Abstract
BackgroundMLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to HNPCC. It is important to develop genotype-phenotype correlations for HNPCC, as is being done for other hereditary cancer syndromes, in order to guide surveillance and treatment strategies in the future.Case presentationWe report a 47 year-old male with hereditary nonpolyposis colorectal cancer (HNPCC) associated with a novel germline mutation in MLH1. This patient expressed a rare and severe phenotype characterized by three synchronous primary carcinomas: ascending and splenic flexure colon adenocarcinomas, and ureteral carcinoma. Ureteral neoplasms in HNPCC are most often associated with mutations in MSH2 and rarely with mutations in MLH1. The reported mutation is a two base pair insertion into exon 10 (c.866_867insCA), which results in a premature stop codon.ConclusionOur case demonstrates that HNPCC patients with MLH1 mutations are also at risk for ureteral neoplasms, and therefore urological surveillance is essential. This case adds to the growing list of disease-causing MMR mutations, and contributes to the development of genotype-phenotype correlations essential for assessing individual cancer risk and tailoring of optimal surveillance strategies. Additionally, our case draws attention to limitations of the Amsterdam Criteria and the need to maintain a high index of suspicion when newly diagnosed colorectal cancer meets the Bethesda Criteria. Establishment of the diagnosis is the crucial first step in initiating appropriate surveillance for colorectal cancer and other HNPCC-associated tumors in at-risk individuals.
Highlights
MLH1 is one of six known genes responsible for DNA mismatch repair (MMR), whose inactivation leads to hereditary nonpolyposis colorectal cancer (HNPCC)
Transmitted in an autosomal dominant fashion, HNPCC is associated with tumorigenesis caused by mutations in one of several genes involved in DNA mismatch repair (MMR) [3]
About 90% of HNPCC cases are associated with mutations in MLH1 (OMIM #120436) or MSH2 (OMIM #609309), and others are associated with mutations in MSH6, PMS1, PMS2, and MLH3 [4]
Summary
In patients with a family history characterized by multiple cases of CRC or extracolonic HNPCC-associated tumors, the possibility of HNPCC must be considered so that appropriate surveillance of at-risk individuals can be instituted. Patients presenting with ureteral cancer, when MSI or suggestive histology is present, should be referred for colonoscopy as well as genetic risk assessment and possible germline testing. In patients with known HNPCC, ureteral cancer surveillance is essential. Reporting of novel disease-causing mutations, including information about ethnicity, is important for establishing genotype-phenotype correlations. It is anticipated that well-defined genotype-phenotype correlations will facilitate tailoring of surveillance strategies in the future. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal
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