Double frameshift mutations in APC and MSH2 in the same individual

Area of Science:

• Oncology
• Genetics
• Gastroenterology

Background:

• Hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch syndrome, is typically linked to germline mutations in DNA mismatch repair genes.
• Familial adenomatous polyposis (FAP) is characterized by numerous adenomatous polyps and is associated with APC gene mutations.

Observation:

• A proband presented with fewer than ten polyps, atypical for FAP, prompting consideration of HNPCC.
• Microsatellite instability analysis of tumor tissue showed high-grade instability.
• Immunohistochemistry revealed absent MSH2 and MSH6 protein expression in tumor cells.

Findings:

• A prophylactic colectomy revealed a pT1N0 adenocarcinoma within a dysplastic adenoma.
• Genomic DNA analysis identified a novel frameshift mutation in MSH2 exon 7 (c.1191_1192dupG) in the proband, inherited from the mother.
• The proband also inherited an APC truncating mutation (del3471-3473GAGA) from the father.
• Follow-up revealed multiple adenomas in the stomach and duodenum, and rectal adenomas.
• The patient subsequently developed an intra-abdominal desmoid tumor.

Implications:

• This case highlights a complex genetic interplay between Lynch syndrome and FAP.
• Early diagnosis and management are crucial for patients with overlapping hereditary cancer syndromes.
• The development of desmoid tumors in this context warrants further investigation.