Nearly one in five women with ovarian carcinoma carried germline mutations associated with risk for the malignancy, according to results of a multi-institutional study.
Barbara M. Norquist, MD, assistant professor of gynecologic oncology at University of Washington School of Medicine, and colleagues used next-generation gene sequencing of DNA samples from either University of Washington’s tissue bank or Gynecologic Oncology Group phase 3 clinical trials to determine the frequency and importance of germline mutations in cancer-associated genes in women with ovarian carcinoma.
Researchers evaluated 1,915 samples to identify germline mutations in a panel of 20 genes that have been linked to a predisposition for cancer.
These genes included BRCA1 and BRCA2 — which are linked to hereditary breast–ovarian cancer syndrome — as well as DNA mismatch repair genes linked to Lynch syndrome, tumor suppressor genes, double-stranded DNA break repair genes, and a series of complex genes related to BRCA1 or theBRCA2 Fanconi anemia pathway.
Median age at diagnosis was 60 years (range, 28-91 years) for patients recruited from University of Washington and 61 years (range, 23-87 years) for patients recruited from the clinical trials. The clinical trial population included a higher percentage of black women (4.3% vs. 1.4%; P < .001). The University of Washington cohort included a greater proportion of fallopian tube carcinomas (13.3% vs. 5.7%; P < .001); early-stage disease (14.6% vs. 0%, as the trials were restricted to advanced-stage patients); and nonserous carcinomas (29.9% vs. 13.1%; P < .001).
Eighteen percent of patients from the entire study population harbored pathogenic germline mutations in genes associated with risk for ovarian carcinoma. Fifteen percent had mutations in either BRCA1 (n = 182) or BRCA2 (n = 98), whereas 0.4% had mutations in the DNA mismatch repair genes.
Researchers determined 3.3% of patients had mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11),PALB2 (n = 12) or BARD1 (n = 4).
“PALB2 is a Fanconi anemia gene whose protein binds BRCA1 and BRCA2 at sites of DNA damage,” Norquist and colleagues wrote. “Mutations in PALB2 are associated with an elevated risk of breast cancer and have been identified in families with both breast cancer and ovarian carcinoma but have not been clearly associated with ovarian carcinoma risk. The PALB2 mutation frequency in our [study] was significant compared with population rates and was associated with similar odds ratios for ovarian carcinoma as RAD51C, RAD51D and BRIP1.”
Among the study population from clinical trials, patients with BRCA2 mutations achieved longer PFS (HR = 0.6; 95% CI, 0.45-0.79) and OS (HR = 0.39; 95% CI, 0.25-0.6) than those without genetic mutations.
The researchers identified several study limitations, including the fact it was not population-based and the cases from the trials were limited to advanced-stage cancers.
The findings “underscore the critical point that criteria often used to predict germline mutation status are imperfect,” Elena M. Stoffel, MD, MPH, assistant professor of internal medicine, and Eric R. Fearon, MD, PhD, professor of oncology and chief of the division of molecular medicine and genetics at University of Michigan Medical School, wrote in an accompanying editorial.
The investigators found no association between histology and mutation status, which challenges the notion of using age, family history or tumor type as selection criteria for genetic testing, Stoffel and Fearon wrote.
“Ascertaining cancer risk associated with the variants identified will require additional work, such as characterization of molecular phenotypes of tumors arising in affected individuals, genotype analyses in affected families and longitudinal clinical outcome data from population-based cohorts,” they wrote. “This important work on the known unknowns — BRIP1 and other mutations statistically associated with ovarian carcinoma risk — will hopefully advance knowledge so that it is on par with the known knowns, like BRCA1 and/or BRCA2 mutations that have established use for clinical management of ovarian cancer risk.”
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