paywalled: Dosage Effect of BRCA1 and BRCA 2 Mutated Allelic Transcript (French Canadian)

Dosage Effect of BRCA1/2-Mutated Allelic Transcript:

We hypothesized that the transcriptome of primary cultures of morphologically normal ovarian surface epithelial cells could be altered by the presence of a heterozygous BRCA1 or BRCA2 mutation.

We aimed to discover early events associated with ovarian carcinogenesis, which could represent putative targets for preventive strategies of this silent killer tumor. We identified the first molecular signature associated with French Canadian BRCA1 or BRCA2 founder mutations in morphologically normal ovarian epithelial cells. We discovered that wild-type and mutated BRCA2 allelic transcripts were expressed not only in morphologically normal but also in tumor cells from BRCA2-8765delAG carriers. Further analysis of morphologically normal ovarian and tumor cells from BRCA1-4446C>T carriers lead to the same observation.

Our data support the idea that one single hit in BRCA1 or BRCA2 is sufficient to alter the transcriptome of phenotypically normal ovarian epithelial cells. The highest level of BRCA2-mutated allele transcript expression was measured in cells originating from the most aggressive ovarian tumor. The penetrance of the mutation and the aggressiveness of the related tumor could depend on a dosage effect of the mutated allele transcript.

JCO abstract: Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers (185delAG, 5382insC, 6174delT)

Breast and Ovarian Cancer Risk and Risk Reduction in Jewish BRCA1/2 Mutation Carriers

Purpose 

Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. 

Methods 

Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. 

Results 

Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers. No significant difference was seen in cancer risk reduction after RRSO among subgroups. 

Conclusion 

Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases. (300T>G mutation)

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.:
Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases.
Fam Cancer. 2012 Mar 1;


Abstract
It is estimated that about 5-10% of ovarian and 2-5% of all breast cancer patients are carriers of a germline BRCA1 or BRCA2 gene mutation. Most families with detected BRCA1 or BRCA2 gene mutation are qualified for molecular testing on the basis of family history of breast or ovarian cancers. The purpose of our study was to establish the frequency of positive family history of cancer in a series of Polish consecutive breast and ovarian cancer patients in two groups, with and without the BRCA1 gene mutations. We analysed the prevalence of four of the most common BRCA1 mutations: 5382insC (c.5266dupC), 300T>G (p.181T>G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5). The patient group consisted of 1,845 consecutive female breast and 363 ovarian cancer cases. 19 out of 37 (51%) of BRCA1-positive ovarian cancer patients and 21 out of 55 (39%) BRCA1-positive breast cancer had negative family history of breast and/or ovarian cancer among first- and second-degree relatives.

In ovarian cancer patients, negative family history was more frequent in those with 300T>G BRCA1 gene mutation than in 5382insC carriers. This finding indicates the necessity of searching for 300T>G mutation in families with a single diagnosis of ovarian cancer in family. The high frequency of mutations detected in breast cancer patients lacking obvious family history shows that breast cancer patients should be qualified for genetic testing on the basis of wide clinical and pathological criteria.

Why Some People Live to 110 - Drugs.com MedNews

"......In what they describe as a first-of-a-kind study, the researchers analyzed the whole genome sequences of a man and a woman who lived past the age of 114 and found that they had as many disease-associated genes as other people.
For example, the man had 37 genetic mutations associated with increased risk for colon cancer....."