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

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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.

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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

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Acknowledgements

We thank Illumina for providing us with part of the SNP arrays, and Ruben van ‘t Slot and Diandhra Erasmus for technical support. This study was supported by the Dutch Cancer Society, grants UL2003–2807 and UL2005–3247.

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Correspondence to Hans Morreau.

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van Puijenbroek, M., Middeldorp, A., Tops, C.M.J. et al. Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas. Familial Cancer 7, 319–330 (2008). https://doi.org/10.1007/s10689-008-9194-8

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  • DOI: https://doi.org/10.1007/s10689-008-9194-8

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