A somatic BRCA2 mutation in RER+ endometrial carcinomas that specifically deletes the amino-terminal transactivation domain.

Mismatch repair deficiency and replication errors (RERs) occur in approximately 20% of sporadic endometrial carcinomas. Frameshift mutations in several cancer predisposing genes, especially in their mononucleotide repeats, are seen in RER+ tumors. In a survey of hereditary breast cancer genes in gynecological cancer, we analyzed the entire coding sequence of BRCA1 and BRCA2 in 51 endometrial tumors, of which 12 were RER+. Seven somatic mutations were identified in six (50%) of the RER+ tumors, but none in RER- tumors. A novel base pair deletion at a (T)10 tract in BRCA2 intron 2, causing an in-frame splice deletion of exon 3, was observed in four tumors, one of which contained a second, truncating BRCA2 mutation. Two tumors exhibited frameshift mutations at polyA tracts in BRCA1 and BRCA2 exon 11, both predicted to result in premature translation termination. Whereas most mutations in BRCA1 and BRCA2 are known to affect the more carboxy-terminal regions interacting with RAD51, and the transactivating BRCT domains of BRCA1, this is the first demonstration of a recurrent BRCA2 mutation that specifically deletes the amino-terminal transactivation domain. Moreover, our results suggest that somatic mutations in BRCA2(and to some extent BRCA1) may confer a growth advantage in RER+ endometrial carcinomas.