Double frameshift mutations in APC and MSH2 in the same individual
Claudio Soravia1, Celia D DeLozier, Zurana Dobbie
1Clinic of Visceral Surgery, Geneva University Hospital, Geneva, Switzerland. csoravia@hin.ch
Abstract:
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 (less than ten) 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.
Insights
This case study highlights a novel MSH2 mutation causing Lynch syndrome (HNPCC) in a patient with familial adenomatous polyposis, leading to adenocarcinoma and desmoid tumors.
Area of Science:
- Genetics
- Oncology
- Gastroenterology
Background:
- Hereditary nonpolyposis colorectal cancer (HNPCC), also known as 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 revealed high-grade instability, and immunohistochemistry showed absent MSH2 and MSH6 protein expression.
- The patient underwent prophylactic colectomy, revealing a pT1N0 adenocarcinoma within an adenoma.
Findings:
- Genomic DNA analysis identified a novel frameshift mutation in MSH2 (c.1,191_1,192dupG) in the proband.
- The proband inherited the MSH2 mutation from his mother and an APC mutation (del3471-3473GAGA) from his father.
- Follow-up revealed multiple adenomas in the stomach, duodenum, and rectum, and the development of an intra-abdominal desmoid tumor.
Implications:
- This case underscores the importance of considering Lynch syndrome in individuals with atypical polyp burden and a family history of polyposis syndromes.
- The co-occurrence of MSH2 and APC mutations highlights complex genetic interactions in colorectal cancer predisposition.
- Early diagnosis and management are crucial for patients with Lynch syndrome and FAP, given the risk of multiple adenomas and extracolonic manifestations like desmoid tumors.
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