Early genetic aberrations in patients with sporadic colorectal cancer

Abstract

Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high‐density SNP array and exome data from The Cancer Genome Atlas (TCGA), we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon, and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm‐specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (eg, APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing (WGS), we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium, and non‐malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment.

Exploiting DNA repair defects in colorectal cancer

“…Hanahan and Weinberg classified ‘genome instability’ as an enabling characteristic of cancer and described how defects in DNA repair lead to loss of chromosomes, particularly at the telomere region (Hanahan and Weinberg, ). Genome instability is identified by structural alterations that include copy number variations and loss of heterozygosity, often observed in CRC cells (Druliner et al ., ), and chromosomal rearrangements (Aguilera and Gomez‐Gonzalez, ). These elements are characteristic of HR defective cells, and specific genomic signatures have been identified in breast and ovarian cancer cells (Davies et al ., ; Hillman et al ., ; Vanderstichele et al ., ).…”

The CARM1-p300-c-Myc-Max (CPCM) transcriptional complex regulates the expression of CUL4A/4B and affects the stability of CRL4 E3 ligases in colorectal cancer

“…The activation of oncogenes and suppression of tumor suppressors are the direct causes that lead to tumorigenesis [13]. Bioinformatic analyses in TCGA (The Cancer Genome Atlas) database and gene expression analyses in CRC tumor tissues and cultured tumor cells demonstrate that a variety of tumor suppressors [e.g., p53, APC (Adenomatous Polyposis Coli), LOH (Loss of Heterozygosity), PTEN (Phosphatase and Tensin Homolog) and ST7 (Suppressor of Tumorigenicity protein 7] and oncogenes [e.g., KRAS (Kirsten Rat Sarcoma), c-Myc, Her2 (Human Epidermal Growth factor receptor 2)] are differentially expressed [14,15]. In recent years, a significant number of miRNAs and lncRNAs are also found to play important roles in the pathogenesis of CRC [16][17][18].…”

RKDOSCNV: A Local Kernel Density-Based Approach to the Detection of Copy Number Variations by Using Next-Generation Sequencing Data

“…For example, the CNV gains at 1p11.2 (Jiang et al, 2011 ), 11q21 (Kazantseva et al, 2016 ), 16q11.2 (Savelyeva et al, 1994 ), and 17q11.1 are associated with breast cancer and are detected by each method, which is described in Figure 9 . Those at 14q11.2 (Kawasaki et al, 2007 ) and 16p11.2 (Weiss et al, 2008 ) are respectively related to lung cancer and autism, that at 10q11.21 (Rees et al, 2016 ) is associated with schizophrenia, those at 1q21 (Grzasko et al, 2012 ) and 2q12.3 (Erickson et al, 2014 ) are associated with multiple myeloma, and those at 14q11.1 (Thean et al, 2018 ) and 18q21.1 (Druliner et al, 2018 ) are associated with colorectal cancer. CNV loss at 20q13.2 (Hidaka et al, 2000 ) is associated with colorectal cancer, that at 14q32.33 (Ledet et al, 2013 ) is associated with prostate cancer, that at 4q13.2 (Yang et al, 2008 ) is associated with osteoporosis, and that at 3q29 (Biamino et al, 2016 ) is related to autism.…”