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.
Highlights
Colorectal cancer (CRC) ranks second to lung cancer in both incidence and mortality in developed countries [1]
The only gene contained within the 16 q23.1 locus is the WWOX tumor suppressor, an inhibitor of the WNT/betacatenin pathway [33], which is frequently activated in colon cancer
Regions of recurrent and focal copy number aberrations (CNAs) identified in these tumors highlight genomic regions most likely to encode oncogenes and tumor suppressors
Summary
Colorectal cancer (CRC) ranks second to lung cancer in both incidence and mortality in developed countries [1]. It is characterized by highly complex patterns of somatic genetic alterations of oncogenes and tumor suppressors that drive initiation and progression [2,3,4]. Understanding the cellular and molecular mechanisms by which these genetic changes facilitate colon cancer formation is critical for development of targeted therapeutic strategies aimed at controlling disease progression while minimizing toxic side effects. One well-established genetic mechanism by which cancer cells alter the activity of oncogenes and tumor suppressors is through changes in gene dosage.
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