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. 2016 Apr;2(4):482-90.
doi: 10.1001/jamaoncol.2015.5495.

Inherited Mutations in Women With Ovarian Carcinoma

Barbara M Norquist  1 , Maria I Harrell  1 , Mark F Brady  2 , Tom Walsh  3 , Ming K Lee  3 , Suleyman Gulsuner  3 , Sarah S Bernards  1 , Silvia Casadei  3 , Qian Yi  4 , Robert A Burger  5 , John K Chan  6 , Susan A Davidson  7 , Robert S Mannel  8 , Paul A DiSilvestro  9 , Heather A Lankes  2 , Nilsa C Ramirez  10 , Mary Claire King  3 , Elizabeth M Swisher  11 , Michael J Birrer  12
Affiliations

Inherited Mutations in Women With Ovarian Carcinoma

Barbara M Norquist et al. JAMA Oncol. 2016 Apr.

Abstract

Importance: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized.

Objective: To determine the frequency and importance of germline mutations in cancer-associated genes in OC.

Design, setting, and participants: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay.

Main outcomes and measures: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status.

Results: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations.

Conclusions and relevance: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr. Mannel reports participation in advisory boards for Endocyte, Astra Zeneca, MedImmune, Oxigene, Advaxis, and Amgen; and his institution was reimbursed for his time. Dr. Burger reports that he previously participated as a consultant to Genentech/Roche during advisory board meetings. No other disclosures are reported.

Figures

Figure 1
Figure 1
Mutation status by clinical characteristics in OC patients. “Other” indicates the genes BRIP1, PALB2, RAD51C, RAD51D, and BARD1, and “MMR” indicates mismatch repair genes, PMS2, MSH6, and MLH1. 61 had unknown or other race/ethnicity and are not shown. Three GOG patients had no listed stage. In the histology section 16 mucinous (all no mutation) are not shown.
Figure 2
Figure 2
Survival by mutation category in GOG 218 and GOG 262. A. PFS by mutation category in GOG 218 and GOG 262. B. OS by mutation category in GOG 218 and GOG 262.
See this image and copyright information in PMC

Comment in

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