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Getting some concept of cancer genetics

Getting some concept of cancer genetics


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I have two groups of patients :Responders to chemotherapyandnon-responders to chemotherapy. I treat this as a dichotomous outcome we can callresponse to chemotherapy.

For a fixed set ofcancer driver genes, I have calculatedcancer cell fraction (ccf)for each group.

Does anyone know of any interaction or relation ofresponse to chemotherapyandccf?


Assuming that my comment is trivial, I think that there is some literature on this question. I'm assuming that the ccf in question is for the relevant tissue type for the cancer.

You might also consider cross-posting to SE Medical Sciences, where people are more familiar with these subjects.

Of course, naively one would expect that a larger ccf would yield a larger possible population of cancer cells to provide "escape" mutations or resistance to chemo, so high ccf should then be negatively predictive. As an extreme example, a highly metastatic cancer will have a high ccf over the whole body, and will be more resistant to chemo just because that's a highly advanced disease.

However, as usual things are a little more complex. The ccf itself has subpopulations. The following I got by just googling around a little bit. For some of the fundamental thinking on this, see this old paper. In this paper, the author puts emphasis for example on the fraction of cancer cells in each stage of the cell cycle; this results in what the author calls "clonogenic" and "nonclonogenic" populations that respectively yield new clones of cancer cells or do not yield new clones. Probably that terminology is somewhat outdated, but it gives a sense of the problem; related are "tumor stem cells". For a more modern treatment, you can look at this.

For a med school lecture treatment, see here to learn a little bit more. For an example of a recent prediction study which uses omic data to predict chemo response, which might be helpful in reformulating your study, see here.

In other words, not all tumor cells are created equal, some are more likely to resist chemo than others. However, overall I would expect that there is probably some kind of relationship between ccf and response to chemo, because they are both related to the mediator variable "number of clonogenic cancer cells"; it's just a somewhat oversimplified model compared to the actual biology, so it looks like the publications in question don't tend to focus on it.


How genes can help in the diagnosis and treatment of cancer

We have already talked about ways genes, gene mutations, and gene variations can affect cancer risk and even lead to cancer. In this section, we are going to talk about how finding certain genes or gene mutations can be helpful in diagnosing cancer, monitoring the effects of treatment, learning about prognosis (outlook), and in treating cancer. In each case, only one or two examples are given. To learn about how genes are important to other kinds of cancer, see our document about that kind of cancer.


Challenging the standard model of cancer

Credit: CC0 Public Domain

In spite of decades of research, cancer remains an enigma. Conventional wisdom holds that cancer is driven by random mutations that create aberrant cells that run amok in the body.

In a new paper published this week in the journal BioEssays, Arizona and Australian researchers challenge this model by proposing that cancer is a type of genetic throwback, that progresses via a series of reversions to ancestral forms of life. In contrast with the conventional model, the distinctive capabilities of cancer cells are not primarily generated by mutations, the researchers claim, but are pre-existent and latent in normal cells.

Regents' Professor Paul Davies, director of Arizona State University's Beyond Center for Fundamental Concepts in Science and Kimberly Bussey, cancer geneticist and bioinformatician from the Precision Medicine Program at Midwestern University, Glendale, Ariz., teamed up with Charles Lineweaver and Anneke Blackburn at the Australian National University (ANU) in Canberra to refine what they call the Serial Atavism Model (SAM) of cancer. This model suggests that cancer occurs through multiple steps that resurrect ancient cellular functions.

Such functions are retained by evolution for specific purposes such as embryo development and wound healing, and are usually turned off in the adult form of complex organisms. But they can be turned back on if something compromises the organism's regulatory controls. It is the resulting resurrection steps, or atavistic reversions, that are mostly responsible for the ability of cancer cells to survive, proliferate, resist therapy and metastasize, the researchers said.

Davies and Bussey are also members of ASU's Arizona Cancer Evolution Center (ACE) which seeks to understand cancer, not just in humans, but across all complex species, in the light of evolutionary processes.

"Cancer research has been transformed in recent years by comparing genetic sequences across thousands of species to determine gene ages," Davies said. Just as geologists can date rock strata, so geneticists can date genes, a technique known as phylostratigraphy.

"The atavistic model predicts that the genes needed for cancer's abilities are mostly ancient—in some cases little changed over billions of years," Davies added.

Lineweaver explained, "In biology, nothing makes sense except in the light of evolution, and in the case of cancer nothing makes sense except in the light of the deep evolutionary changes that occurred as we became multicellular organisms."

"The atavistic model of cancer has gained increasing traction around the world," added Bussey. "In part, this is because it makes many predictions that can be tested by phylostratigraphy, unlike the conventional somatic mutation theory."

Blackburn, a cancer biologist in ANU's John Curtin School of Medical Research, agreed.

"Appreciation of the importance of gene ages is growing among oncologists and cancer biologists," she said. "Now we need to use this insight to develop novel therapeutic strategies. A better understanding of cancer can lead to better therapeutic outcomes."


Getting some concept of cancer genetics - Biology

Another perspective on cancer: Evolution within
October 2007

Where's the evolution?
Iconic examples of evolution (birds evolving from dinosaurs, hominids evolving an upright posture, or a lineage of lobe-finned fish evolving four legs and moving onto land) might seem unrelated to the growth of a cancerous tumor, but the process underlying them both — natural selection — is identical. We typically think of natural selection acting among individuals, favoring those carrying advantageous traits and making those traits more common in the next generation. However, the key elements of this process — variation, inheritance, and selective advantage — characterize not just populations of organisms in a particular environment, but also populations of cells within our own bodies. The cells lining your intestines, for example, are not genetically uniform there is variation among them. Some of those cells have incurred chance mutations as they have divided. If one of those mutations (or a series of mutations) allows its bearer to evade cell death and reproduce more prolifically than others, it will pass that mutation on to its daughter cells, and cells bearing that mutation will increase in frequency over time. Like organisms in an ecosystem, cell lineages within one's own body compete for resources. A cell lineage that gains an advantage in that competition, accumulating mutations that allow it to grab extra resources and escape the body's control mechanisms, will proliferate and may evolve into a cancerous tumor.


Though the evolution of a population in an ecosystem and cell lineages in a body rely on the same basic process, there are a few key differences between selection at these different levels. First, whole organisms reproduce much more slowly than individual cells do. This means that while the evolution of a new species or a major transition (such as the evolution of birds from dinosaurs) may take millions of years, the evolution of a cell lineage into a cancerous form can take place on the scale of months or years. Second, natural selection generally increases the evolutionary fitness of individuals, favoring those whose traits allow them to survive and produce more healthy offspring however, selection at lower levels may increase the fitness of cellular lineages at the cost of the individual. In the case of cancer, this is especially obvious: cancerous cells have an advantage in comparison to other cells in the body, but are disadvantageous to the organism. Selection at the cellular level may wind up hampering the organism's survival and reproduction, acting in exact opposition to selection at the individual level.

Why has counteracting these negative effects at the level of the individual (i.e., finding a cure) been so difficult? An evolutionary perspective reveals the answer: cancer — even within one person — isn't a single entity. It's a diverse and evolving population of cell lineages. A single tumor, for example, is made up of a variety of cell types, produced as the cells proliferated and incurred different mutations. All of this diversity means that the population of cells could easily include a mutant variety that happens to be resistant to any individual chemotherapy drug we might administer. To make matters even more difficult, treating the patient with that drug creates an environment in which the few resistant cancer cells have a strong selective advantage in comparison to other cells. Over time, those resistant cells will increase in frequency and continue to evolve. It's not surprising then that a simple cure for cancer has yet to be developed: treating even a single type of cancer is a bit like trying to take aim at a whole set of moving targets all at once.

    Emphasize early detection. The less time that a cancerous cell lineage has to evolve, the less diverse that population of cells will become and, consequently, the easier it will be to target the rogue cells as a group.

Treating cancer means controlling a diverse population of rapidly evolving cell lineages. This challenge helps explain why research has not yet provided us with a cure, but also points the way toward new solutions that take that evolution into account. Research into developing and optimizing these treatments continues, aided by funds generated through events such as National Breast Cancer Awareness Month. Pink sneaker sales and fundraising walks may seem unrelated to evolution, but the cause that they represent is an inherently evolutionary problem.

  • Merlo, L. M. F., Pepper, J. W., Reid, B. J., and Maley, C. C. (2006). Cancer as an evolutionary and ecological process. Nature Reviews Cancer 6:924-935.

    from Howard Hughes Medical Institute

Understanding Evolution resources:

Discussion and extension questions

    Describe the basic characteristics necessary for evolution via natural selection to occur.

. The article above describes how natural selection acts on two levels of this hierarchy: populations of organisms and cell lineages. Describe a third level of the hierarchy at which natural selection can act. Explain how that situation meets the criteria necessary for natural selection to occur.

Related lessons and teaching resources

    : In this classroom activity for grades 9-12, students learn why evolution is at the heart of a world health threat by investigating the increasing problem of antibiotic resistance in such menacing diseases as tuberculosis.

: This article for grades 9-12 examines how scientist Andy Ellington has co-opted the power of artificial selection to construct new, useful molecules in his lab. The results of his work could help protect us from terrorist attacks and fight HIV and cancer.

    Greaves, M. (2000). Cancer: The evolutionary legacy. Oxford: Oxford University Press.


Causes

A genetic predisposition refers to a genetic variation which increases the likelihood of disease. These are passed on from parents to children, but not all children will necessarily receive the gene types which predispose to disease.

Many people are familiar with single gene mutations (such as those in the BRCA gene), but a combination of changes on several genes may also confer a genetic predisposition. Genome wide association studies that are now being done that look for single changes in DNA (single gene polymorphisms) that are relatively common in the population. With diseases such as cancer, it may be combination of variations in several genes that confers risk, rather than single gene mutations. The science is young with cancer, but it shedding light in many conditions. For example, age-related macular degeneration was once thought to be primarily environmental, but gene wide association studies have found that variations in three genes may account for as many as 75% of cases.

We are now learning that polymorphisms that influence the function of miRNA may help predict the risk of female cancers.  

Examples of Specific Genes and Hereditary Cancer Syndromes

A few examples of gene mutations that predispose to cancer and hereditary cancer syndromes include:

  • BRCA mutations that raise breast and ovarian cancer risk (as well as others)
  • RB1: Roughly 40% of children who develop retinoblastoma have an abnormal RB1 gene
  • Familial adenomatous polyposis (FAP) (hereditary non-polyposis colorectal cancer)

In addition to these and several others, it's likely that more genetic predisposition genes will be found in the future.

Genetic Testing

Genetic testing is now available for several cancers, including:

  • Breast cancer
  • Ovarian cancer
  • Colon cancer
  • Thyroid cancer
  • Prostate cancer
  • Pancreatic cancer
  • Melanoma
  • Sarcoma
  • Kidney cancer
  • Stomach cancer

Caution Regarding Home Genetic Testing

A strong word of caution is in order for people who are considering home genetic testing for cancer. If these tests are positive, you may have a predisposition, but a negative home test could be very misleading. For example, the 23andme test detects only three of over one thousand BRCA mutations.

Importance of Genetic Counseling

Genetic counseling is important for people who may have a genetic predisposition to cancer for a few reasons. One is to understand accurately the limitations of testing and to be prepared

A very important reason to pursue genetic counseling is that the genetic tests we have available at the current time are incomplete. You may have genetic testing which is negative but still be at risk for hereditary cancer. A good genetic counselor may be able to determine if you are at risk by looking closely at your family history.

The Silver Lining of Having a Genetic Predisposition

Having a genetic predisposition to a disease such as cancer can be frightening, but it may be helpful to think of this in another way if you are anxious. If you have an increased likelihood of developing a condition you may be on alert for symptoms, and your doctor may check you more carefully than someone without that predisposition. What this could mean is that if you do develop the disease, it may be caught earlier than if you were not watching for the disease and in this sense, you may actually have a greater chance of surviving a condition than if you were not on the lookout.

An example of this could be someone with a genetic predisposition to breast cancer. Based on a possible increased risk you might be more likely to do breast exams, see your doctor more frequently, perhaps begin having mammograms earlier or even yearly breast MRIs. If you did develop breast cancer it may be detected at an earlier—and more survivable stage—than it would be in someone who is not alerted to the possibility. Those who are at a very high risk may consider preventive tamoxifen or a preventive mastectomy.


Liang Cao, Ph.D.

Dr. Cao’s current research is on the investigations of tumor biomarkers and their roles in cancer drug development. He did some early work on homologous recombination and tumor suppressor gene functions, both at Harvard and Harvard Medical School. He was an Associate Professor at the Medical School of University of Hong Kong with a research interest on viral oncogenesis. He also led research and development programs in biotech and biopharmaceutical companies, and is an inventor of more than 30 US patents on therapeutics, diagnostics, and bio-assay technologies. At NCI, he was initially involved in using the NGS technology to investigate the pathogenic mechanism of a fusion oncoprotein of in a childhood sarcoma. More recently, his group is focused on biomarkers for early stage drug development, on novel protein assays for treatment assessment, and on circulating tumor DNA analysis for patient selection and monitoring.

1. Biomarkers studies in early drug development

2. Development of novel tumor antigen tests and protein biomarker analysis in clinical trials

3. Circulating tumor DNA analytical technologies in clinical trials

Contact Info

1) Biomarkers studies in early drug development to cover areas including pharmacokinetics, pharmacodynamics, mechanism of action, dose-response relationship, and proof of therapeutic concept on novel cancer therapeutic agents. We have successful experiences with PK/PD analyses of various targeted and immunotherapy agents, including a first-in-class and first-in-human immune checkpoint inhibitor developed by EMD, Serono, and Merck group.

2) Development of novel tumor antigen tests, including assay development, analytical and clinical validation, as well as generation of clinical data for intended clinical uses during drug development. We recently developed a new assay for the treatment assessment and progression evaluation of mesothelioma. We are engaged in multiple NCI intramural and NCI-sponsored extramural studies to evaluate the effectiveness of the assay for anti-mesothelin immunotherapies.

3) Circulating tumor DNA analytic technologies in clinical trials, including digital PCR and digital NGS for exploratory research and for translation of circulating tumor DNA biomarkers into diagnostics. Our recent work has been examining cell-free DNA (cfDNA) in patients with HPV-associated cancer. Our work demonstrated the potential of cfDNA analysis in disease monitoring, and in providing the proof-of-concept data on a novel immunotherapy. Our results suggest the feasibility of cfDNA based patient genotyping for a T cell immunotherapy and the assay is being evaluated as a potential companion diagnostic.


Apoptosis

Apoptosis is also referred to as programmed cell death. It is an essential process for removing cells that are stressed, damaged, or worn out. It is estimated that over 50 billions cells undergo apoptosis each day in adults. Apoptosis is also carefully regulated through complex mechanisms. Mutations that affect these regulatory pathways have the potential to contribute to carcinogenesis by failing to eliminate abnormal neoplastic cells or by failing to eliminate cells with other mutations that are premalignant. Defects in apoptosis can also confer resistance to chemotherapy, radiation, and immune-mediated cell destruction.

Proto-oncogenes, anti-oncogenes (tumor suppressor genes), and apoptosis, play a central role in understanding the pathogenesis of cancer. In short, mutations and inherited abnormalities can cause these regulatory control mechanisms to become dysfunctional. As you will see, mutations in any of these mechanisms can cause a cell to divide or survive longer than normal, and if multiple mutations affecting these regulatory mechanisms accumulate in a single cell, the cell will have lost all control with respect to cell division. This single cell, dividing repeatedly and without regulation will create an ever expanding clone of cells which will also undergo unregulated cell division. This is the essence of cancer.


Abstract

The co-occurrence of diseases can inform the underlying network biology of shared and multifunctional genes and pathways. In addition, comorbidities help to elucidate the effects of external exposures, such as diet, lifestyle and patient care. With worldwide health transaction data now often being collected electronically, disease co-occurrences are starting to be quantitatively characterized. Linking network dynamics to the real-life, non-ideal patient in whom diseases co-occur and interact provides a valuable basis for generating hypotheses on molecular disease mechanisms, and provides knowledge that can facilitate drug repurposing and the development of targeted therapeutic strategies.


Concept 4 Biology - Mutations & Pedigrees

Autosomal dominant disorders
Caused by the presence of at least 1 dominant allele on autosomes
Dominant genetic disorders are less common than recessive disorders
At least one parent must have the disease in order to pass it on .
It is still possible to have unaffected children if one parent is hetero and the other is homo recessive.
Examples
Achondroplasia (Dwarfism)
Huntington's disease: damages the nervous system and usually appears during adulthood.

Sex linked Disorders
Caused by the presence of an allele on the X sex chromosome
Examples:
Colorblindness: found in 1 in 10 males and 1 in 100 females
Hemophilia: does not allow normal blood clotting to occur
Muscular dystrophy: results in the progressive weakening and loss of skeletal muscle

Autosomal chromosome disorders
Often caused by nondisjunction of autosomes = the failure to separate homologous chromosomes during meiosis.
Causes an abnormal number of chromosomes due to a mistake in meiosis
Example:
Down syndrome: most common form of trisomy involving three copies of chromosomes 21.


Genetic inheritance

Inheritance is the backbone of genetics and is an important topic to cover in an introduction to genetics. Long before DNA had been discovered and the word ‘genetics’ had been invented, people were studying the inheritance of traits from one generation to the next.

Genetic inheritance occurs both in sexual reproduction and asexual reproduction. In sexual reproduction, two organisms contribute DNA to produce a new organism. In asexual reproduction, one organism provides all the DNA and produces a clone of themselves. In either, genetic material is passed from one generation to the next.

Experiments performed by a monk named Gregor Mendel provided the foundations of our current understanding of how genetic material is passed from parents to their offspring.

Last edited: 31 August 2020

Want to learn more?

This is world’s #1 textbook for beginning biologists and has been hugely valuable to me over the years. This is the resource that I recommend above anything else for aspiring biologists.



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