High frequency of copy-neutral LOH in MUTYH-associated polyposis carcinomas.
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 near-diploid adenomas, 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 gains (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: fluorescence 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 tumorigenesis of MAP.
Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands.
A
A
Middeldorp
M
M
van Puijenbroek
M
M
Nielsen
W E
WE
Corver
E S
ES
Jordanova
N
N
ter Haar
C M J
CM
Tops
H F A
HF
Vasen
E H
EH
Lips
R
R
van Eijk
F J
FJ
Hes
J
J
Oosting
J
J
Wijnen
T
T
van Wezel
H
H
Morreau
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D043171:Chromosomal Instability / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics*; D053842:Microsatellite Instability; D008875:Middle Aged
D014408:Biomarkers, Tumor; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase