title: Genome-wide copy neutral LOH is infrequent in familial and sporadic microsatellite unstable carcinomas.
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.
authors.affiliation: Department of Pathology, Leiden University Medical Center, Building L1Q, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: Marjo
authors.initials: M
authors.lastname: van Puijenbroek
authors.forename: Anneke
authors.initials: A
authors.lastname: Middeldorp
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Ronald
authors.initials: R
authors.lastname: van Eijk
authors.forename: Heleen M
authors.initials: HM
authors.lastname: van der Klift
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Juul Th
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Jan
authors.initials: J
authors.lastname: Oosting
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D018628:Gene Dosage; D006801:Humans; D019656:Loss of Heterozygosity; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1