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Influence of selection criteria on mutation detection in patients with hereditary nonpolyposis colorectal cancer
Author(s) -
Heinimann Karl,
Scott Rodney J.,
Buerstedde JeanMarie,
Weber Walter,
Siebold Karl,
Attenhofer Michèle,
Müller Hansjakob,
Dobbie Zuzana
Publication year - 1999
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/(sici)1097-0142(19990615)85:12<2512::aid-cncr4>3.0.co;2-g
Subject(s) - dna mismatch repair , microsatellite instability , germline mutation , genetics , colorectal cancer , mutation , medicine , lynch syndrome , cancer , genetic testing , gene , biology , microsatellite , allele
BACKGROUND Hereditary nonpolyposis colorectal cancer (HNPCC) is linked genetically to mutations in DNA mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a specific phenotype, the original selection criteria may be too restrictive in identifying additional families. The current study was performed to determine whether a relaxation of the Amsterdam criteria (AC) could be applied to identify more families associated with DNA MMR. METHODS Twenty‐eight unrelated Swiss families (15 complying with the AC and 13 fulfilling extended criteria [EC] to include other tumors of the HNPCC spectrum as well) were screened for mutations in the MMR genes hMSH2 and hMLH1 , using single‐stranded conformation polymorphism and direct DNA sequencing. Microsatellite instability (MSI) was determined in 14 families. A comparison was made between the phenotypic characteristics of the mutation positive and mutation negative families. RESULTS Ten AC families (67%) harbored germline mutations in hMLH1 (6 kindreds) or hMSH2 (4 kindreds). In none of the EC kindreds could an unambiguous disease‐causing mutation be identified. Seven of eight AC families were found to display MSI whereas all colorectal carcinomas (CRC) in eight EC kindreds were MSI stable. CRC patients from mutation positive families had an earlier age at diagnosis (44 years vs. 49 years) and appeared to have a better survival (11.1 years vs. 7.7 years). CONCLUSIONS Extending the AC to include extracolonic tumors of the HNPCC spectrum results in a very low mutation detection rate for hMSH2 and hMLH1 . The EC families appear to represent an alternative genetic entity not necessarily related to DNA MMR gene mutations because they do not display MSI. Cancer 1999;85:2512–8. © 1999 American Cancer Society.