From the Journals

Study confirms BRCA1 and BRCA2 linked to seven cancers


 

FROM JAMA ONCOLOGY

A large case-control study finds the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is broader than previously determined from prior analyses showing associations with breast, ovarian, prostate, and pancreatic cancers. The finding, published in JAMA Oncology suggests a possible broader clinical relevance for BRCA1 and BRCA2 genetic testing.

Pathogenic variants in BRCA1 were found to be associated with biliary tract cancer, in BRCA2 with esophageal cancer, and in BRCA1/2 with gastric cancer.

“The results suggest the range of cancer types associated with pathogenic variants in BRCA1 and BRCA2 is likely broader than that determined from previous analysis of largely European ancestry cohorts,” wrote authors who were led by Yukihide Momozawa, DVM, PhD, RIKEN Center for Integrative Medical Sciences, Japan.

“These risk association findings, together with our analysis of an association with family history of cancer and clinical phenotypes, are relevant for developing and adapting guidelines about genetic testing, treatment options, and treatability with PARP [poly adenosine diphosphate-ribose polymerase] inhibitors for each cancer type,” the authors wrote.

Dr. Momozawa and associates conducted a large-scale sequencing study across 14 common cancer types in 63,828 patients (mean age 64 years, 42% female) and 37,086 controls on data drawn from a Japanese nationwide biobank between April 2003 and March 2018. They estimated the risk of each cancer type and determined clinical characteristics associated with pathogenic variant carrier status, while also investigating the utility of family history in detecting patients with pathogenic variants.

Three hundred fifteen pathogenic variants were identified. An odds ratios of greater than 4.0 (with P < 1 × 10−4 as the threshold of significance) for the pathogenic variants were found for biliary tract cancer (OR, 17.4; 95% confidence interval, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2. Two other cancer types were found to be associated with BRCA1, and four other cancer types with BRCA2. Enrichment of carrier patients was shown in biliary tract, female breast, ovarian, and prostate cancers in accordance with increased numbers of reported cancer types in relatives.

Male patients with breast cancer had a very high carrier frequency of pathogenic variants in BRCA2 (18.9%), but not BRCA1 (1.89%). Patients with ovarian cancer showed the next highest proportion (BRCA1, 4.86%; BRCA2, 3.42%). Frequency exceeding 1% was seen for several other cancer types (two cancer types for BRCA1, four cancer types for BRCA2). More than one cancer types was identified in 4,128 patients (6.3%). Carrier frequency of pathogenic variants in BRCA1 was 0.44% with one cancer type, 0.85% with two cancer types, and 0.69% with three cancer types. It was 0.97%, 1.40%, and 1.74%, respectively, in BRCA2.

“The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of seven cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing,” the authors wrote.

PARP inhibitors were developed based on the mechanism in BRCA1 and BRCA2 of homologous recombination repair defects associated with pathogenic variants. PARP inhibitors have been found to have therapeutic efficacy also in pathogenic variants found to be enriched in prostate and pancreatic cancers. While risk for additional cancer types (for example, biliary tract cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, and stomach cancer) has been reported after analyzing family members for the presence of pathogenic variants and performing case-control analyses, evidence for an association with these cancer types has not been considered sufficient for them to be adopted into clinical management guidelines, the authors wrote.

In an interview, Dr. Momozawa said that BRCA1 and BRCA2 genetic testing should be expanded in Japan. “But further studies are needed to reveal how much. If a clinical trial of a PARP inhibitor for these three cancer types reveals its clinical utility, the importance of this expansion will increase.”

Dr. Momozawa and associates state that while their selection of controls without a family history of cancer affects the generalizability of the study results, the estimated cumulative risks were comparable with those based on prospective cohorts, suggesting the study design did not greatly affect the results.

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