title: Chromosomal instability in MYH- and APC-mutant adenomatous polyps.
abstract: The vast majority of colorectal cancers display genetic instability, either in the chromosomal instability (CIN) or microsatellite instability (MIN) forms. Although CIN tumors are per definition aneuploid, MIN colorectal cancers, caused by loss of mismatch repair function, are usually near diploid. Recently, biallelic germ line mutations in the MYH gene were found to be responsible for MYH-associated polyposis (MAP), an autosomal recessive predisposition to multiple colorectal polyps, often indistinguishable from the dominant familial adenomatous polyposis (FAP) syndrome caused by inherited APC mutations. Here, we analyzed MYH- and APC-mutant polyps by combining laser capture microdissection, isothermal genomic DNA amplification, and array comparative genomic hybridization. Smoothed quantile regression methods were applied to the MAP and FAP genomic profiles to discriminate chromosomes predominantly affected by gains and losses. Up to 80% and 60% of the MAP and FAP polyps showed aneuploid changes, respectively. Both MAP and FAP adenomas were characterized by frequent losses at chromosome 1p, 17, 19, and 22 and gains affecting chromosomes 7 and 13. The aneuploid changes detected at early stages of MYH-driven tumorigenesis may underlie accelerated tumor progression, increased cancer risk, and poor prognosis in MAP.
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Rotterdam, the Netherlands.
authors.forename: Joana
authors.initials: J
authors.lastname: Cardoso
authors.forename: Lia
authors.initials: L
authors.lastname: Molenaar
authors.forename: Renee X
authors.initials: RX
authors.lastname: de Menezes
authors.forename: Monique
authors.initials: M
authors.lastname: van Leerdam
authors.forename: Carla
authors.initials: C
authors.lastname: Rosenberg
authors.forename: Gabriela
authors.initials: G
authors.lastname: Möslein
authors.forename: Julian
authors.initials: J
authors.lastname: Sampson
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Judith M
authors.initials: JM
authors.lastname: Boer
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000782:Aneuploidy; D043171:Chromosomal Instability; D016000:Cluster Analysis; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase