High frequency of copy neutral LOH in MUTYH-associated polyposis carcinomas

A. Middeldorp1, M. van Puijenbroek1, M. Nielsen2, W.E. Corver1, E.S. Jordanova1, N. ter Haar1, C.J.M. Tops2, H.F.A. Vasen3, E.H. Lips1, R. van Eijk R1, F.J. Hes 2, J. Oosting1, J. Wijnen2,4, T. van Wezel T1, H. Morreau1
Department of Pathology, Leiden University Medical Center1; Department of Clinical Genetics, Leiden University Medical Center2; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden3; Department of Human Genetics, Leiden University Medical Center4

Genetic instability is known to drive colorectal carcinogenesis. Generally, a distinction is made between two types of genetic instability: chromosomal instability (CIN) and microsatellite instability (MIN or MSI). Most CIN tumours are aneuploid, whereas MSI tumours are considered near-diploid. However, for MUTYH-associated polyposis (MAP) the genetic instability involved in the carcinogenesis remains unclear, as both aneuploid adenomas and near-diploid carcinomas have been reported. Remarkably, our analysis of 26 MAP carcinomas, using SNP arrays and flow sorting, showed that these tumours are often near-diploid (52%) and mainly contain chromosomal regions of copy neutral loss of heterozygosity (LOH) (71%). This is in contrast to sporadic colon cancer, where physical loss is the main characteristic. The percentage of chromosomal amplifications (24%) is comparable to sporadic colorectal cancers with CIN. Furthermore, we verified our scoring of copy neutral LOH versus physical loss in MAP carcinomas by two methods: fluorescent in situ hybridization, and LOH analysis using polymorphic markers on carcinoma fractions purified by flow sorting. The results presented in this study suggest that copy neutral LOH is an important mechanism in the tumourigenesis of MAP.