Purpose Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination (HR) DNA repair genes is uncertain. Experimental Design Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the HR pathway. Results 31% of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous ovarian carcinomas had similar rates of HR mutations to serous carcinomas (28% vs. 31%, p=0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic HR mutations was highly predictive of primary platinum sensitivity (p=0.0002) and improved overall survival (p=0.0006), with median overall survival 66 months in germline HR mutation carriers, 59 months in cases with a somatic HR mutation, and 41 months for cases without an HR mutation. Conclusions Germline or somatic mutations in HR genes are present in almost one-third of ovarian carcinomas, including both serous and non-serous histologies. Somatic BRCA1/2 mutations and mutations in other HR genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of HR mutations in non-serous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Inherited loss-of-function mutations in BRCA1 and BRCA2 and other tumor suppressor genes predispose to ovarian carcinomas, but the overall burden of disease due to inherited mutations is not known. Using targeted capture and massively parallel genomic sequencing, we screened for germ-line mutations in 21 tumor suppressor genes in genomic DNA from women with primary ovarian, peritoneal, or fallopian tube carcinoma. Subjects were consecutively enrolled at diagnosis and not selected for age or family history. All classes of mutations, including point mutations and large genomic deletions and insertions, were detected. Of 360 subjects, 24% carried germ-line loss-of-function mutations: 18% in BRCA1 or BRCA2 and 6% in BARD1, BRIP1, CHEK2, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, or TP53. Six of these genes were not previously implicated in inherited ovarian carcinoma. Primary carcinomas were generally characterized by genomic loss of normal alleles of the mutant genes. Of women with inherited mutations, >30% had no family history of breast or ovarian carcinoma, and >35% were 60 y or older at diagnosis. More patients with ovarian carcinoma carry cancer-predisposing mutations and in more genes than previously appreciated. Comprehensive genetic testing for inherited carcinoma is warranted for all women with ovarian, peritoneal, or fallopian tube carcinoma, regardless of age or family history. Clinical genetic testing is currently done gene by gene, with each test costing thousands of dollars. In contrast, massively parallel sequencing allows such testing for many genes simultaneously at low cost. O varian carcinoma is the most deadly of gynecological malignancies; the majority of women are diagnosed with advanced stage disease when the chance of cure is small. Inherited mutations in BRCA1 and BRCA2 create a lifetime risk of ovarian carcinoma of between 20% (for BRCA2) and 50% or even higher (for BRCA1) (1). It has been previously estimated that 13-15% of patients with ovarian carcinoma in North America carry germ-line mutations in BRCA1 or BRCA2 (2, 3). Hereditary ovarian carcinoma also occurs in the context of Lynch syndrome [hereditary nonpolyposis colorectal cancer (HNPCC)], but the proportion of ovarian carcinoma explained by germ-line mutations in the mismatch repair genes has not been determined. Inherited mutations in RAD51C, RAD51D, and PALB2 have also been reported in patients with familial ovarian carcinoma (4-6). The overall proportion of ovarian carcinoma due to germ-line mutations in these genes and the roles of other tumor suppressor genes, particularly those implicated in inherited breast cancer, remain unknown.Women with early stage ovarian carcinoma have far better survival than women whose carcinomas are diagnosed at later stages, but current methods of early detection have not proven effective (7). In contrast, risk-reducing salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations dramatically reduces risk of ovarian carcinoma and significantly decreases overall mortality (8-10). It is critically i...

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Background Uterine serous carcinoma (USC) is not recognized as part of any defined hereditary cancer syndrome, and its association with hereditary breast and ovarian carcinoma and Lynch syndrome are uncertain. Methods Using targeted capture and massively parallel genomic sequencing, we assessed 151 subjects with USC for germline mutations in 30 tumor suppressor genes, including BRCA1, BRCA2, the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2), TP53, and ten other genes in the Fanconi anemia (FA)-BRCA pathway. Ten cases with <10% serous histology were also assessed. Results Seven subjects (4.6%) carried germline loss-of-function mutations: three (2.0%) in BRCA1, two (1.3%) in TP53, and two (1.3%) in CHEK2. One subject with <10% serous histology had an MSH6 mutation. Subjects with MSH6 and TP53 mutations had neither personal nor family histories suggestive of Lynch or Li-Fraumeni syndromes. Of the 22 women with USC and a personal history of breast carcinoma, the frequency of BRCA1 mutations was 9%, compared to 0.9% in 119 women with no such history. Conclusions Approximately 5% of women with USC have germline mutations in three different tumor suppressor genes: BRCA1, CHEK2, and TP53. Mutations in DNA mismatch repair genes that cause Lynch syndrome are rare in USC. The germline BRCA1 mutation rate in USC subjects of 2% is higher than expected in a non-founder population, suggesting that USC is associated with hereditary breast and ovarian carcinoma in a small proportion of cases. Women with USC and breast cancer should be offered genetic testing for BRCA1 and BRCA2 mutations.

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Objective:The presence of tumor infiltrating lymphocytes (TIL) and defects in homologous recombination (HR) are each important prognostic factors in ovarian carcinoma (OC). We characterized the association between HR deficiency (HRD) and the presence of TILs in a cohort of OC patients and the relative contribution to overall survival. Methods:Patients with carcinoma of the ovary, fallopian tube, or peritoneum were prospectively enrolled. Malignant neoplasm and serum samples were collected. Immunohistochemistry for CD3+ T cells and CD68+ tumor associated macrophages (TAMs) was performed on specimens collected at primary surgery. Damaging germline and somatic mutations in genes in the HRmediated repair (HRR) pathway were identified using BROCA sequencing. HRD was defined as a damaging mutation in one of 12 genes in the HRR pathway or promoter hypermethylation in BRCA1 or RAD51C.Results: Ninety-eight of 250 patients included in the analysis had HRD OC (39.2%). HRD OC were enriched for CD3+ TILs and CD68+ TAMs. High CD3+ TIL was present in 65.3% of HRD OC compared to 43.4% of non-HRD OC (p=0.001). High CD68+ TAM was present in 66.3% of HRD OC compared to 50.7% of non-HRD OC (p=0.015). Patients with HRD OC and high CD3+ TILs had the longest median overall survival compared to non-HRD OC with low CD3+ TILs (70.9 vs. 35.8 months, adjusted HR 0.38, 95% CI (0.25-0.59)).