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Published Online: 8 June 2005

Deletions Account for 17% of Pathogenic Germline Alterations in MLH1 and MSH2 in Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Families

Publication: Genetic Testing
Volume 9, Issue Number 2

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is due to defects in DNA mismatch repair (MMR) genes MSH2, MLH1, MSH6, and to a lesser extent PMS2. Of 466 suspected HNPCC families, we defined 54 index patients with either tumors of high microsatellite instability (MSI-H) and/or loss of expression for either MLH1, MSH2, and/or MSH6, but without a detectable pathogenic point mutation in these genes. This study cohort was augmented to 64 patients by 10 mutation-negative index patients from Amsterdam families where no tumors were available. Deletion/duplication screening using the multiplex ligation-dependent probe amplification (MLPA) revealed 12 deletions in MSH2 and two deletions in MLH1. These deletions constitute 17% of pathogenic germline alterations but elucidate the susceptibility to HNPCC in only 22% of the mutation-negative study cohort, pointing towards other mutation mechanisms for an inherited inactivation of MLH1 or MSH2. We describe here four novel deletions. One novel and one known type of deletion were found for three and two unrelated families, respectively. MLPA analysis proved a reliable method for the detection of genomic deletions in MLH1 and MSH2; however, sequence variations in the ligation-probe binding site can mimic single exon deletions.

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Published In

cover image Genetic Testing
Genetic Testing
Volume 9Issue Number 2Summer 2005
Pages: 138 - 146
PubMed: 15943554

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Published online: 8 June 2005
Published in print: Summer 2005

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Monika Grabowski
Institute of Human Genetics, University of Munich, 80336 Munich, Germany.
Center of Medical Genetics, 80336 Munich, Germany.
Yvonne Mueller-Koch
Institute of Human Genetics, University of Munich, 80336 Munich, Germany.
Eva Grasbon-Frodl
Institute for Neuropathology, University of Munich, 81377 Munich, Germany.
Udo Koehler
Center of Medical Genetics, 80336 Munich, Germany.
Gisela Keller
Institute of Pathology, Technical University of Munich, 81675 Munich, Germany.
Holger Vogelsang
Department of Surgery, Technical University of Munich, 81675 Munich, Germany.
Wolfgang Dietmaier
Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
Reinhard Kopp
Department of Surgery, University of Munich, 81377 Munich, Germany.
Ulrike Siebers
Institute of Human Genetics, Westfälische Wilhelms–Universität Münster, 48149 Münster, Germany.
Wolfgang Schmitt
Medical Department, Krankenhaus München-Neuperlach, 81737 München, Germany.
Birgit Neitzel
Center of Medical Genetics, 80336 Munich, Germany.
Maria Gruber
Center of Medical Genetics, 80336 Munich, Germany.
Christa Doerner
Center of Medical Genetics, 80336 Munich, Germany.
Brigitte Kerker
Institute of Human Genetics, University of Munich, 80336 Munich, Germany.
Petra Ruemmele
Institute of Pathology, University of Regensburg, 93053 Regensburg, Germany.
Gabriele Henke
Institute of Human Genetics, University of Munich, 80336 Munich, Germany.
Elke Holinski-Feder
Institute of Human Genetics, University of Munich, 80336 Munich, Germany.
Center of Medical Genetics, 80336 Munich, Germany.

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