Epigenetic modification and cancer: mark or stamp? (BRCA/fallopian tube....)

Epigenetic modification and cancer: mark or stamp?

Abstract

Hypotheses are built upon data, but data require hypotheses before they can be understood. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop. In this commentary on ‘Promoter hypermethylation patterns in Fallopian tube epithelium of BRCA1 and BRCA2 germline mutation carriers’ by Bijron et al. published in the February 2012 issue of Endocrine-Related Cancer, the need for new grammar and some new hypotheses in epigenetics is discussed. Meanwhile, data suggesting an important role of epigenetic modification in the cause, progression and treatment of cancer continues to accumulate............

Introduction

In hereditary tumours, the first hit occurs in the germ line, whereas in non-hereditary tumours, the first hit occurs in the cell from which the tumour arises. The second hits are always somatic, and can inactivate the second allele in various different ways. The development of the ‘two-hit’ hypothesis of carcinogenesis was a key event in cancer genetics because it provided a testable model of how tumours develop (Knudson 1971, 1978). Although there have been extensions and revisions to the basic model (Tomlinson et al. 2001), the essential elements of the basic hypothesis remain intact, 40 years on. In the original ‘test case’ of RB-1 mutations in retinoblastoma, these events were physical alterations in the structure of the chromosome or gene (Cavenee et al. 1983), and the perception was such that physical changes put a ‘stamp’ on the tumour that could be detected by examination of genomic DNA.............

continue to read full paper

Epigenetics does not mean that thinking makes it so : Respectful Insolence

Epigenetics does not mean that thinking makes it so : Respectful Insolence

".....The not-so-subtle implication is that the reason one gets sick is because of one's habits. Of course, there are a lot of lifestyle diseases, but the implications goes beyond the sensible, science-based observation that obesity and lack of exercise increase the risk of certain diseases, into the realm of stating that if you just eat the right foods and do the right exercises you'll never get sick.

Utter nonsense, of course.

There's also a dark side to this sort of thinking, and that's the flip side of the argument. If you can nearly completely control the state of your health by what you eat and do, the not-so-subtle implication is that if you get sick it must be your fault. After all, if we have complete control over our health through our lifestyle, then it follows that if you're sick, you must be doing something wrong....."

"The latest way that quacks are trying to push the idea that you have near total control over your health is by abusing new findings in epigenetics. Epigenetics is the study of heritable changes in gene expression or phenotype that are not caused by changes in the underlying gene sequence........ It's a fascinating area of research, because it suggests that gene expression can be altered longer than transiently by environmental influences. Of course, given that organisms and biology are affected by environmental influences, this is almost a trivial observation; the power of epigenetics is that it can explain how such changes in gene expression can come about.....

Cancer's epicentre - The Economist

Cancer's epicentre - The Economist:

The Economist

Cancer's epicentre The Economist THE biggest conceptual breakthrough in the war on cancer was the realisation by the 1980s that it is always a genetic disease. Sometimes the genetic flaw is inherited. Sometimes it is the result of exposure to an outside agent such as tobacco smoke or radioactivity. Sometimes it is plain bad luck; a miscopying of a piece of DNA during the normal process of cell division. Turning that breakthrough into medicine, though, is hard. No one has worked out how to repair DNA directly. It is, rather, a question of discovering the biochemical consequences of the genetic damage and trying to deal with those instead. But recently, another pattern has emerged. It is too early to call it a breakthrough as significant as the cancer-is-caused-by-broken-genes finding, but it might be.......

Bioinformatics and epigenetics - computer-aided cancer diagnosis - medical press

The relatively young research field of epigenetics is the talk of the town. Many scientists expect the research on biochemical modifications beyond the actual DNA strand to lead to huge progress in the understanding of the regulation of gene activity in the years to come. Just how promising the results of epigenetic research are in terms of concrete medical applications is demonstrated by the work of Thomas Lengauer and Christoph Bock from the Max Planck Institute for Informatics in Saarbrücken. With the help of computers, they trawl through the genomes of cancer patients in search for suspect structures, and develop fast and simple new tools for improving cancer diagnosis in hospitals.


"Although Thomas Lengauer regards epigenome analysis as playing a crucial role in the attainment of rapid progress in cancer diagnosis in the near future, he plays down expectations with regard to the development of new drugs. “Many scientists point to the potential of future drugs that can repair defects in the epigenome of diseased cells. I tend to be more cautious in this regard. Such targeted interventions involve significant risks, not least because little or nothing is currently known about the highly-complex gene regulation mechanisms being manipulated here.”"

Genome Research publishes special issue: Cancer Genomics

Genome Research (www.genome.org) publishes online and in print today a special issue entitled, "Cancer Genomics," highlighting insights gained form cutting-edge genomic and epigenomic analyses of cancer.

Included in this special issue are novel biological insights gained from genomic analyses of pancreatic cancer, ovarian cancer, and melanoma, including, functional genomic analyses of breast cancer genes, large scale colorectal and breast cancer epigenomics, advances in methodology identifying driver genes and networks in cancer, in genome-wide cancer association analyses, and using next-generation sequencing technology to detect driver mutations.

Additionally, the issue includes unique perspectives from leaders in the field on the translation of cancer genomics to improved outcomes in medicine. The following sections highlight several of the papers published in the issue:

1. Whole-genome and whole-exome sequencing: Searching for the drivers of cancer
2. Circulating free DNA holds clues to cancer diagnosis and risk of relapse
3. Epigenomic analyses shed new light on breast, colon, and prostate cancers
4. Cutting-edge methods to detect the genes and networks that drive cancer
    

Cancer Epigenetics - 2010 - CA (includes discussions Lynch Syndrome etc...)

"The term “epigenetics” refers to variability in gene expression, heritable through mitosis and potentially meiosis, without any underlying modification in the actual genetic sequence."

No Gene-Environment Interactions Found in Million Women Study of Breast Cancer 2010 - CA: A Cancer Journal for Clinicians - Wiley Online Library

".....Regarding the question of gene-environment interactions, lead author Ruth Travis, MD, PhD, adds that “Results from this study suggest that common genetic and environmental factors (reproductive and lifestyle factors) act independently on breast cancer risk, so regardless of common inherited genetic variation, a woman can still reduce her risk by modifying her lifestyle, for example by maintaining a healthy body weight and limiting alcohol intake.”

The absence of interactions means that priorities for risk-reducing strategies are similar for most women (for example, being based on known risks associated with lifestyle and reproductive factors) regardless of the common genetic risk factors for the disease, she says. Dr. Travis is an epidemiologist, research fellow, and senior scientist in the cancer epidemiology unit at Oxford University....."

full free text: Targeted Epigenetic Therapies: The Next Frontier? — J. Natl. Cancer Inst. (includes discussion regarding clear cell/ARIDIa mutation

Targeted Epigenetic Therapies: The Next Frontier?

1. Rabiya S. Tuma

When researchers look for mutations associated with cancer, they often expect to come up with alterations in signaling molecules or transcription factors. But an increasing number of the mutations found are in genes that regulate the epigenome—a system that alters DNA structure and regulates gene activity without changing the nucleotide sequence itself.

On Sept. 8, investigators published two independent reports online—one in Science and one in the New England Journal of Medicine—showing that mutations in an epigenetic regulatory gene, ARID1a, were associated with approximately half of the ovarian clear-cell cancers tested.

Methylation profiles of hereditary and sporadic ovarian cancer - Histopathology - abstract

Conclusions: 

 CDH13, GSTP1 and RASSF1 are frequently methylated in both sporadic and BRCA1-associated ovarian cancers. Interestingly, methylation of BRCA1, while frequent in sporadic ovarian cancer, never occurred in the hereditary group. BRCA1-associated ovarian cancers mimic their sporadic counterparts in extent and pattern of promoter methylation of several common tumour suppressor genes. This finding could have implications for future chemotherapy regimens based on epigenetic changes

full free access: Preparing for a Consumer-Driven Genomic Age Health Policy and Reform

"Advances in genomic technologies permit the simultaneous analysis of millions of variants across the genome and may soon allow for meaningful estimation of one’s risks of developing cancer, diabetes, and other common diseases. These advances are converging with the movement toward consumer-driven health care and patient empowerment. Whereas in the past, medical testing was firmly under the control of medical practitioners, genomic information is now increasingly available outside traditional medical settings. Patients are no longer subordinate, passive recipients of physician-initiated genetic testing; rather, patients can instigate their own testing and often know more than their clinicians about particular genetic topics. Indeed, health care providers are increasingly bypassed altogether, as patients embrace direct-to-consumer (DTC) genetic tests and turn to social networks for help in interpreting their results. In the future, a primary role of health care professionals may be to interpret patients’ DTC genetic test results and advise them about appropriate follow-up. How can we maximize the benefits of these new developments and minimize the harms? How can we encourage patients’ involvement and autonomy yet establish appropriate safeguards while avoiding inappropriate paternalism? How do we promote the understanding that interpretations of genomic information may evolve as research unravels the meaning of gene–gene and gene–environment interactions and the roles of noncoding DNA sequences, copy-number variants, epigenetic mechanisms, and behavioral factors in health and disease?..."cont'd

IU-OSU center gets $9 million more for cancer epigenetics: IU News Room: Indiana University (includes ovarian cancer)

"Over the next five years, Nephew said the OSU/IU-led team will study epigenetic changes in prostate, breast, and ovarian cancer cells that cause resistance to hormonal therapy or traditional chemotherapy. Nephew said a major objective is to identify a panel of epigenetic biomarkers for predicting responsiveness to anti-hormone treatments and chemotherapies in cancer patients."

Epigenetics of ovarian cancer: From the lab to the clinic.

 Epigenetics: Study of how proteins and other molecules that bind to DNA and chromosomes can change gene expression without changing the DNA sequence

CONCLUSIONS: Although the epigenetics of ovarian cancer is still in its beginnings, it holds promising potential in early stage ovarian cancer detection, evaluation of prognosis/drug resistance and targeted cancer treatment.

Epigenetic therapies for chemoresensitization of epithelial ovarian cancer

AACR upcoming conference: Cancer Epigenetics

"The study of epigenetic mechanisms in cancer, such as DNA methylation, histone modifications, nucleosome positioning and non-coding RNA expression, has revealed a plethora of events that contribute to the neoplastic phenotype through stable changes in the expression of genes critical to transformation pathways...Therefore, improved understanding of normal epigenetic programs is necessary to better understand malignancy-specific epigenetic alterations.....numerous other clinical applications of the field being explored in areas such as cancer screening and early detection, prevention, classification for epidemiology and prognostic purposes, and predicting outcomes after standard therapy."