scholarly journals The genetic analysis of a founder Northern American population of European descent identifies FANCI as a candidate familial ovarian cancer risk gene

2020 ◽  
Author(s):  
Caitlin T Fierheller ◽  
Laure Guitton-Sert ◽  
Wejdan M Alenezi ◽  
Timothée Revil ◽  
Kathleen K Oros ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Family History ◽  
Serous Carcinoma ◽  
Ovarian Cancer Risk ◽  
Repair Pathway ◽  
Degree Relative ◽  
Pathogenic Variants ◽  
Familial Ovarian Cancer ◽  
History Of

AbstractSome familial ovarian cancer (OC) could be due to rare risk alleles in genes that each account for a relatively small proportion of cases not due to BRCA1 and BRCA2, major risk genes in the homologous recombination (HR) DNA repair pathway. We report a new candidate OC risk allele, FANCI c.1813C>T in a Fanconi anemia (FA) gene that plays a role upstream of the HR DNA repair pathway. This variant was identified by whole exome sequencing of a BRCA1 and BRCA2 mutation-negative French Canadian (FC) OC family from a population exhibiting founder effects. In FCs, the c.1813C>T allele was detected in 7% (3/43) of familial and 1.6% (7/439) of sporadic OC cases; and in 3.7% (3/82) of familial breast cancer (BC) cases with a family history of OC and in 1.9% (3/158) of BC only families. This allele was significantly associated with FC BRCA1 and BRCA2 mutation-negative OC families (OR=5.6; 95%CI=1.6-19; p=0.006). Although FANCI c.1813C>T was detected in 2.5% (74/2950) of cancer-free FC females, carriers had a personal history of known OC risk reducing factors, and female/male carriers were more likely to have reported a first-degree relative with OC (ρ=0.037; p=0.011). Eight rare potentially pathogenic FANCI variants were identified in 3.3% (17/516) of Australian OC cases, including 10 carriers of FANCI c.1813C>T. Potentially pathogenic FANCI variants were significantly more common in AUS OC cases with a family history of OC than in isolated OC cases (p=0.027). The odds ratios (OR) were >3 for carriers of any of the seven rarest FANCI alleles, and 1.5 for c.1813C>T. Data from the OC Association Consortium revealed that the ORs for the c.1813C>T allele were highest for the most common OC subtypes. Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the FA pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level; unstable by formaldehyde or mitomycin C treatment; and exhibited sensitivity to cisplatin but not to olaparib (a poly [ADP-ribose] polymerase inhibitor). By tissue microarray analyses, FANCI protein was robustly expressed in fallopian tube epithelial cells but expressed at low-to-moderate levels in 88% (83/94) of high-grade serous carcinoma OC samples. This is the first study to describe potentially pathogenic variants in OC in a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that potentially pathogenic FANCI variants may modify OC risk in cancer families.

Association of Parity and Ovarian Cancer Risk by Family History of Breast or Ovarian Cancer in a Population-Based Study of Postmenopausal Women

Epidemiology ◽  
2002 ◽  
Vol 13 (1) ◽  
pp. 66-71 ◽  
Author(s):  
Celine M. Vachon ◽  
Pamela J. Mink ◽  
Carol A. Janney ◽  
Thomas A. Sellers ◽  
James R. Cerhan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Family History ◽  
Cancer Risk ◽  
Postmenopausal Women ◽  
Population Based ◽  
Ovarian Cancer Risk ◽  
Population Based Study ◽  
History Of

Pathogenic Variants in BRIP1, RAD51C, and RAD51D Identified with Multi-Gene Panel Testing for Hereditary Cancers

2020 ◽  
Author(s):  
Shelly Cummings ◽  
Susana San Roman ◽  
Jennifer Saam ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Diagnosis ◽  
Fold Increase ◽  
Ovarian Cancer Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of

Abstract Background: Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013-May 2019 were included (N=631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results: PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years in BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D.Conclusions: These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45-50 in RAD51D PV carriers and possibly, until age 50-55 in BRIP and RAD51C PV carriers.

scholarly journals Serous Tubal Intraepithelial Carcinoma: An Incidental Finding at the Time of Prophylactic Bilateral Salpingo-Oophorectomy

2015 ◽  
Vol 2015 ◽  
pp. 1-4 ◽  
Author(s):  
Monique Hiersoux Vaughan ◽  
Susan C. Modesitt ◽  
Yunchuan Mo ◽  
Elisa R. Trowbridge
Keyword(s):  
Ovarian Cancer ◽  
Pelvic Organ Prolapse ◽  
Family History ◽  
Pelvic Organ ◽  
Serous Carcinoma ◽  
Ca 125 ◽  
Management Options ◽  
Serous Tubal Intraepithelial Carcinoma ◽  
History Of ◽  
Intraepithelial Carcinoma

Background.Serous tubal intraepithelial carcinoma (STIC) is a precursor lesion for high-grade pelvic serous carcinoma. The incidence of STIC is estimated to occur in 0.6% to 6% of women who are BRCA positive or have a strong family history of breast or ovarian cancer.Case.A 56-year-old woman underwent robotic-assisted sacrocolpopexy, rectocele repair, and concurrent bilateral salpingo-oophorectomy for recurrent stage 3 pelvic organ prolapse and reported family history of ovarian cancer. Histopathologic examination of her left fallopian tube revealed STIC.Conclusion.We report this rare occurrence of STIC in a patient undergoing surgery primarily for pelvic organ prolapse and having a family history of ovarian cancer. Possible management options include observation with annual physical exam and CA-125, surgical staging, or empiric chemotherapy. However, due to the lack of consensus regarding management options, referral to a gynecologic oncologist is recommended.

scholarly journals A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Caitlin T. Fierheller ◽  
Laure Guitton-Sert ◽  
Wejdan M. Alenezi ◽  
Timothée Revil ◽  
Kathleen K. Oros ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Cell Lines ◽  
Carrier Frequency ◽  
Pathogenic Variant ◽  
Fanconi Anaemia ◽  
Repair Pathway ◽  
French Canadian ◽  
Pathogenic Variants ◽  
Gene And Protein Expression

Abstract Background Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. Methods Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. Results In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7–19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. Conclusions This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families.

Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk.

1998 ◽  
Vol 16 (7) ◽  
pp. 2417-2425 ◽  
Author(s):  
T S Frank ◽  
S A Manley ◽  
O I Olopade ◽  
S Cummings ◽  
J E Garber ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Family History ◽  
Sequence Analysis ◽  
Detection Methods ◽  
Ovarian Cancer Risk ◽  
Brca1 And Brca2 ◽  
Degree Relative ◽  
Increased Risk ◽  
Cancer Mutations

PURPOSE Previous studies of mutations in BRCA1 or BRCA2 have used detection methods that may underestimate the actual frequency of mutations and have analyzed women using heterogeneous criteria for risk of hereditary cancer. PATIENTS AND METHODS A total of 238 women with breast cancer before age 50 or ovarian cancer at any age and at least one first- or second-degree relative with either diagnosis underwent sequence analysis of BRCA1 followed by analysis of BRCA2 (except for 27 women who declined analysis of BRCA2 after a deleterious mutation was discovered in BRCA1). Results were correlated with personal and family history of malignancy. RESULTS Deleterious mutations were identified in 94 (39%) women, including 59 of 117 (50%) from families with ovarian cancer and 35 of 121 (29%) from families without ovarian cancer. Mutations were identified in 14 of 70 (20%) women with just one other relative who developed breast cancer before age 50. In women with breast cancer, mutations in BRCA1 and BRCA2 were associated with a 10-fold increased risk of subsequent ovarian carcinoma (P = .005). CONCLUSION Because mutations in BRCA1 and BRCA2 in women with breast cancer are associated with an increased risk of ovarian cancer, analysis of these genes should be considered for women diagnosed with breast cancer who have a high probability of carrying a mutation according to the statistical model developed with these data.

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.

scholarly journals Age of ovarian cancer diagnosis among BRIP1, RAD51C, and RAD51D mutation carriers identified through multi-gene panel testing

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Shelly Cummings ◽  
Susana San Roman ◽  
Jennifer Saam ◽  
Ryan Bernhisel ◽  
Krystal Brown ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Risk ◽  
Cancer Diagnosis ◽  
Fold Increase ◽  
Ovarian Cancer Risk ◽  
Risk Genes ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Gene Panel Testing ◽  
History Of

Abstract Background Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013–May 2019 were included (N = 631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~ 3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~ 2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years for BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D. Conclusions These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45–50 in RAD51D PV carriers and possibly until age 50–55 in BRIP and RAD51C PV carriers.

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