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 similar t o 20% of sporadic endometrial carcinomas. Frameshift mutations in several c ancer predisposing genes, especially in their mononucleotide repeats, are s een in RER+ tumors. In a survey of hereditary breast cancer genes in gyneco logical cancer, we analyzed the entire coding sequence of BRCA1 and BRCA2 i n 51 endometrial tumors, of which 12 were RER+. Seven somatic mutations wer e identified in six (50%) of the RER+ tumors, but none in RER- tumors. A no vel 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 framesh ift mutations at polyA tracts in BRCA1 and BRCA2 exon 11, both predicted to result in premature translation termination. Whereas most mutations in BRC A1 and BRCA2 are known to affect the more carboxy-terminal regions interact ing 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 t hat somatic mutations in BRCA2 (and to some extent BRCA1) may confer a grow th advantage in RER+ endometrial carcinomas. Genes Chromosomes Cancer 24:20 7-212, 1999. (C) 1999 Wiley-Liss, Inc.