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Chromosomal Instability in MYH- and APC-Mutant Adenomatous Polyps

¹ Department of Pathology, Josephine Nefkens Institute; Departments of ² Pediatric Oncology and ³ Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, the Netherlands; ⁴ Center for Human and Clinical Genetics and Departments of ⁵ Molecular and Cellular Biology and ⁶ Pathology, Leiden University Medical Center, Leiden, the Netherlands; ⁷ Department of Surgery, Heinrich Heine University, Dusseldorf, Germany; and ⁸ Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom

Requests for reprints: Riccardo Fodde, Department of Pathology, Erasmus Medical Center, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands. Phone: 31-10-408-8490; Fax: 31-10-408-8450; E-mail: r.fodde{at}erasmusmc.nl.

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. (Cancer Res 2006; 66(5): 2514-9)

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