abstract: [Clinical aspects of familial ovarian cancer - current status and issues in Japan] (focus on brca)

Blogger's Note: the [ ] indicates translated version


[Clinical aspects of familial ovarian cancer - current status and issues in Japan]

Abstract
Familial ovarian cancer occurs as part of two genetically distinct syndromes: hereditary breast and ovarian cancer(HBOC) and hereditary nonpolyposis colorectal cancer(HNPCC) (Lynch Syndrome) .

HBOC caused by inherited mutations of BRCA1/2 and HNPCC caused by mismatch-repair genes are considered responsible for about 65 to 75% and 10 to 15% of familial ovarian cancers, respectively. Germline mutations of BRCA1 are considered responsible for about 50% of ovarian cancer families and 80% of breast-ovarian cancer families. BRCA2 mutations are less common than BRCA1 mutations in ovarian cancer families. A high proportion of serous adenocarcinomas at an advanced stage has been reported with BRCA-related ovarian cancers in several studies. It is controversial whether BRCA-related ovarian cancer patients carry a better prognosis despite the aggressive tumor-pathological characteristics of their disease, compared to sporadic cases. However, a good therapeutic response may be attributable to platinum-based chemotherapy. Recently in Japan, gene testing of BRCA1/2 has been available as a routine clinical test for diagnosing ovarian cancer families. Because the mutation spectrum of BRCA1/2 in Japanese was different from that of non-Ashkenazi individuals, the clinical application of BRCA1/2 gene testing for Japanese has been advocated. Approximately 1-5% of ovarian cancer pa-tients in Japan are thought to have a family history of breast and/or ovarian cancer. The prevalence of deleterious mutations of BRCA1/2 in Japanese was reportedly significantly higher than that of non-Ashkenazi individuals despite the low frequency of familial cases in Japan. Although the age at diagnosis of ovarian cancers with BRCA1/2 mutation in the United States was earlier than those of the sporadic cases, there were no differences among Japanese. These results suggest that clinical and genetic aspects of BRCA-related ovarian cancer of the Japanese are different from those of Caucasians.

A serious issue in this field is how the results will lead to a basis for the clinical application of a cancer prevention strategy targeting BRCA mutation carriers in Japanese.

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.......

bloggers: Gregory D. Pawelski on Genomics And Targets For The Treatment Of Cancer: Is Our New World Turning Into "Pharmageddon" Or Are We On The Threshold Of Great Discoveries?

Gregory D. Pawelski on Genomics And Targets For The Treatment Of Cancer: Is Our New World Turning Into "Pharmageddon" Or Are We On The Threshold Of Great Discoveries?

"I was telling your old colleague, Dr. Herman Kattlove, who posted about this on his blog, I thought his "genetic heterogeneity" terminology was more befitting than what was used in the title of the British study (Intratumor Heterogeneity). "Taking one biopsy sample of a tumor may not be enough to reveal its full genetic identity," was described by Medical News Today's Catharine Paddock, PhD. The study is significant because it suggests relying on one sample could overlook (other) important biomarkers that help make tailored treatments effective, explaining perhaps why personalized cancer therapy has been less successful than expected. Dr. Robert Nagourney, Medical and Laboratory Director at Rational Therapeutics, Inc., Long Beach, California, pointed out the disturbing news regarding the predictive validity and clinical applicability of human tumor genomic analysis for the selection of (targeted) chemotherapeutic agents. He also pointed out the accompanying editorial by Dr. Dan Longo, which made several points worth noting. First, he states that "DNA is not the whole story." This should be familiar to those who follow cell function analysis. Dr. Longo references Albert Einstein, who said, "Things should be made as simple as possible, but not simpler." Dr. Nagourney appreciates and applauds Dr. Long's comments for they echo his sentiments completely. The article of the study is only the most recent example of a growing litany of observations that call into question molecular biologist's preternatural fixation on genomic analyses. Human biology is not simple and malignantly transformed cells more are more complex still. Investigators who insist upon using genomic platforms to force disorderly cells into artificially ordered sub-categories, have once again been forced to admit that these oversimplifications fail to provide the needed insights for the advancement of cancer therapeutics. Those laboratories and corporations that offer "high price" genomic analyses for the selection of "high price" chemotherapy drugs take notice of this and related articles carefully as these reports portend a troubling future for their current business model ("personalized" cancer treatment)."

OMICS Publishing Group | Full-text | Peutz-Jegher Syndrome in Gynecologic Pathology (PJS and ovarian cancer)

OMICS Publishing Group | Full-text | Peutz-Jegher Syndrome in Gynecologic Pathology

Tutorials (2): Genetic Testing Registry (GTR) - YouTube

Tutorials: Genetic Testing Registry (GTR) - YouTube

Genetic Information Non-Discrimination Act Charges

Genetic Information Non-Discrimination Act Charges:

The following chart represents the total number of charge receipts filed and resolved under Genetic Information Non-Discrimination. The data are compiled by the Office of Research, Information and Planning from data compiled from EEOC's Integrated Mission System.

abstract: Genetic profiles distinguish different types of hereditary ovarian cancer

"The results indicate that HBOC and HNPCC (Lynch Syndrome) associated ovarian cancer develop along distinct genetic pathways and genetic profiles can thus be applied to distinguish between different types of hereditary ovarian cancer."

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.

full free access: Colorectal cancer molecular biology moves into clinical practice - Gut (extensive review including Lynch Syndrome genetics, colorectal cancer biomarkers, treatment options...)

Gut 2011;60:116-129 doi:10.1136/gut.2009.206250

Cancers | Free Full-Text | Familial Pancreatic Cancer (extensive lain english review)

Note: see table 1 for spectrum of genes eg; MSH 1/2/6, FAMM, BRCA2....

abstract: Familial non-polyposis colorectal carcinoma (Lynch syndrome) in Germany

abstract: (Lynch Syndrome) Analysis of EPCAM Protein Expression in Diagnostics of Lynch Syndrome ( -/+ MSH2)

abstract + Free Full-Text (2010) Familial Pancreatic Cancer (includes discussion regarding BRCA/Lynch Syndrome/FAMMM and others)

Abstract: Pancreatic cancer’s high mortality rate equates closely with its incidence, thereby showing the need for development of biomarkers of its increased risk and a better understanding of its genetics, so that high-risk patients can be better targeted for screening and early potential lifesaving diagnosis. Its phenotypic and genotypic heterogeneity is extensive and requires careful scrutiny of its pattern of cancer associations, such as malignant melanoma associated with pancreatic cancer, in the familial atypical multiple mole melanoma syndrome, due to the CDKN2A germline mutation. This review is designed to depict several of the hereditary pancreatic cancer syndromes with particular attention given to the clinical application of this knowledge into improved control of pancreatic cancer.
Keywords: phenotypic and genotypic heterogeneity; high mortality; genetic counseling; biomarker paucity; FAMMM syndrome; Li-Fraumeni syndrome; Lynch syndrome; pancreatic cancer

abstract: A 67-Year-Old Woman with BRCA 1 Mutation Associated with Pancreatic Adenocarcinoma case report/discussion

Abstract

INTRODUCTION: There are approximately 40,000 new cases of pancreatic adenocarcinoma diagnosed in the USA each year. It is estimated that 5-10% of all patients with pancreatic cancer have a first-degree relative with the disease, while up to 20% of cases have a hereditary component. Individuals who carry a germline mutation in the BRCA 1 or 2 genes have an increased lifetime risk of developing pancreatic adenocarcinoma when compared with the general population.

CASE REPORT: Here, we present a case of metastatic pancreatic adenocarcinoma arising in a 67-year-old carrier of a BRCA 1 germline mutation.

DISCUSSION: In patients with known BRCA 1 or 2 mutation-associated pancreatic adenocarcinoma, the addition of a DNA cross-linking agent such as cisplatin, oxaliplatin, or mitomycin to a standard gemcitabine chemotherapy backbone should be considered. Poly ADP-ribose inhibitors are a novel class of drug, which have demonstrated promising efficacy in trials of BRCA 1 and 2 mutant breast and ovarian cancer, and are currently undergoing prospective evaluation in advanced pancreatic cancer.

Expert Opinion on Medical Diagnostics - KRAS mutations - Summary

What the reader will gain: KRAS mutations in mCRC and NSCLC primary tumors predict resistance to EGFR-targeted therapy. In pancreatic cancer, KRAS may prove useful as a diagnostic biomarker to screen for early neoplasia. Furthermore, quantitative KRAS mutation analysis could have the potential to distinguish pancreatic cancer from other conditions such as chronic pancreatitis.

With respect to ovarian and endometrial cancer, further studies should focus on determining reliable biomarkers for predicting response to EGFR-targeted therapy. Besides EGFR inhibition, KRAS may also serve as a diagnostic and predictive biomarker for evolving therapies directed against mutant RAS proteins.

Take home message: KRAS has been recognized as an outstanding predictive biomarker to select mCRC and NSCLC patients for EGFR-targeted therapies; however, multi-determinant approaches including other molecular markers should facilitate the identification of patients likely to respond to such therapies.

See also blog post:

Wednesday, July 21, 2010

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)

Assessing Women at High Risk of Breast Cancer: A Review of Risk Assessment Models: Abstract and Introduction

".......In addition to increasing the risks of breast and ovarian cancers, germline mutations in BRCA1 and BRCA2 are associated with an increased risk of prostate cancer and BRCA2 mutations are associated with increased risks of pancreatic and gastric cancers and melanoma.^[12] BRCA mutations tend to cluster within certain ethnic groups, such as Ashkenazi Jews,^[13–15] and in some populations, such as those in the Netherlands,^[16] Iceland,^[17,18] and Sweden.^[19] Germline mutations that are associated with familial breast cancer have been identified in other genes, including TP53, PTEN, ATM, CHEK2, NBS1, RAD50, BRIP, and PALB2, and others are suspected.^[20,21]"


Women who are at high risk of breast cancer can be offered more intensive surveillance or prophylactic measures, such as surgery or chemoprevention. Central to decisions regarding the level of prevention is accurate and individualized risk assessment. This review aims to distill the diverse literature and provide practicing clinicians with an overview of the available risk assessment methods. Risk assessments fall into two groups: the risk of carrying a mutation in a high-risk gene such as BRCA1 or BRCA2 and the risk of developing breast cancer with or without such a mutation. Knowledge of breast cancer risks, taken together with the risks and benefits of the intervention, is needed to choose an appropriate disease management strategy. A number of models have been developed for assessing these risks, but independent validation of such models has produced variable results. Some models are able to predict both mutation carriage risks and breast cancer risk; however, to date, all are limited by only moderate discriminatory accuracy. Further improvements in the knowledge of how to best integrate both new risk factors and newly discovered genetic variants into these models will allow clinicians to more accurately determine which women are most likely to develop breast cancer. These steady and incremental improvements in models will need to undergo revalidation....cont'd

Genetic Risk Score Associated With Breast Cancer Risk; Predictive of Type of Disease

>“In this large study including 10,306 women with breast cancer and 10,393 without the disease, we confirm that some of the more important common genetic variants for breast cancer have different effects on different tumor types.”

PLoS ONE: Functional Exploration of the Adult Ovarian Granulosa Cell Tumor-Associated Somatic FOXL2 Mutation p.Cys134Trp (c.402C>G)

Conclusions/Significance

Here, we confirm the specificity of the FOXL2 c.402C>G mutation in adult OGCTs and begin the exploration of its molecular significance. This is the first study demonstrating that the p.Cys134Trp mutant does not have a strong impact on FOXL2 localization, solubility, and transactivation abilities on a panel of proven target promoters, behaving neither as a dominant-negative nor as a loss-of-function mutation. Further studies are required to understand the specific molecular effects of this outstanding FOXL2 mutation.

Gene-Testing Companies May Need U.S. Regulators Review, FDA Letters Say - Bloomberg

A KRAS-Variant in Ovarian Cancer Acts as a Genetic Marker of Cancer Risk (full access)