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Beta2‐microglobulin mutations in microsatellite unstable colorectal tumors
Author(s) -
Kloor Matthias,
Michel Sara,
Buckowitz Boris,
Rüschoff Josef,
Büttner Reinhard,
HolinskiFeder Elke,
Dippold Wolfgang,
Wagner Rudolf,
Tariverdian Mirjam,
Benner Axel,
Schwitalle Yvette,
Kuchenbuch Beate,
von Knebel Doeberitz Magnus
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22691
Subject(s) - microsatellite instability , msh2 , mlh1 , lynch syndrome , dna mismatch repair , cancer research , germline mutation , colorectal cancer , germline , biology , msh6 , cancer , mutation , medicine , genetics , gene , microsatellite , allele
Defects of DNA mismatch repair (MMR) cause the high level microsatellite instability (MSI‐H) phenotype. MSI‐H cancers may develop either sporadically or in the context of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome that is caused by germline mutations of MMR genes. In colorectal cancer (CRC), MSI‐H is characterized by a dense lymphocytic infiltration, reflecting a high immunogenicity of these cancers. As a consequence of immunoselection, MSI‐H CRCs frequently display a loss of human leukocyte antigen (HLA) class I antigen presentation caused by mutations of the β 2 ‐microglobulin (β 2m ) gene. To examine the implications of β 2m mutations during MSI‐H colorectal tumor development, we analyzed the prevalence of β 2m mutations in MSI‐H colorectal adenomas ( n = 38) and carcinomas ( n = 104) of different stages. Mutations were observed in 6/38 (15.8%) MSI‐H adenomas and 29/104 (27.9%) MSI‐H CRCs. A higher frequency of β 2m mutations was observed in MSI‐H CRC patients with germline mutations of MMR genes MLH1 or MSH2 (36.4%) compared with patients without germline mutations (15.4%). The high frequency of β 2m mutations in HNPCC‐associated MSI‐H CRCs is in line with the hypothesis that immunoselection may be particularly pronounced in HNPCC patients with inherited predisposition to develop MSI‐H cancers. β 2m mutations were positively related to stage in tumors without distant metastases (UICC I‐III), suggesting that loss of β 2m expression may promote local progression of colorectal MSI‐H tumors. However, no β 2m mutations were observed in metastasized CRCs (UICC stage IV, p = 0.04). These results suggest that functional β2m may be necessary for distant metastasis formation in CRC patients. © 2007 Wiley‐Liss, Inc.