Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers.

Background: Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC-related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

Methods: Seventy-seven probands were identified who had familial ovarian cancer and negative BRCA gene mutation testing. Their pedigrees were analyzed for HNPCC syndrome. DNA samples underwent gene sequencing and Southern blot analysis for mutations in the 3 most common HNPCC-associated genes: mutL homolog 1 (MLH1) and mutS homolog 2 (MSH2) with reflex testing for MSH6 if tests for the first 2 genes were negative.

Results: None of the probands met Amsterdam criteria for the clinical diagnosis of HNPCC. DNA testing revealed 2 patients (2.6%) with deleterious mutations in the MSH2 gene. An additional 8 patients (10.4%) had substitutions in either the MLH1 gene or the MSH2 gene that were classified as variants of uncertain significance. If Amsterdam criteria were expanded to include ovarian cancer, then 15 of 77 patients (19.5%) would have met these expanded criteria. One deleterious mutation was noted in this group, yielding a mutation incidence of 6.7%. This percentage may be even higher if any of the identified variants of uncertain significance are confirmed to be deleterious.

Conclusions: HNPCC should be considered when evaluating patients with suspected hereditary ovarian cancer who have had negative BRCA mutation testing.