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Altered Expression of MLH1, MSH2, and MSH6 in Predisposition to Hereditary Nonpolyposis Colorectal Cancer

Elise Renkonen, Yange Zhang, Hannes Lohi, Reijo Salovaara, Wael M. Abdel-Rahman, Mef Nilbert, Kristiina Aittomäki, Heikki J. Järvinen, Jukka-Pekka Mecklin, Annika Lindblom, Päivi Peltomäki

From the Departments of Medical Genetics and Pathology, University of Helsinki; the Department of Clinical Genetics and the Second Department of Surgery, Helsinki University Hospital, Helsinki; and the Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland; the Division of Human Cancer Genetics, The Ohio State University, Columbus, OH; the Department of Oncology, University Hospital, Lund; and the Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.

Address reprint requests to Päivi Peltomäki, MD, Department of Medical Genetics, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FIN-00014 University of Helsinki, Finland; e-mail: paivi.peltomaki{at}helsinki.fi.

Purpose: A considerable fraction (30% to 70%) of families with verified or putative hereditary nonpolyposis colorectal cancer fails to show mutations in DNA mismatch repair (MMR) genes. Our purpose was to address the genetic etiology of such families.

Materials and Methods: We scrutinized a population-based cohort of 26 families from Finland that had screened mutation-negative by previous techniques. Blood was tested for allelic messenger RNA (mRNA) expression of MLH1, MSH2, and MSH6 by single nucleotide primer extension (SNuPE), and tumor tissue for MMR protein expression by immunohistochemistry (IHC) as well as for microsatellite instability (MSI). Full-length cDNAs of genes implicated by SNuPE or IHC were cloned and sequenced.

Results: Unbalanced mRNA expression of MLH1 alleles was evident in two families. An inherited nonsense mutation was subsequently identified in one family, and complete silencing of the mutated allele was identified in the other family. Extinct protein expression by IHC implicated MLH1 in these two and in four other families, MSH2 in four families, and MSH6 in one family. Although no unequivocal genomic mutations were detected in the latter families, haplotype and other findings provided support for heritable defects. With one exception, all tumors with IHC alterations showed MSI, in contrast to the remaining families, which showed neither IHC changes nor MSI.

Conclusion: Our expression-based strategy stratified the present "mutation-negative" cohort into two discrete categories: families linked to the major MMR genes MLH1, MSH2, and MSH6 (11 [42%] of 26) and those likely to be associated with other, as yet unknown susceptibility genes (15 [58%] of 26).

Supported by the Sigrid Juselius Foundation, the Academy of Finland, the Finnish Cancer Foundation, the Science Foundation of Helsinki University, the Paulo Foundation, the National Institutes of Health (grant CA82282), and the Swedish Cancer Society.

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