Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression.
Colorectal cancer (CRC) development is in most cases marked by the accumulation of genomic alterations including gain of the entire q-arm of chromosome 13. This aberration occurs in 40%-60% of all CRC and is associated with progression from adenoma to carcinoma. To date, little is known about the effect of the 13q amplicon on the expression of the therein located genes and their functional relevance. We therefore aimed to identify candidate genes at the 13q amplicon that contribute to colorectal adenoma to carcinoma progression in a gene dosage-dependent manner. Integrative analysis of whole genome expression and DNA copy number signatures resulted in the identification of 36 genes on 13q of which significant overexpression in carcinomas compared with adenomas was linked to a copy number gain. Five genes showing high levels of overexpression in carcinomas versus adenomas were further tested by quantitative reverse transcription-PCR in two independent sample sets of colorectal tumors (n = 40 and n = 47). DIS3 and LRCH1 revealed significant overexpression in carcinomas compared with adenomas in a 13q gain dependent manner. Silencing of DIS3 affected important tumorigenic characteristics such as viability, migration, and invasion. In conclusion, significant overexpression of DIS3 and LRCH1 associated with adenoma to carcinoma progression is linked to the CRC specific gain of 13q. The functional relevance of this copy number aberration was corroborated for DIS3, thereby identifying this gene as novel candidate oncogene contributing to the 13q-driven adenoma to carcinoma progression.
Department of Pathology, VU University Medical Center, PO Box 7057, 1007MB, Amsterdam, The Netherlands.
Florence L M
FL
de Groen
Oscar
O
Krijgsman
Marianne
M
Tijssen
Lianne E M
LE
Vriend
Bauke
B
Ylstra
Erik
E
Hooijberg
Gerrit A
GA
Meijer
Renske D M
RD
Steenbergen
Beatriz
B
Carvalho
D000236:Adenoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002882:Chromosomes, Human, Pair 13 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics* / Q000378:metabolism; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D011446:Prospective Studies
C508643:LRCH1 protein, human; D008840:Microfilament Proteins; D063326:Exosome Multienzyme Ribonuclease Complex; C551543:DIS3 protein, human