Genetic diagnosis strategy of hereditary non-polyposis colorectal cancer

Sheng, Jian-qiu; Zhang, Hong; Ji, Min; Fu, Lei; Mu, Hong; Zhang, Mingzhi; Han, Min; Li, Aiqin; Wei, Zhi; Sun, Zhaoxia; Wu, Zi-tao; Xia, Changhong; Liu, Shirong

doi:10.3748/wjg.15.983

Cited by 9 publications

(1 citation statement)

References 24 publications

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“…Heritable DNA methylation abnormalities have been identified in two Lynch syndrome-associated genes, MLH1 [33][34][35][36][37][38][39][40] and MSH2. 22,31,32,41,42 Heritable MLH1 promoter hypermethylation appears to be a relatively rare event, and the mechanism for this alteration has not yet been determined.…”

Section: 32mentioning

confidence: 99%

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

Rumilla

Schowalter

Lindor

et al. 2011

The Journal of Molecular Diagnostics

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Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ϳ80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3= EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation. Lynch syndrome is an autosomal dominant predisposition syndrome in which patients have a propensity to develop colorectal adenocarcinoma, endometrial carcinoma, sebaceous neoplasms, upper urinary tract urothelial carcinomas, central nervous system neoplasms, and ovarian and hepatobiliary neoplasms.1-4 The underlying genetic basis for this syndrome is the presence of a mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. [5][6][7][8][9][10] The defining phenotype of tumors from these patients is the presence of tumor microsatellite instability [11][12][13] and loss of protein expression of the affected enzyme in the tumor nuclei as detected by immunohistochemical staining.14 -16 The spectrum of mu-

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