scholarly journals CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival

Cancers ◽  
2022 ◽  
Vol 14 (2) ◽  
pp. 353
Author(s):  
Jordi Minguillón ◽  
María José Ramírez ◽  
Llorenç Rovirosa ◽  
Pilar Bustamante-Madrid ◽  
Cristina Camps-Fajol ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Dna Damage ◽  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Increased Risk

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

scholarly journals Predictors of risk-reducing surgery intentions following genetic counseling for hereditary breast and ovarian cancer

2018 ◽  
Vol 10 (2) ◽  
pp. 337-346 ◽  
Author(s):  
Mary Kathleen Ladd ◽  
Beth N Peshkin ◽  
Leigha Senter ◽  
Shari Baldinger ◽  
Claudine Isaacs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Genetic Counseling ◽  
Cancer Risk ◽  
Prophylactic Surgery ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Affective Factors ◽  
Risk Reducing

Abstract Risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) are increasingly used to reduce breast and ovarian cancer risk following BRCA1/BRCA2 testing. However, little is known about how genetic counseling influences decisions about these surgeries. Although previous studies have examined intentions prior to counseling, few have examined RRM and RRSO intentions in the critical window between genetic counseling and test result disclosure. Previous research has indicated that intentions at this time point predict subsequent uptake of surgery, suggesting that much decision-making has taken place prior to result disclosure. This period may be a critical time to better understand the drivers of prophylactic surgery intentions. The aim of this study was to examine predictors of RRM and RRSO intentions. We hypothesized that variables from the Health Belief Model would predict intentions, and we also examined the role of affective factors. Participants were 187 women, age 21–75, who received genetic counseling for hereditary breast and ovarian cancer. We utilized multiple logistic regression to identify independent predictors of intentions. 49.2% and 61.3% of participants reported intentions for RRM and RRSO, respectively. Variables associated with RRM intentions include: newly diagnosed with breast cancer (OR = 3.63, 95% CI = 1.20–11.04), perceived breast cancer risk (OR = 1.46, 95% CI = 1.17–1.81), perceived pros (OR = 1.79, 95% CI = 1.38–2.32) and cons of RRM (OR = 0.81, 95% CI = 0.65–0.996), and decision conflict (OR = 0.80, 95% CI = 0.66–0.98). Variables associated with RRSO intentions include: proband status (OR = 0.28, 95% CI = 0.09–0.89), perceived pros (OR = 1.35, 95% CI = 1.11–1.63) and cons of RRSO (OR = 0.72, 95% CI = 0.59–0.89), and ambiguity aversion (OR = 0.79, 95% CI = 0.65–0.95). These data provide support for the role of genetic counseling in fostering informed decisions about risk management, and suggest that the role of uncertainty should be explored further.

scholarly journals Common Variants at the 19p13.1 and ZNF365 Loci Are Associated with ER Subtypes of Breast Cancer and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

2012 ◽  
Vol 21 (4) ◽  
pp. 645-657 ◽  
Author(s):  
Fergus J. Couch ◽  
Mia M. Gaudet ◽  
Antonis C. Antoniou ◽  
Susan J. Ramus ◽  
Karoline B. Kuchenbaecker ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Common Variants ◽  
Brca1 And Brca2 ◽  
Mutation Carriers

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

2012 ◽  
Vol 30 (12) ◽  
pp. 1321-1328 ◽  
Author(s):  
Brian S. Finkelman ◽  
Wendy S. Rubinstein ◽  
Sue Friedman ◽  
Tara M. Friebel ◽  
Shera Dubitsky ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Risk Reduction ◽  
Ovarian Cancer Risk ◽  
Jewish Women ◽  
Cancer Risks ◽  
Breast And Ovarian Cancer ◽  
Mutation Carriers ◽  
Significant Difference

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; odds ratio, 1.87; 95% CI, 1.44 to 2.42). 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 (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). 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.

Oral Contraceptives and Risk of Ovarian Cancer and Breast Cancer Among High-Risk Women: A Systematic Review and Meta-Analysis

2013 ◽  
Vol 31 (33) ◽  
pp. 4188-4198 ◽  
Author(s):  
Patricia G. Moorman ◽  
Laura J. Havrilesky ◽  
Jennifer M. Gierisch ◽  
Remy R. Coeytaux ◽  
William J. Lowery ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Meta Analysis ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Mutation Carriers ◽  
History Of ◽  
Meta Analyses

Purpose To estimate the risks of ovarian cancer and breast cancer associated with oral contraceptive (OC) use among women at elevated risk owing to mutations in BRCA1/2 or a strong family history. Methods We searched PubMed, Embase, the Cochrane Database of Systematic Reviews, and ClinicalTrials.gov for studies published 2000 to 2012 that evaluated associations between OC use and breast or ovarian cancer among women who are carriers of a BRCA1/2 mutation or have a family history of breast or ovarian cancer. Results From 6,476 unique citations, we identified six studies examining ovarian cancer risk in BRCA1/2 mutation carriers and eight studies examining breast cancer risk in BRCA1/2 mutation carriers. For BRCA1/2 mutation carriers combined, meta-analysis showed an inverse association between OC use and ovarian cancer (odds ratio [OR], 0.58; 95% CI, 0.46 to 0.73) and a nonstatistically significant association with breast cancer (OR, 1.21; 95% CI, 0.93 to 1.58). Findings were similar when examining BRCA1 and BRCA2 mutation carriers separately. Data were inadequate to perform meta-analyses examining duration or timing of use. For women with a family history of ovarian or breast cancer, we identified four studies examining risk for ovarian cancer and three for breast cancer, but differences between studies precluded combining the data for meta-analyses, and no overall pattern could be discerned. Conclusion Our analyses suggest that associations between ever use of OCs and ovarian and breast cancer among women who are BRCA1 or BRCA2 mutation carriers are similar to those reported for the general population.

Multi-center prospective analysis of risk-reducing salpingo-oophorectomy to prevent BRCA-associated breast and ovarian cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1003-1003 ◽  
Author(s):  
N. D. Kauff ◽  
S. M. Domchek ◽  
T. M. Friebel ◽  
J. B. Lee ◽  
R. Roth ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Genetic Test ◽  
Ovarian Cancer Risk ◽  
Test Results ◽  
Breast And Ovarian Cancer ◽  
Genetic Test Results ◽  
Risk Reducing

1003 Background: Our groups previously reported on the efficacy of risk-reducing salpingo-oophorectomy (RRSO) for the prevention of BRCA-associated breast and ovarian cancer. (Kauff ND, et al. NEJM 2002; Rebbeck TR, et al. NEJM 2002) Limitations of those reports included relatively short prospective follow-up and lack of power to analyze the protection of RRSO when participants were stratified by BRCA1 vs. BRCA2. To address these limitations, we have pooled our updated datasets to provide robust estimates of the efficacy of RRSO. Methods: 886 women ≥ 30 years of age, with a deleterious mutation in BRCA1 or BRCA2 and ovaries in-situ at time of genetic test results, were enrolled on prospective follow-up studies at one of eleven centers from 11/1/1994 - 12/1/2004. Women chose to participate in either ovarian surveillance or undergo RRSO. Follow-up information was collected by questionnaire and medical record review. Follow-up time was counted from time of RRSO or from time of genetic test results for women who did not undergo RRSO. After excluding cancers diagnosed within the first 6 months of follow-up, the effect of RRSO on time to diagnosis of breast or BRCA-associated gynecologic cancer was analyzed using a Cox proportional-hazards model. Results: 559 (63%) participants underwent RRSO a median of 5 months after genetic test results. 12 occult ovarian or fallopian tube cancers were diagnosed at time of RRSO. During a mean 40 months follow-up, RRSO was associated with a 52% reduction in breast cancer risk and a 91% reduction in ovarian cancer risk (see Table ). When the cohort was stratified by mutation status, RRSO was associated with a reduced risk of BRCA1-associated ovarian cancer and BRCA2-associated breast cancer. Conclusions: The results confirm that RRSO is highly protective against BRCA-associated breast and ovarian cancer. These results also generate the hypothesis that the protection conferred by RRSO against specific cancers may differ between carriers of BRCA1 and BRCA2 mutations. [Table: see text] No significant financial relationships to disclose.

Do breast cancer treatment and imaging providers follow hereditary breast and ovarian cancer risk screening guidelines?

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. e17626-e17626
Author(s):  
Christine B. Weldon ◽  
Julia Rachel Trosman ◽  
Melissa A Simon ◽  
Danielle Dupuy ◽  
Betty Roggenkamp ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Treatment ◽  
Breast Cancer Treatment ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Risk Screening ◽  
Screening Guidelines

scholarly journals DNA repair gene ERCC2 polymorphisms and associations with breast and ovarian cancer risk

2008 ◽  
Vol 7 (1) ◽  
pp. 36 ◽  
Author(s):  
Dominique Bernard-Gallon ◽  
Rémy Bosviel ◽  
Laetitia Delort ◽  
Luc Fontana ◽  
Alain Chamoux ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Cancer Risk ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Repair Gene ◽  
Dna Repair Gene

scholarly journals Association of the Variants CASP8 D302H and CASP10 V410I with Breast and Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

2010 ◽  
Vol 19 (11) ◽  
pp. 2859-2868 ◽  
Author(s):  
Christoph Engel ◽  
Beatrix Versmold ◽  
Barbara Wappenschmidt ◽  
Jacques Simard ◽  
Douglas F. Easton ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Brca2 Mutation ◽  
Ovarian Cancer Risk ◽  
Breast And Ovarian Cancer ◽  
Brca1 And Brca2 ◽  
Mutation Carriers

scholarly journals MNGI-12. PLEIOTROPIC MLLT10 VARIATION CONFERS RISK OF MENINGIOMA, BREAST, AND OVARIAN CANCERS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi142-vi142
Author(s):  
Kyle Walsh ◽  
Chenan Zhang ◽  
Lisa Calvocoressi ◽  
Helen Hansen ◽  
Andrew Berchuck ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cancer Risk ◽  
Risk Allele ◽  
Meta Analysis ◽  
Ovarian Cancer Risk ◽  
Genome Wide Association Studies ◽  
Ovarian Cancers ◽  
Genome Wide ◽  
Increased Risk

Abstract BACKGROUND Women ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome 10p12 near previous GWAS hits for breast and ovarian cancers. METHODS To elucidate the pleiotropic role of 10p12 variation in predisposition to diverse tumors - possibly via a common mediating factor - we performed imputation‐based fine‐mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28108 cases, 22209 controls), and ovarian cancer (25509 cases, 40941 controls). Analyses were stratified by sex (meningioma), estrogen receptor status (breast), and histotype (ovarian), then combined using ASSET meta-analysis. Lead variants were queried for association with >700 additional traits to identify potential effect-mediators. RESULTS Two-sided ASSET meta-analysis identified a lead variant near the MLLT10 promoter (P=1.4x10-13) associated with significantly increased risk of meningioma in women (OR=1.42, 95% CI: 1.20–1.69) and non-significantly increased risk in men (OR=1.19, 95% CI: 0.91–1.57). The meningioma risk allele was also associated with ovarian cancer risk (OR=1.09, 95% CI: 1.06–1.12) and ER+ breast cancer risk (OR=1.05, 95% CI: 1.02–1.08), but protected against ER- breast cancer (OR=0.91, 95% CI: 0.86–0.96). The risk allele was associated with higher body fat percentage, waist circumference and BMI at genome-wide levels (P< 5.0x10-8), but mediation analysis adjusting for BMI did not attenuate its association with meningioma risk. CONCLUSION We identify a MLLT10 eQTL that confers risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, but which protects against ER- breast cancer. Our results implicate a possible estrogenic mechanism underlying meningioma tumorigenesis.

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