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.

Single-cell DNA sequencing reveals a late-dissemination model in metastatic colorectal cancer

“…In patient CRC1, the primary and metastatic cells shared highly similar profiles, including amplifications of several known oncogenes (EGFR, MET, CDK6, CDX2, WNT2, CDK8, ZNF217) and deletions of tumor suppressors (CTNNB1, APC, TP53, SMAD4, TP53) that have previously been reported in colon cancer ( Fig. 5C; Xie et al 2012). However, the primary tumor cells in CRC1 also contained an additional amplification of Chromosome 17q (ERBB2) and a 1.4-Mb homozygous deletion on Chromosome 4q32.3 that were not present in the metastasis.…”

Portrait of the PI3K/AKT pathway in colorectal cancer

“…Two to four percent of CRC patients display ERBB2 (17q12) amplification, and this is correlated with increased protein expression [5,75,[83][84][85][86][87]. Activating mutations in the ERBB2 kinase-domain are found in about 3% of colorectal cancers and co-occur with KRAS aberrations, suggesting that these mutations may also have independent roles in the carcinogenic process [5,75,88].…”

Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer

“…To assess to what extent SMAD4 expression by IHC reflects SMAD4 mRNA expression, we used previously reported expression (16)(17)(18)(19).…”

“…To date, the most important prognostic factor and treatment determinant remains disease stage (15). Identification of tissue biomarkers capable of improving outcome through better patient stratification and selection for specific treatment is gaining momentum, as reflected in studies on microsatellite instability (MSI), loss of heterozygosity (LOH) of 18q, copy-number aberrations (CNA) and the mutation status of KRAS, BRAF, and TP53 (16)(17)(18)(19). In spite of increasingly detailed molecular mapping of colorectal cancer, only few markers have shown some promise in clinical practice in terms of capability to predict disease course.…”