DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1

DcR3 binds to ovarian cancer via heparan sulfateproteoglycans and modulates tumor cells response toplatinum with corresponding alteration in theexpression of BRCA1

Background
Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC). In our previous work Decoy Receptor 3 (DcR3) was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness.

Conclusions
Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy.The paradoxical responses seen were related to the expression pattern of HSPGs available on the cells surface to interact with. Although the mechanism behind this is not completely known alterations in DNA repair pathways including the expression of BRCA1 appear to be involved.

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.

Studying Therapy Response and Resistance in Mouse Models for BRCA1-Deficient Breast Cancer

health media: BRCA1 Breast Cancer Risk Linked To Other Genes

"...People who carry certain mutations of the BRCA1 gene are known to have a higher risk of developing breast cancer.

Couch told the media that their findings should be "useful in helping determine individual risk for breast cancer in BRCA1 carriers".

"It also provides insights into hormone-receptor-negative breast cancer in the general population," he added.

For the study, Couch and colleagues conducted four phases of genome-wide association studies (GWAS) that altogether involved 20 research centers in 10 North American and European countries and Israel.

For the first phase, to identify candidate gene variants, they scanned the genomes of 1,193 carriers of BRCA1 mutations who were under 40 and had invasive breast cancer and compared them to scans of about the same number of controls: BRCA1 carriers of similar age who did not have breast cancer.

In comparing the genomes from the two populations the researchers examined over half a million genetic alterations. They found 96 pieces of DNA called SNPs, or "snips", short for single nucleotide polymorphisms, that they thought would be likely candidates because they differed between the two populations...."cont'd

Objective To identify risk factors for the presence of a non-invasive lesion of the fallopian tube in women with a BRCA1 or BRCA2 mutation (abstract)

Objective

To identify risk factors for the presence of a non-invasive lesion of the fallopian tube in women with a BRCA1 or BRCA2 mutation.

Conclusion

The prevalence of tubal p53 signature and TIC (tubal intra-epithelial carcinoma)  increases with age at salpingectomy and with BMI. Oral contraceptive use is associated with a decrease in the prevalence of TICs.

Risk factors for carcinoma of the fallopian tube in women with and without a germline BRCA mutation

Reminder on stats: < 1.0 is decreased risk; > 1.0 is increased risk; OR=overall risk; edited some stats for ease of reading - see abstract/read more:

Conclusions

Parity and oral contraceptive use are associated with reduced risks of fallopian tube cancer. In contrast, hormone replacement therapy may be associated with an increase in the risk of fallopian tube cancer.

Oral contraceptive use and breast or ovarian cancer risk in BRCA1/2 carriers: A meta-analysis

CONCLUSIONS: OC users carrying an ascertained BRCA1/2 mutation have a reduced risk of ovarian cancer, proportional to the duration of use. There is no evidence that recent OC formulations increase breast cancer risk in carriers

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA 1 by Structural and Functional Assays

Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays.

Lee MS, Green R, Marsillac SM, Coquelle N, Williams RS, Yeung T, Foo D, Hau DD, Hui B, Monteiro AN, Glover JN.

Authors' Affiliations: Department of Biochemistry, School of Systems Molecular Medicine, University of Alberta, Edmonton, Alberta, Canada; National Institute of Environmental Health Sciences, Durham, North Carolina; Risk Assessment, Detection, and Intervention Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; and Molecular Biology Program, Institute of Biophysics Carlos Chagas Fo., Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
Abstract

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer....... Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk.

Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

BACKGROUND:
Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2.

CONCLUSIONS:
These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.

Teal Toes: Women’s Health Week, Ovarian Cancer media/video - link between breast/ovarian cancers

Note: no mention of other genetic risks aside from the BRCA's

Gene link to cancer risk in families - protein RAD51C (news item) breast and ovarian

Note: this report is worthwhile reading especially for those who test negative for BRCA 1/2

"No significant mutations were found in RAD51C in the 620 families with breast cancer only.  However, when they looked at the breast and ovarian cancer families, things got really interesting.  In all, they were able to identify a total of 6 mutations in the 480 families that had sufficient evidence to implicate them in the breast and ovarian cancer susceptibility.  Thus, in this German study of women with unexplained familial breast and ovarian cancer, the cancer susceptibility in 1.3% of the families could be explained by heterozygous mutations in the RAD51C gene."

Sleep disturbances in asymptomatic BRCA1/2 mutation carriers: women at high risk for breast-ovarian cancer

"Fatigue and carrier status were significant predictors of sleep quality, accounting for 15.7% of the variance.
In conclusion, asymptomatic BRCA1/2 carriers experience poor sleep quality compared to non-carriers and controls. Our study design is unique in that it offers insight regarding the nature of being an asymptomatic carrier, and affords the opportunity to examine factors that may contribute to the development of insomnia in women at risk for breast-ovarian cancer."

media article: The inherited malignancy of breast cancer (and ovarian cancer)

Note: good article, albeit complicated subject matter - excerpts of important information:

Genetic Alliance Weighs in On AMP's Desire to Outlaw Gene Patenting GenomeWeb

Molecular Cancer | Full text | Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas

full free access: Is no news good news? Inconclusive genetic test results in BRCA1 and BRCA2 from patients and professionals' perspectives

Small study but included view of patients and physician views.