open access: A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome - study of 19 BRCA carriers

A Pilot study of the Sharing Risk Information Tool (ShaRIT) for Families with Hereditary Breast and Ovarian Cancer Syndrome 

 ".....ShaRIT strives to ease the “burden of the messenger” and decrease the possibility of mis-communicating and misinterpreting
important medical information to their relatives."

BRCA 1/2 Decision Tool - Stanford Medicine Cancer Institute

 Blogger's Note: variables can be changed eg. age/prophylactic surgery/s (type), easy to use, tip: hold your cursor over the chart to show %'s (outcomes)

BRCA Decision Tool

abstract: Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival.

Clinical characteristics and outcomes of BRCA-associated ovarian cancer: genotype and survival

Cancer Genet. 2012 Jan;205(1-2):34-41


Abstract
Previous studies have suggested that BRCA-related epithelial ovarian cancer (EOC) conveys improved survival compared with that of sporadic EOC, but few studies have evaluated differences between BRCA genotypes.

We compared characteristics and outcome by genotype in BRCA-associated EOC. Patients with BRCA-associated EOC who were diagnosed between January 30,1981, and December 30, 2008, were retrospectively identified through institutional review board-approved registry studies. We examined clinical characteristics, including event-free survival (EFS) and overall survival (OS), for BRCA1 versus BRCA2 patients. We identified 197 cases (148 BRCA1 cases; 49 BRCA2 cases); the median follow-up period was 63 months. BRCA2 patients were older (55.4 vs. 51.1 y) and had fewer poorly differentiated tumors (67% vs. 82%). No difference in EFS was observed. OS at 5 years was 75% in BRCA2 patients versus 61% in BRCA1 patients; this was not statistically significant. A non-significant trend toward improved OS was observed in BRCA2 patients with advanced-stage disease (hazard ratio = 0.59; 95% confidence interval 0.32-1.08).

Age and grade differed significantly between BRCA1 and BRCA2 carriers in our study population. Whereas no overall differences in EFS or OS were observed, there was a trend toward improved OS in BRCA2 carriers with advanced-stage disease.

This may reflect important differences between BRCA genotypes and should be validated in larger studies.

abstract: DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome (eg. BRCA2, MSH3 (polymorphisms)...)

DNA repair gene polymorphisms and risk of early onset colorectal cancer in Lynch syndrome:

Source:Cancer Epidemiology, Volume 36, Issue 2


DNA repair plays a pivotal role in maintaining genomic integrity with over 130 genes involved in various repair pathways that include base excision repair, nucleotide excision repair, double strand break repair and DNA mismatch repair. Polymorphisms within genes that are involved in these processes have been widely reported to be associated with cancer susceptibility in an extensive range of malignancies that include colorectal cancer (CRC).

Lynch syndrome is caused by inherited germline mutations in DNA mismatch repair genes, predominantly in MLH1 and MSH2, that predispose to a variety of epithelial malignancies, most notably CRC. Despite being a relatively well understood hereditary cancer syndrome there remain several questions in relation to genetic influences on disease expression. Since Lynch syndrome is associated with a breakdown in DNA mismatch repair variation in other DNA repair genes may influence disease expression.

In this report we have genotyped 424 Australian and Polish Lynch syndrome participants for eight common DNA repair gene polymorphisms to assess any association with the age of CRC onset.

 The DNA repair gene SNPs included in the study were: BRCA2 (rs11571653), MSH3 (rs26279), Lig4 (rs1805386), OGG1 (rs1052133), XRCC1 (rs25487), XRCC2 (rs3218536 and rs1799793) and XRCC3 (rs861539). Cox multi-variant regression modelling failed to provide any convincing evidence of an effect in any of the polymorphisms analysed. The data suggest that polymorphisms in DNA repair genes do not contribute to cancer risk in a population of CRC patients who are at increased risk of disease as a result in a deficiency of DNA mismatch repair.

(click on pdf for full paper) Gynecologic Oncology Case Reports: A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

Gynecologic Oncology Case Reports | Articles in Press | ScienceDirect.com

A Case of Endometrial Cancer in the Context of a BRCA2 Mutation and Double Heterozygosity for Lynch Syndrome

In Press, Accepted Manuscript, Available online 15 March 2012
Ping Gong, Sarah Charles, Norman Rosenblum, Zoe Wang, Agnieszka K. Witkiewicz

 Show preview  |   PDF (458 K)   |   Related articles  |  Related reference work articles    

Highlights

► Endometrial cancer with BRCA2 mutation and double heterozygosity for Lynch syndrome 

► Loss of MLH1 and PMS2 by immunohistochemical stain 

► MSH1 and MSH6 gene mutations by genomic sequencing

abstract: Evaluation of Iniparib as a PARP Inhibitor (BRCA2....)

Evaluation of Iniparib as a PARP Inhibitor:

Purpose:

Poly(ADP-ribose) polymerase (PARP) inhibitors are undergoing extensive clinical testing for their single-agent activity in homologous recombination (HR)-deficient tumors and ability to enhance the action of certain DNA-damaging agents. Compared with other PARP inhibitors in development, iniparib (4-iodo-3-nitrobenzamide) is notable for its simple structure and the reported ability of its intracellular metabolite 4-iodo-3-nitrosobenzamide to covalently inhibit PARP1 under cell-free conditions. The present preclinical studies were conducted to compare the actions iniparib with the more extensively characterized PARP inhibitors olaparib and veliparib.

Results:

Consistent with earlier reports, olaparib and veliparib selectively induced apoptosis and inhibited colony formation in cells lacking BRCA2 or ATM. Moreover, like earlier generation PARP inhibitors, olaparib and veliparib sensitized cells to the topoisomerase I poisons camptothecin and topotecan. Finally, olaparib and veliparib inhibited formation of pADPr in intact cells. In contrast, iniparib exhibited little or no ability to selectively kill HR-deficient cells, sensitize cells to topoisomerase I poisons, or inhibit pADPr formation in situ. In further experiments, iniparib also failed to sensitize cells to cisplatin, gemcitabine, or paclitaxel.


Conclusions:

While iniparib kills normal and neoplastic cells at high (>40 μmol/L) concentrations, its effects are unlikely to reflect PARP inhibition and should not be used to guide decisions about other PARP inhibitors.  

Clin Cancer Res; 18(6); 1655–62. ©2012 AACR.

abstract: 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance

"...Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy."

Preventive Surgeries Linked To Lower Risk Of Breast And Ovarian Cancer - BRCA mutations/international study

news article:



free full text/paper:
http://jama.ama-assn.org/cgi/content/full/304/9/967

"Women who have in herited mutations inthe BRCA1 or BRCA2(BRCA1/2) genes have substantially elevated risks of breast cancer and ovarian cancer, with a lifetime risk of breast cancer of 56% to 84%.^1-3 The estimated ovarian cancer risks range from 36% to 63% for BRCA1 mutation carriers and 10% to 27% for BRCA2 mutation carriers.^3-6 Women who are mutation carriers have cancer risk–management options that include risk-reducing salpingo-oophorectomy, risk-reducing mastectomy, annual cancer screening, and chemoprevention. Due to the lack of effective screening for ovarian cancer, salpingo-oophorectomy is strongly recommended once childbearing is complete."

Protein made by breast cancer gene purified - BRCA 2/RAD51

Identification of a Danish breast/ovarian cancer family double heterozygote for BRCA1 and BRCA2 mutations

Abstract
Mutations in the two breast cancer susceptibility genes BRCA1 and BRCA2 are associated with increased risk of breast and ovarian cancer. Patients with mutations in both genes are rarely reported and often involve Ashkenazi founder mutations. ......Since the BRCA1 Arg1699Gln mutation is also suggested to be disease-causing, we consider this family double heterozygote for BRCA1 and BRCA2 mutations.

clinical trial: Attitudes About Childbearing And Fertility With Inherited Breast And Ovarian Cancer Syndromes (HBOC) - Full Text View - ClinicalTrials.gov

Purpose

Objectives:

- To evaluate the attitudes and opinions of women undergoing genetic counseling for hereditary breast and ovarian cancer syndrome, both before and after testing, in regards to pregnancy and fertility

International distribution and age estimation of the Portuguese BRCA2 c.156_157insAlu founder mutation

"We recommend that all suspected HBOC families from Portugal or with Portuguese ancestry are specifically tested for this rearrangement (BRCA2 c.156_157insAlu)."

Cancer drug olaparib (PARP inhibitor) shows early promise | Philadelphia Inquirer (BRCA 1/2)

Somatic Mutations in BRCA1 and BRCA2 Could Expand the Number of Patients That Benefit From Poly (ADP Ribose) Polymerase Inhibitors in Ovarian Cancer

ABSTRACT

Purpose
The prevalence of BRCA1/2 mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA1/2 changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.

Conclusion
BRCA1/2 somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.

Testing for CHEK2 in the cancer genetics clinic: ready for prime time?

Abstract

Narod SA.
Testing for CHEK2 in the cancer genetics clinic: ready for prime time?

The 1100delC mutation of the CHEK2 gene was found to be a cause of breast cancer in 2002. The lifetime risk of breast cancer among women with a mutation and with a family history of breast cancer is approximately 25%. These women are good candidates for screening with MRI and for chemoprevention with tamoxifen. It is reasonable to test for this single mutation when women undergo testing for BRCA1 and BRCA2.

abstract and free full text: How old is this mutation? - a study of three Ashkenazi Jewish founder mutations

The three mutations analyzed were MSH2*1906 G->C, APC*I1307K, and BRCA2*6174delT.

"Mutation age estimates (averages):
16.8 generations for MSH2
106 generations for I1037K
90 generations for 6174delT

Cancer prevalence in 129 breast-ovarian cancer families tested for BRCA1 and BRCA2 mutations (South Africa)

Note: small study (Caucasian); stomach cancer link/BRCA2 (?)

"Stomach cancer prevalence was significantly elevated in the BRCA2-positive families compared with the general population."

Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2 JCO

"The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation."

Candidate gene association studies: successes and failures

Abstract

"Epidemiologic studies of twins indicate that 20-40% of common tumors such as breast, colorectal, and prostate cancers are inherited. However, the effect of high penetrance tumor susceptibility genes such as APC, BRCA1, BRAC2, MSH1, MLH2 and MSH6 only accounts for a small fraction of these cancers. Low to moderate penetrance tumor susceptibility genes likely account for the large remaining proportion of familial cancer risk...."

abstract: Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2

Results: Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance.

Conclusion: The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.