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Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Oncogene volume 26, pages 4541–4549 (2007)Cite this article

Abstract

Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P=0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, P<0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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Acknowledgements

We thank Saila Saarinen for expert technical assistance. Heli Surma-Aho and Katja Kuosa are acknowledged for assistance with sample collection. This study was supported by the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Cancer Foundation, the Finnish Cultural Foundation, the Finnish Cultural Foundation Kymenlaakso Fund, the Paulo Foundation, the Ida Montin Foundation, the Helsinki University Funds, Swedish Research Council and Swedish Cancer Foundation.

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Authors and Affiliations

  1. Department of Medical Genetics, University of Helsinki, Helsinki, Finland

    M Ollikainen, W M Abdel-Rahman, J Kere & P Peltomäki

  2. Department of Biosciences and Nutrition, Karolinska Institutet and Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden

    U Hannelius, C M Lindgren & J Kere

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  1. M Ollikainen
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Correspondence to M Ollikainen.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Ollikainen, M., Hannelius, U., Lindgren, C. et al. Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach. Oncogene 26, 4541–4549 (2007). https://doi.org/10.1038/sj.onc.1210236

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