Article

Familial Cancer

, 7:319

First online:

Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas

  • Marjo van PuijenbroekAffiliated withDepartment of Pathology, Leiden University Medical Center
  • , Anneke MiddeldorpAffiliated withDepartment of Pathology, Leiden University Medical Center
  • , Carli M. J. TopsAffiliated withCenter Human and Clinical Genetics, Leiden University Medical Center
  • , Ronald van EijkAffiliated withDepartment of Pathology, Leiden University Medical Center
  • , Heleen M. van der KliftAffiliated withCenter Human and Clinical Genetics, Leiden University Medical Center
  • , Hans F. A. VasenAffiliated withThe Netherlands Foundation for the Detection of Hereditary Tumors
  • , Juul Th. WijnenAffiliated withCenter Human and Clinical Genetics, Leiden University Medical Center
  • , Frederik J. HesAffiliated withCenter Human and Clinical Genetics, Leiden University Medical Center
  • , Jan OostingAffiliated withDepartment of Pathology, Leiden University Medical Center
    • , Tom van WezelAffiliated withDepartment of Pathology, Leiden University Medical Center
    • , Hans MorreauAffiliated withDepartment of Pathology, Leiden University Medical Center Email author 

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Abstract

Mismatch repair deficiency in tumors can result from germ line mutations in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2), or from sporadic promoter hypermethylation of MLH1. The role of unclassified variants (UVs) in MMR genes is subject to debate. To establish the extend of chromosomal instability and copy neutral loss of heterozygosity (cnLOH), we analyzed 41 archival microsatellite unstable carcinomas, mainly colon cancer, from 23 patients with pathogenic MMR mutations, from eight patients with UVs in one of the MMR genes and 10 cases with MLH1 promoter hypermethylation. We assessed genome wide copy number abnormalities and cnLOH using SNP arrays. SNP arrays overcome the problems of detecting LOH due to instability of polymorphic microsatellite markers. All carcinomas showed relatively few chromosomal aberrations. Also cnLOH was infrequent and in Lynch syndrome carcinomas usually confined to the locus harbouring pathogenic mutations in MLH1, MSH2 or PMS2 In the carcinomas from the MMR-UV carriers such cnLOH was less common and in the carcinomas with MLH1 promoter hypermethylation no cnLOH at MLH1 occurred. MSI-H carcinomas of most MMR-UV carriers present on average with more aberrations compared to the carcinomas from pathogenic MMR mutation carriers, suggesting that another possible pathogenic MMR mutation had not been missed. The approach we describe here shows to be an excellent way to study genome-wide cnLOH in archival mismatch repair deficient tumors.

Keywords

Lynch syndrome HNPCC MSI-H Chromosomal instability Copy neutral loss of heterozygosity Mismatch repair (MMR) genes Unclassified variants MLH1 hypermethylation SNP array