Familial Cancer

, 7:319

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

Authors

  • Marjo van Puijenbroek
    • Department of PathologyLeiden University Medical Center
  • Anneke Middeldorp
    • Department of PathologyLeiden University Medical Center
  • Carli M. J. Tops
    • Center Human and Clinical GeneticsLeiden University Medical Center
  • Ronald van Eijk
    • Department of PathologyLeiden University Medical Center
  • Heleen M. van der Klift
    • Center Human and Clinical GeneticsLeiden University Medical Center
  • Hans F. A. Vasen
    • The Netherlands Foundation for the Detection of Hereditary Tumors
  • Juul Th. Wijnen
    • Center Human and Clinical GeneticsLeiden University Medical Center
  • Frederik J. Hes
    • Center Human and Clinical GeneticsLeiden University Medical Center
  • Jan Oosting
    • Department of PathologyLeiden University Medical Center
  • Tom van Wezel
    • Department of PathologyLeiden University Medical Center
    • Department of PathologyLeiden University Medical Center
Article

DOI: 10.1007/s10689-008-9194-8

Cite this article as:
van Puijenbroek, M., Middeldorp, A., Tops, C.M.J. et al. Familial Cancer (2008) 7: 319. doi:10.1007/s10689-008-9194-8

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 syndromeHNPCCMSI-HChromosomal instabilityCopy neutral loss of heterozygosityMismatch repair (MMR) genesUnclassified variantsMLH1 hypermethylationSNP array

Abbreviations

CGH

Comparative genomic hybridization

CIN

Chromosomal instability

CNA

Copy number aberrations

cnLOH

Copy neutral loss of heterozygosity

CRC

Colorectal cancer

FFPE

Formalin-fixed paraffin-embedded

GCS

Gene call score

GTS

Gene train score

IHC

Immunohistochemistry

LOH

Loss of heterozygosity

LP

Linkage panels

MMR

Mismatch repair

MSI

Microsatellite instability

MSI-H

Microsatellite instability

MSS

Microsatellite stable

rGCS

Relative gene call score

SRO

Smallest region of overlap

UVs

Unclassified variants

Copyright information

© Springer Science+Business Media B.V. 2008