee said, noting that a similar approach could work in lung cancer with CT scans.

By identifying which genes are mutated within those who end up developing cancer, researchers might then be able to stratify patients into different groups. NCI's Landi said that the additional information about environmental exposures alongside other information on methylation status, histological features, radiological imaging, and more could be combined with deep learning to identify lung cancer subtypes among never smokers.

"We hope to be able to identify subgroups of lung cancer cases that are associated with specific exposures or endogenous processes," Landi said of her Sherlock-lung study. "And then we could identify potential strategies to prevent them or treat them."

An organism's genotype (e.g., in the zygote) translated into the adult phenotype through development during an organism's ontogeny, and subject to influences by many environmental effects. In this context, a phenotype (or phenotypic trait) can be viewed as any definable and measurable characteristic of an organism, such as its body mass or skin color.

Apart from the true monogenic genetic disorders, environmental factors may determine the development of disease in those genetically predisposed to a particular condition. Stress, physical and mental abuse, diet, exposure to toxins, pathogens, radiation and chemicals found in almost all [ quantify ] personal-care products and household cleaners are common environmental factors that determine a large segment of non-hereditary disease.

If a disease process is concluded to be the result of a combination of genetic and environmental factor influences, its etiological origin can be referred to as having a multifactorial pattern.

Cancer is often related to environmental factors. [2] Maintaining a healthy weight, eating a healthy diet, minimizing alcohol and eliminating smoking reduces the risk of developing the disease, according to researchers. [2]

Environmental triggers for asthma [3] and autism [4] have been studied too.

The exposome encompasses the set of human environmental (i.e. non-genetic) exposures from conception onwards, complementing the genome. The exposome was first proposed in 2005 by cancer epidemiologist Christopher Paul Wild in an article entitled "Complementing the genome with an "exposome": the outstanding challenge of environmental exposure measurement in molecular epidemiology". [5] The concept of the exposome and how to assess it has led to lively discussions with varied views in 2010, [6] [7] 2012, [8] [9] [10] [11] [12] [13] and 2014. [14] [15]

In his 2005 article, Wild stated, "At its most complete, the exposome encompasses life-course environmental exposures (including lifestyle factors), from the prenatal period onwards." The concept was first proposed to draw attention to the need for better and more complete environmental exposure data for causal research, in order to balance the investment in genetics. According to Wild, even incomplete versions of the exposome could be useful to epidemiology. In 2012, Wild outlined methods, including personal sensors, biomarkers, and 'omics' technologies, to better define the exposome. [8] He described three overlapping domains within the exposome:

  1. a general external environment including the urban environment, education, climate factors, social capital, stress,
  2. a specific external environment with specific contaminants, radiation, infections, lifestyle factors (e.g. tobacco, alcohol), diet, physical activity, etc.
  3. an internal environment to include internal biological factors such as metabolic factors, hormones, gut microflora, inflammation, oxidative stress.

In late 2013, this definition was explained in greater depth in the first book on the exposome. [16] [17] In 2014, the same author revised the definition to include the body's response with its endogenous metabolic processes which alter the processing of chemicals. [18]

For complex disorders, specific genetic causes appear to account for only 10-30% of the disease incidence, but there has been no standard or systematic way to measure the influence of environmental exposures. Some studies into the interaction of genetic and environmental factors in the incidence of diabetes have demonstrated that "environment-wide association studies" (EWAS, or exposome-wide association studies) may be feasible. [19] [20] However, it is not clear what data sets are most appropriate to represent the value of "E". [21]

As of 2016, it may not be possible to measure or model the full exposome, but several European projects have started to make first attempts. In 2012, the European Commission awarded two large grants to pursue exposome-related research. [22] The HELIX project at the Barcelona-based Centre for Research in Environmental Epidemiology was launched around 2014, and aimed to develop an early-life exposome. [23] A second project, Exposomics, based at Imperial College London, launched in 2012, aimed to use smartphones utilising GPS and environmental sensors to assess exposures. [22] [24]

In late 2013, a major initiative called the "Health and Environment-Wide Associations based on Large Scale population Surveys" or HEALS, began. Touted as the largest environmental health-related study in Europe, HEALS proposes to adopt a paradigm defined by interactions between DNA sequence, epigenetic DNA modifications, gene expression, and environmental factors. [25]

In December 2011, the US National Academy of Sciences hosted a meeting entitled "Emerging Technologies for Measuring Individual Exposomes." [26] A Centers for Disease Control and Prevention overview, "Exposome and Exposomics", outlines the three priority areas for researching the occupational exposome as identified by the National Institute for Occupational Safety and Health. [11] The National Institutes of Health (NIH) has invested in technologies supporting exposome-related research including biosensors, and supports research on gene-environment interactions. [27] [28]

The idea of a Human Exposome Project, analogous to the Human Genome Project, has been proposed and discussed in numerous scientific meetings, but as of 2017, no such project exists. Given the lack of clarity on how science would go about pursuing such a project, support has been lacking. [29] Reports on the issue include:

  • a 2011 review on the exposome and exposure science by Paul Lioy and Stephen Rappaport, "Exposure science and the exposome: an opportunity for coherence in the environmental health sciences" in the journal Environmental Health Perspectives. [30]
  • a 2012 report from the United States National Research Council "Exposure Science in the 21st Century: A Vision and A Strategy", outlining the challenges in systematic evaluations of the exposome. [31][32]

The concept of the exposome has contributed to the 2010 proposal of a new paradigm in disease phenotype, "the unique disease principle": Every individual has a unique disease process different from any other individual, considering uniqueness of the exposome and its unique influence on molecular pathologic processes including alterations in the interactome. [33] This principle was first described in neoplastic diseases as "the unique tumor principle". [34] Based on this unique disease principle, the interdisciplinary field of molecular pathological epidemiology (MPE) integrates molecular pathology and epidemiology. [35]

Global change is driven by many factors however the five main drivers of global change are: population growth, economic growth, technological advances, attitudes, and institutions. [36] These five main drivers of global change can stem from socioeconomic factors which in turn, these can be seen as drivers in their own regard. Socioeconomic drivers of climate change can be triggered by a social or economic demand for resources such as a demand for timber or a demand for agricultural crops. In tropical deforestation for instance, the main driver is economic opportunities that come the extraction of these resources and the conversion of this land to crop or rangelands. [37] These drivers can be manifested at any level, from the global level demand for timber all the way to the household level.

An example of how socioeconomic drivers affect climate change can be seen in the soy bean trading between Brazil and China. The trading of soy beans from to Brazil and China has grown immensely in the past few decades. This growth in trade between these two countries is stimulated by socioeconomic drivers. Some of the socioeconomic drivers in play here are the rising demand for Brazilian soy beans in China, the increase in land use change for soy bean production in Brazil, and the importance of strengthening foreign trade between the two countries. [38] All of these socioeconomic drivers have implications in climate change. For instance, an increase in the development for soy bean croplands in Brazil means there needs to be more and more land made available for this resource. This causes the general land cover of forest to be converted into croplands which in its own regard has an impact on the environment. [39] This example of land use change driven by a demand of a resource, isn’t only happening in Brazil with soy bean production.

Another example came from The Renewable Energy Directive 2009 Union when they mandated biofuel development for countries within their membership. With an international socioeconomic driver of increasing the production biofuels comes affects in land use in these countries. When agricultural cropland shift to bioenergy cropland the original crop supply decreases while the global market for this crop increases. This causes a cascading socioeconomic driver for the need for more agricultural croplands to support the growing demand. However, with the lack of available land from the crop substitution to biofuels, countries must look into areas further away to develop these original croplands. This causes spillover systems in countries where this new development takes place. For instance, African countries are converting savanna's into cropland and this all stems from the socioeconomic driver of wanting to develop biofuels. [40] Furthermore, socioeconomic driver that cause land use change don’t all occur at an international level. These drivers can be experienced all the way down to the household level. Crop substitution doesn't only come from biofuel shifts in agriculture, a big substitution came from Thailand when they switched the production of opium poppy plants to non-narcotic crops. This caused Thailand's agricultural sector to grow, but it caused global rippling effects (opium replacement).

For instance, in Wolong China, locals use forests as fuelwood to cook and heat their homes. So, the socioeconomic driver in play here is the local demand for timber to support subsistence in this area. With this driver, locals are depleting their supply for fuelwood so they have to keep moving further away to extract this resource. This movement and demand for timber is in turn contributing to the loss of pandas in this area because their ecosystem is getting destroyed. [41]

However, when researching local trends the focus tends to be on outcomes instead of on how changes in the global drivers affect outcomes. [42] With this being said, community level planning needs to be implemented when analyzing socioeconomic drivers of change.

In conclusion, one can see how socioeconomic drivers at any level play a role in the consequences of human actions on the environment. These drivers all have cascading effects on land, humans, resources, and the environment as a whole. With this being said, humans need to fully understand how their socioeconomic drivers can change the way we live. For instance, going back to the soy bean example, when the supply can’t meet the demand for soy beans the global market for this crop increases which then in turn affects countries that rely on this crop for a food source. These affects can cause a higher price for soy beans at their stores and markets or it can cause an overall lack of availability for this crop in importing countries. With both of these outcomes, the household level is being affected by a national level socioeconomic driver of an increased demand for Brazilian soy beans in China. From just this one example alone, one can see how socioeconomic drivers influence changes at a national level that then lead to more global, regional, communal, and household level changes. The main concept to take away from this is the idea that everything is connected and that our roles and choices as humans have major driving forces that impact our world in numerous ways.

For more information about genetic predisposition to disease:

The Genetic Science Learning Center at the University of Utah provides more information about calculating the risk of genetic diseases and predicting disease based on family history.

The Coriell Personalized Medicine Collaborative explains genetic and nongenetic risk factors for complex diseases.

More detailed information about the genetics of breast and ovarian cancer, as well as other cancers, is available from the National Cancer Institute.

The National Human Genome Research Institute explains the calculation of polygenic risk scores and what information the scores can provide.

Genetic factors

Gene polymorphisms have been investigated as possible markers of increased susceptibility to periodontal diseases: IL-1, IL-4, IL-10 TNF-α Fcγ receptor human leukocyte antigen vitamin D receptor and N-formyl peptide receptor [55]. Relationships between smoking and genetic susceptibility to periodontal diseases have been strengthened with respect to genotypes associated with cytokines (IL-1, IL-6, and IL-10), the immune system (Fcγ receptor), bone metabolism (vitamin D receptor), and xenobiotics metabolism (N-acetyltransferase and myeloperoxidase). These studies have been listed in Table 3.

IL-1 polymorphisms have been intensively studied using a cross-sectional approach, except for one study that employed a longitudinal design [56]. The relationship with respect to smoking is controversial. The association between positive genotypes and the severity of periodontal disease was independent of smoking [57, 58], suggesting no relationship between smoking and IL-1 genotypes however, relationships between IL-1-positive genotypes and smoking was evident [59–63]. Logistic regression analysis of periodontal disease with genotype-negative non-smokers as a reference group exhibited odds ratios of 0.98 for genotype-positive non-smokers, 2.37 for genotype-negative smokers, and 4.50 for genotype-positive smokers, thus suggesting synergism between IL-1 polymorphism and smoking [64].

Non-smokers with moderate periodontitis and periodontally healthy subjects displayed a higher incidence of IL-6 G-genotype than severe periodontitis subjects [65]. The difference in the occurrence of the IL-10 GG genotype between severe chronic periodontitis and control groups was more evident in non-smokers [66]. Gene coding for the ligand-binding chain of interferon gamma receptor 1, a cytokine that plays a pivotal role in defense against infection, was significantly associated with periodontitis in combination with smoking [67]. IgG-binding factors, namely Fcγ receptors, could influence the ability of phagocytosis. Genotypes of Fcγ receptor, FcγRIIa, and FcγRIIIb, may be associated with periodontal disease in smokers [68, 69]. Vitamin D receptor Taq-I TT polymorphism was moderately associated with both the presence and progression of periodontitis in smokers [70]. Gene polymorphisms for enzymes that can metabolize smoking-derived substances may contribute to individual susceptibility to the risk of periodontitis among smokers. Subjects with the polymorphic cytochrome P450 1A1 M2 allele and glutathione S-transferase M1 allele exhibited an increased risk of periodontitis [71].

Genetics & Periodontal Disease

The good news is that the list of acknowledged and proven periodontal risk factors is relatively short and well-understood.

The good news is that the list of acknowledged and proven periodontal risk factors is relatively short and well-understood.

Thomas M. Hassell, DDS, PhD, and

Viewed globally, the oral-health care professions face only two adversaries: dental caries and periodontal disease. On the one hand, the hereditary basis for susceptibility to caries is rather well-founded, and mechanisms for long-term caries prevention, including systemic and topical fluorides, have been generally acknowledged for decades.

On the other hand, the genetics of susceptibility to inflammatory periodontal diseases have remained elusive. This fact derives from the complexity of the disease, the continuous emergence of new knowledge about its pathogenesis, the relative contributions of a myriad of microorganisms to its etiology, and the vagueness of clinical diagnosis and statistical quantification. It is also a result of the periodontal community`s own penchant for arcane and ever-changing nomenclature to classify the periodontal diseases, which continues to evolve today.

The theory that host genetic make-up may act in combination with environmental factors to influence periodontal disease is not new. In 1930, it was concluded that susceptibility and immunity to periodontal disease were "probably inherited." Even earlier, the German-language dental literature provided a series of undocumented, but nonetheless intriguing, quotations on the topic:

"Pedigree analyses reveal again and again that blood relatives often suffer from pyorrhea." (Moral, 1924)

"I often have observed that the parents of children with advanced pyorrhea lost their teeth early." (Sachs, 1925)

"The susceptibility to true alveolar pyorrhea is due to a specific lack of host resistance, which is most likely not acquired, but inherited." (Reinmoller, 1925)

"Inheritance plays a massive role in periodontitis. I once saw a mother of eight who had periodontal disease, and so did four of her children." (Boenheim, 1928)

In the face of a known pathogenic challenge, some people succumb, while others seem inherently resistant. It has been recognized since the earliest days of dentistry and medicine that some diseases or conditions are familial or "run in families." As an example of this phenomenon, let`s consider tobacco smoke and lung cancer.

Fact: Not all people who smoke develop cancer. And yet, tobacco smoke contains over 4,700 chemical compounds, over 40 of which are acknowledged carcinogens. Thirty years ago, Dr. Tokuhata studied lung cancer in several thousand smokers, nonsmokers, and their relatives. He provided an instructive and revealing diagram (Figure 1), which implicated a "familial factor" in the pathogenesis of lung cancer. His diagram shows the synergistic interaction between the familial factor and the tobacco factor. People who have both of these factors are subjected to a dramatic increase in lung cancer. Dr. Tokuhata referred to this as a "booster factor."

Ten years later, other scientists were able to explain this phenomenon when they discovered that some people have a genetic ability to convert potential (tobacco-derived) carcinogens into active carcinogens, while other people do not. Members of the latter group are less susceptible to the disease, even though they are exposed to the same carcinogens - tobacco by-products.

Subsequent research - much of it performed by Dr. Victor McKusick - led to the assignment of what is now known as the "heritability estimate" for many medical conditions. This is a quantitative measure of the extent to which a person`s genetic constitution can be held "responsible" for the fact that disease develops when the challenge is present. Figure 2 provides the Heritability Estimates for some common diseases. It reveals that varicose veins, for example, are 100 percent heritable (not at all influenced by environmental factors), while stomach ulcers are only about 35 percent heritable. Recent clinical research has demonstrated that the Heritability Estimate for clinical signs of periodontal disease probably ranges between 40 and 80 percent. That means that when challenged by the presence of pathogen-containing dental plaque, some people will develop periodontitis, while others will be resistant to it.

In post-war Bonn, Germany, periodontal disease was studied by means of the "human twin paradigm," which had been employed for clinical research in medicine and psychology since 1876. In 13 sets of identical twins over the age of 25, severe periodontitis was detected in four twin sets. Both twins in the four twin sets were affected and concordant for relevant clinical parameters including pocket formation, gingival recession, subgingival calculus accumulation, tooth mobility, and periodontal pocket suppuration. The researcher was quick to acknowledge that his sample size was quite small, but he suggested that his preliminary findings should stimulate expanded studies of adult twins in periodontology, and should include non-identical (fraternal) twins as the ideal control group.

Almost 40 years went by before this advice was heeded by the community of periodontal scientists. Thus, only since 1989, and up until the present time, have clinical examinations of human twins contributed new knowledge about the major role that genetics plays in periodontal disorders.

Today, twin studies typically are used to detect genetic variance for traits or conditions that are multifactorial. The comparison of the similarity of identical twins with that of fraternal twins is based on the difference in shared genes and the similarity of shared environments, so that a greater degree of similarity for identical twins is evidence for genetic variance. For the simple model on which estimates of heritability are based for Mendelian traits, you would expect the correlation for identical twins to be no more than twice that for fraternal twins. However, this does not always hold true for multigenic traits. An even greater difference between the similarity of identical and fraternal twins suggests that a more complex genetic model - gene-environment interaction - or greater shared environment for identical twins is a better explanation of the observed correlations. A near-equal correlation for identical and fraternal twins suggests that shared environmental factors - not genes - account for any observed similarities.

Since 1984, dental researchers in Minnesota also have studied twins reared apart. Presumably, such twins have no more shared environment than any two unrelated individuals, and certainly share less of their environment than do twins reared together. Thus, including twins reared apart in a study design facilitates stronger conclusions about the importance of genetic variation and shared environment in familial clustering in a disease process.

Thirty years ago, a clinical study of periodontal health in 26 twin pairs aged 12-17 years found no evidence of a genetic contribution to variation in gingival recession, sulcus probing depth, or indices of gingivitis, calculus, and plaque. However, more recent and well-controlled studies of more appropriately-aged twins support the concept that genetic variation may contribute to individual differences in risk for the more common adult periodontitis.

For example, in a large, population-based twin study of questionnaire-assessed periodontal disease, identical twins were found to be more concordant for periodontal disease than were fraternal twins. Thus, if one is an identical (monozygous) twin, the risk of developing periodontal disease if one`s sibling has had periodontal disease is 28-31 percent vs. 8-16 percent for fraternal twins. Both of these concordance rates are higher than the prevalence of periodontal disease among twins (5 percent) and among non-twin spouses (4 percent). However, age and gender differences in the risk for periodontal disease - and other risk factors for periodontal disease (e.g., smoking) - were not specifically taken into account in these analyses.

Twin similarity for clinical measures of periodontal disease and for potential host-risk factors for periodontal disease has recently been assessed. After age and gender effects on each measure were taken into account, the similarities of identical twins reared together, fraternal twins reared together, and identical twins reared apart were compared for attachment loss, pocket-probing depth, gingival index, and plaque index. The greater similarity of identical twins - whether reared together or apart - suggests that there is a genetic contribution to variations in levels of supragingival plaque and clinical measures of periodontal health. However, the low degree of similarity in fraternal twins for most measures suggested that the genetic model may not be a straightforward additive model, but may instead be an interaction between genes at one locus (dominance), among genes at more than one locus (epistasis), or between genes and other risk factors.

The difference in similarity of alveolar bone height for identical twins reared together and fraternal twins suggests that genetic variation contributes to individual differences in alveolar bone height. The difference in similarity between identical twins reared apart and those reared together suggests that shared environmental factors also contribute to variation in alveolar bone height.

Another field of science that has emerged relatively recently is the field of in-vitro biology. In-vitro biology has permitted periodontal scientists to ask relevant questions about the possible genetic mechanisms operating to control periodontal disease susceptibility. The ability to harvest human cells - blood cells and somatic cells - and to maintain their viability in isolation in the laboratory under various experimental conditions has provided a fertile landscape for experimentation and hypothesis-testing.

For example, scientists studied the ability of human-blood neutrophils in vitro to migrate through a filtering membrane toward a known chemotactic substance. As a result of these studies, they were first able to ascertain that a cell-migration defect - i.e., inability or slowness of movement - represented one component of the pathogenesis of a form of periodontal disease. This form is known to have a genetic base. It is termed juvenile periodontitis, namely the inadequate host response to etiologic substances.

In-vitro studies of human gingival and periodontal connective tissue cells - known as fibroblasts - have contributed much to our understanding of tissue destruction and regeneration. In-vitro investigations of alveolar bone cells - called osteoblasts - provided breakthrough information about the roles played by various byproducts of microorganisms in the initiation of bone resorption.

The in-vitro method permits exposure of cells from identical and fraternal twins to various exogenous agents to assess whether response to such agents could be under genetic control. The first exploration of this hypothesis evaluated the response of gingival fibroblasts from twins to the anti-epileptic drug, phenytoin (Dilantin). It showed that the effect of phenytoin on general-protein synthesis - and specifically on collagen synthesis - was under strong genetic control. The researchers concluded that the gingival enlargement and overgrowth often elicited by phenytoin also is a genetically determined response. Clearly, not all people who take phenytoin on a chronic regimen develop gingival overgrowth only those who are genetically susceptible do so.

Both homeostasis and repair of periodontal soft tissues are regulated for the most part by resident fibroblastic cells. An important attribute of such cells is their ability to proliferate when necessary to replace lost or damaged tissues. In-vitro study of fibroblasts derived from twins has demonstrated that the cellular-proliferation rate of these cells is under strong genetic control (see Figures 3 and 4).

The concept of a cellular basis for genetic susceptibility to adult periodontitis also has been subjected to laboratory investigation by means of the in-vitro twin paradigm. Since 1960, numerous authors have studied the effects of putative periodontal-pathogenic microorganisms and their byproducts upon human cells in culture. Over 30 different microorganisms have been identified as putatively pathogenic thus, some researchers have tried to ascertain the effects of such microorganisms upon cultured cells derived from human oral tissues. One advantage of the in-vitro method is that individual microorganisms can be studied in isolation. For example, Treponema denticola was shown to attach to cultured epithelial cells, while Porphyromonas gingivalis had deleterious effects on the proliferation rate of human gingival fibroblasts. The byproducts of Porphyromonas gingivalis also altered fibroblast morphology.

Based on these findings, it follows that susceptibility of gingival connective tissue cells to the effects of oral microorganisms is a genetically influenced trait. To test this hypothesis, paired twins` gingival fibroblasts were exposed to bacterial extracts. Control cultures revealed cells with intact connective tissue fibers perfectly lined up and appearing to actively migrate within the culture dish. However, after exposure to bacterial extracts, the more diffuse or clumped the cells became. Extended exposure resulted in frank disruption of the cell membranes of cultured fibroblasts. The similarity between cells of identical twins was greater than that for cells of fraternal twins. This finding is consistent with a significant genetic influence on individual variation of response to bacterial challenge. With statistical analysis, identical twins showed significant similarity while cell cultures from fraternal twins exhibited no similarity.

It is now clear that the susceptibility to alveolar bone loss is not under simple Mendelian control. The mechanisms are multigenic and complex, with environmental factors (pathogenic microorganisms, smoking, stress etc.) playing a significant role in whether the trait "alveolar bone loss" is expressed or not. Genetic control of periodontal disease resistance or susceptibility could be exerted through many different biologic pathways.

Another genetic study of human twins revealed significant genetic control of salivary proteins (e.g., lactoferrin, lysozyme, peroxidases, and secretory IgA) that have important antimicrobial properties. These components of human saliva can significantly influence the colonization and growth of periodontal pathogenic microorganisms. Thus, a genetic defect resulting in subnormal salivary levels of such antimicrobial substances could render the host more susceptible to bacterial colonization and subsequent periodontal breakdown.

The twin model for studying periodontal disease susceptibility has been used very little thus far. It is a powerful technique - both in vivo and in vitro - for dissecting out hereditary factors in disease pathogenesis, and future research efforts should be targeted toward exploiting this well-established methodology.

Clinical predictive testing

Although large clinical studies of family groups and twins have provided valuable evidence of a strong hereditary component of periodontal disease susceptibility, such studies do not provide information about individual susceptibility. The inability of clinicians to determine the future course of a patient`s periodontal health leads to treatment decisions that are based more on intuition than on scientific fact. Inevitably, many patients are either undertreated based on the lack of objective findings at the time of clinical examination or they are overtreated in an attempt to make sure the best possible level of periodontal health is achieved.

Several "high tech" methods for periodontal diagnosis have appeared on the market over the past decade, such as tests for the presence of putative pathogenic microorganisms, tests for enzymes, host-derived tissue-breakdown products, and inflammatory mediators. Such tests are, indeed, applicable to individual patients. However, these tests are almost exclusively diagnostic, not predictive. That is to say, clinical and biological evaluations can tell the dentist and dental hygienist about the current status of the patient`s periodontium, but these signs, symptoms, and clinical judgments have very weak prognostic value.

For example, it is a relatively straightforward clinical process to diagnose moderate and advanced periodontitis. However, up until very recently, no mechanism existed for determining which patients with mild or no disease will respond negatively to bacterial plaque and then progress to a more severe periodontitis that demands more extensive clinical treatment. The lack of reliable markers for patient susceptibility to severe periodontitis has, until now, prevented early identification of those persons who are most at risk, and it has also prevented the delivery of therapy that would be appropriate in view of the individual risk.

To date, clinical treatment for periodontitis has been based upon the so-called "Plaque-Antiplaque Model," which is a simple, three-point hypothesis:

(1) Periodontitis treatment is antibacterial because bacteria cause the disease.

(2) Specific and nonspecific bacteria are identified as the antibacterial targets.

(3) Reduction, control, and elimination of sites conducive to bacterial colonization are effective treatments for most patients.

Over the years, this model was given considerable support from the scientific community, and it has been the driving force for many clinical treatment decisions. The major difficulty with the plaque-antiplaque model is its failure to take into account the fact that, while specific bacteria are necessary for disease development, bacteria alone are not sufficient to cause disease. In other words, the presence of bacteria does not automatically mean that the patient will have the disease.

This reminds us of the 1964 paradigm, established by Dr. Tokuhata, for smoking and lung cancer: Tobacco alone does not cause the disease rather, there is a synergistic interaction between tobacco and one or more familial-host susceptibility factors. The same paradigm can be applied to periodontal diseases. (See Figure 5.)

The bacterial etiology of periodontitis, while important, cannot explain all of the variability we see in practice. Some patients have abundant plaque and little or no disease other patients have only a small amount of plaque, but suffer severe disease. Many patients respond well to standard, conservative periodontal therapy, but some patients do not. Therefore, universal application of a standard-treatment method - antiplaque therapy - to every patient results in a mix of good and not-so-good clinical results.

A recent advance in periodontal research has provided oral health care practitioners with a new and powerful tool for early detection of disease susceptibility. By means of a simple blood test, it is now possible to ascertain early on whether a patient - who might present in the dental office today with healthy-appearing periodontal tissues - is genetically destined for periodontal destruction. The finger-stick test, and more recently, a saliva test, represent the most contemporary technology of research at the level of the gene, permitting genetic analysis of how an individual can be expected, in the future, to respond to challenges by known periodontal, pathogenic microorganisms and their byproducts. The test is called "PST," for Periodontitis Susceptibility Test, and is available from Interluken Genetics. The test does not diagnose currently active disease rather, it is an assessment of whether a patient is likely to develop severe periodontitis in the future.

The test actually analyzes specific genetic markers associated with increased Interleukin-1 (IL-1) production. This suggests a genetic mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immuno-inflammatory response that leads to more severe periodontitis. These "markers" for disease actually are functional. Monocytes from patients who are genotype-positive produce more IL-1 when stimulated by bacterial antigen. This is significant because the pathologic process resulting from increased IL-1 has been strongly associated with the pathology of periodontitis. Production of IL-1 is believed to lead to more generalized and severe disease.

Despite this genetic risk factor, smoking far outweighs the IL-1 genotype as a pathogenic consideration that is, smoking is a more significant risk factor than being IL-1 genotype-positive. For patients with greater than a 20 pack-year history of smoking, the impact of the smoking itself is such a dominant environmental factor that it eclipses much of the genetic influence in determining disease severity. It is likely that smoking, combined with other risk factors, can have some additive effects, but scientific evidence for this has not yet been published.

Additionally, most of the IL-1 genotype research to date has looked at people of Caucasian Northern-European heritage. Thus, the direct applicability of these data to other racial and ethnic groups is subject to question.

The list of acknowledged and proven periodontal risk factors is relatively short and well-understood: smoking, stress, compromised immune system, and poor oral hygiene.

Clinical and laboratory research over the past decade, including family-group studies, the human-twin paradigm, and in-vitro evaluation of human cellular responses to bacteria, have confirmed that there is a strong genetic component of susceptibility to periodontitis and periodontal destruction. This permits adding a fifth Orisk factorO to the list: genetic susceptibility due to the IL-1 genotype.

Three of these five major risk factors can be eliminated or modified:

x A patient can elect to stop smoking.

x A patient can improve oral hygiene.

x A patient can take measures to reduce the level of stress (or take stress-reducing medications).

The risk factor of a significantly compromised immune system is, fortunately, quite rare it seems to become manifest only in those few patients who suffer juvenile or early-onset forms of periodontitis.

The risk factor of genetic susceptibility due to IL-1 genotype is predictive for future severe disease, and it is estimated that 30% of the (Caucasian) population is positive for the IL-1 genotype. This leads to a new paradigm in periodontics, based on risk and susceptibility, rather than on plaque-antiplaque exclusively. This will elicit behavioral changes in both clinicians and the patients they treat.

Traditional concepts of treatment and prevention, which have relatively little prognostic or diagnostic value, will be replaced by more pro-active health and disease management, wherein risk and predisposition assessment will be used as first priority decision-making guides. Clinicians will be able to identify and monitor periodontal risk much earlier, and this will improve the opportunity for successful therapeutic outcomes. This also will maximize cost-to-benefit equations.

Periodontics today finds itself at the leading edge of biomedical science in terms of genetic-risk assessment. The dental and dental hygiene professions are poised to take advantage of new scientific evidence to improve the quality of life for their patients.

Thomas M. Hassell, DDS, Dr. med. dent., PhD, is affiliate professor of periodontics at the University of Washington, Seattle, Wash., and principal scientist of the Optiva Corporation, Snoqualmie, Wash. Trisha O?Hehir, RDH, BS, is a senior consulting editor for RDH magazine and the Editor of Perio Reports.

Environmental Carcinogens and Cancer Risk

Any substance that causes cancer is known as a carcinogen. But simply because a substance has been designated as a carcinogen does not mean that the substance will necessarily cause cancer. Many factors influence whether a person exposed to a carcinogen will develop cancer, including the amount and duration of the exposure and the individual’s genetic background. Cancers caused by involuntary exposures to environmental carcinogens are most likely to occur in subgroups of the population, such as workers in certain industries who may be exposed to carcinogens on the job.

How can exposures to carcinogens be limited?

In the United States, regulations have been put in place to reduce exposures to known carcinogens in the workplace. Outside of the workplace, people can also take steps to limit their exposure to known carcinogens, such as quitting smoking, limiting sun exposure, limiting alcohol drinking, or, for those of the appropriate age, having HPV and HBV vaccination. See Risk Factors for Cancer for more information about known and suspected carcinogens.

Who decides which environmental exposures cause cancer in humans?

Two organizations—the National Toxicology Program (NTP), an interagency program of the U.S. Department of Health and Human Services (HHS), and the International Agency for Research on Cancer (IARC), the cancer agency of the World Health Organization—have developed lists of substances that, based on the available scientific evidence, are known or are reasonably anticipated to be human carcinogens.

Specifically, the NTP publishes the Report on Carcinogens every few years. This congressionally mandated publication identifies agents, substances, mixtures, or exposures (collectively called “substances”) in the environment that may cause cancer in humans. The 2016 edition lists 62 known human carcinogens and includes descriptions of the process for preparing the science-based report and the criteria used to list a substance as a carcinogen.

IARC also produces science-based reports on substances that can increase the risk of cancer in humans. Since 1971, the agency has evaluated more than 1,000 agents, including chemicals, complex mixtures, occupational exposures, physical agents, biological agents, and lifestyle factors. Of these, more than 500 have been identified as carcinogenic, probably carcinogenic, or possibly carcinogenic to humans.

IARC convenes expert scientists to evaluate the evidence that an agent can increase the risk of cancer. The agency describes the principles, procedures, and scientific criteria that guide the evaluations. For instance, agents are selected for review based on two main criteria: (a) there is evidence of human exposure and (b) there is some evidence or suspicion of carcinogenicity.

How does the NTP decide whether to include a substance on its list of known human carcinogens?

As new potential carcinogens are identified, they are evaluated scientifically by the NTP’s Board of Scientific Counselors and the NTP Director. Next, a draft Report on Carcinogens monograph is prepared, which is reviewed by other scientific experts as needed, the public, and other federal agencies. The draft monograph is then revised as necessary and released for additional public comment and peer review by a dedicated panel of experts. Lastly, a finalized monograph and recommendation for listing is sent to the HHS Secretary for approval.

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