Double frameshift mutations in APC and MSH2 in the same individual

Heterozygous germline DNA mismatch repair gene mutations are typically associated with HNPCC. Here we report the case of a proband whose father was known for familial adenomatous polyposis. The number of polyps (<10) was not typical of polyposis, therefore the diagnosis of HNPCC was entertained. Microsatellite instability analyses were performed on peripheral blood and biopsy of a right-sided dysplastic adenoma. The tumour tissue showed high-grade instability and subsequently immunohistochemistry showed that neither MSH2 nor MSH6 proteins were expressed in tumour cells. Prophylactic colectomy was performed and an adenocarcinoma developing within the adenoma was diagnosed (pT1N0). Genomic DNA analysis revealed a novel mutation in MSH2 as: a frameshift mutation in exon 7 (c.1,191_1,192dupG). Both parents of the proband were analyzed for MSH2 and APC mutations, and in the father a truncating mutation in exon 15 of APC was identified as del3471-3473GAGA. This mutation was found to be present in the proband. His mother was found to bear the MSH2 exon 7 mutation. At follow-up, the proband was diagnosed with fundic, antral and duodenal adenomas (one fundic adenoma showed low-grade dysplasia). Several tubular rectal adenomas with low-grade dysplasia were excised. The patient later developed an intra-abdominal desmoid tumour.