title: A comprehensive characterization of genome-wide copy number aberrations in colorectal cancer reveals novel oncogenes and patterns of alterations.
abstract: To develop a comprehensive overview of copy number aberrations (CNAs) in stage-II/III colorectal cancer (CRC), we characterized 302 tumors from the PETACC-3 clinical trial. Microsatellite-stable (MSS) samples (n = 269) had 66 minimal common CNA regions, with frequent gains on 20 q (72.5%), 7 (41.8%), 8 q (33.1%) and 13 q (51.0%) and losses on 18 (58.6%), 4 q (26%) and 21 q (21.6%). MSS tumors have significantly more CNAs than microsatellite-instable (MSI) tumors: within the MSI tumors a novel deletion of the tumor suppressor WWOX at 16 q23.1 was identified (p<0.01). Focal aberrations identified by the GISTIC method confirmed amplifications of oncogenes including EGFR, ERBB2, CCND1, MET, and MYC, and deletions of tumor suppressors including TP53, APC, and SMAD4, and gene expression was highly concordant with copy number aberration for these genes. Novel amplicons included putative oncogenes such as WNK1 and HNF4A, which also showed high concordance between copy number and expression. Survival analysis associated a specific patient segment featured by chromosome 20 q gains to an improved overall survival, which might be due to higher expression of genes such as EEF1B2 and PTK6. The CNA clustering also grouped tumors characterized by a poor prognosis BRAF-mutant-like signature derived from mRNA data from this cohort. We further revealed non-random correlation between CNAs among unlinked loci, including positive correlation between 20 q gain and 8 q gain, and 20 q gain and chromosome 18 loss, consistent with co-selection of these CNAs. These results reinforce the non-random nature of somatic CNAs in stage-II/III CRC and highlight loci and genes that may play an important role in driving the development and outcome of this disease.
authors.affiliation: Oncology Research, Pfizer Worldwide Research and Development, San Diego, California, United States of America. tao.xie@pfizer.com
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: Giovanni
authors.initials: G
authors.lastname: D' Ario
authors.forename: John R
authors.initials: JR
authors.lastname: Lamb
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bosman
authors.forename: Arnaud D
authors.initials: AD
authors.lastname: Roth
authors.forename: Pu
authors.initials: P
authors.lastname: Yan
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bougel
authors.forename: Antonio Fabio
authors.initials: AF
authors.lastname: Di Narzo
authors.forename: Vlad
authors.initials: V
authors.lastname: Popovici
authors.forename: Eva
authors.initials: E
authors.lastname: Budinská
authors.forename: Mao
authors.initials: M
authors.lastname: Mao
authors.forename: Scott L
authors.initials: SL
authors.lastname: Weinrich
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rejto
authors.forename: J Graeme
authors.initials: JG
authors.lastname: Hodgson
mesh_terms: D002885:Chromosomes, Human, Pair 16; D015179:Colorectal Neoplasms / Q000235:genetics*; D018628:Gene Dosage; D015894:Genome, Human; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D009857:Oncogenes