Identification of genes expressed by immune cells of the colon that are regulated by colorectal cancer-associated variants.

A locus on human chromosome 11q23 tagged by marker rs3802842 was associated with colorectal cancer (CRC) in a genome-wide association study; this finding has been replicated in case-control studies worldwide. In order to identify biologic factors at this locus that are related to the etiopathology of CRC, we used microarray-based target selection methods, coupled to next-generation sequencing, to study 103 kb at the 11q23 locus. We genotyped 369 putative variants from 1,030 patients with CRC (cases) and 1,061 individuals without CRC (controls) from the Ontario Familial Colorectal Cancer Registry. Two previously uncharacterized genes, COLCA1 and COLCA2, were found to be co-regulated genes that are transcribed from opposite strands. Expression levels of COLCA1 and COLCA2 transcripts correlate with rs3802842 genotypes. In colon tissues, COLCA1 co-localizes with crystalloid granules of eosinophils and granular organelles of mast cells, neutrophils, macrophages, dendritic cells and differentiated myeloid-derived cell lines. COLCA2 is present in the cytoplasm of normal epithelial, immune and other cell lineages, as well as tumor cells. Tissue microarray analysis demonstrates the association of rs3802842 with lymphocyte density in the lamina propria (p = 0.014) and levels of COLCA1 in the lamina propria (p = 0.00016) and COLCA2 (tumor cells, p = 0.0041 and lamina propria, p = 6 × 10(-5)). In conclusion, genetic, expression and immunohistochemical data implicate COLCA1 and COLCA2 in the pathogenesis of colon cancer. Histologic analyses indicate the involvement of immune pathways

Colon and Rectal Cancer Survival by Tumor Location and Microsatellite Instability: The Colon Cancer Family Registry

Cancers in the proximal colon, distal colon, and rectum are frequently studied together; however, there are biological differences in cancers across these sites, particularly in the prevalence of microsatellite instability

Association between hMLH1 hypermethylation and JC virus (JCV) infection in human colorectal cancer (CRC)

Incorporation of viral DNA may interfere with the normal sequence of human DNA bases on the genetic level or cause secondary epigenetic changes such as gene promoter methylation or histone acetylation. Colorectal cancer (CRC) is the second leading cause of cancer mortality in the USA. Chromosomal instability (CIN) was established as the key mechanism in cancer development. Later, it was found that CRC results not only from the progressive accumulation of genetic alterations but also from epigenetic changes. JC virus (JCV) is a candidate etiologic factor in sporadic CRC. It may act by stabilizing β-catenin, facilitating its entrance to the cell nucleus, initialing proliferation and cancer development. Diploid CRC cell lines transfected with JCV-containing plasmids developed CIN. This result provides direct experimental evidence for the ability of JCV T-Ag to induce CIN in the genome of colonic epithelial cells. The association of CRC hMLH1 methylation and tumor positivity for JCV was recently documented. JC virus T-Ag DNA sequences were found in 77% of CRCs and are associated with promoter methylation of multiple genes. hMLH1 was methylated in 25 out of 80 CRC patients positive for T-Ag (31%) in comparison with only one out of 11 T-Ag negative cases (9%). Thus, JCV can mediate both CIN and aberrant methylation in CRC. Like other viruses, chronic infection with JCV may induce CRC by different mechanisms which should be further investigated. Thus, gene promoter methylation induced by JCV may be an important process in CRC and the polyp-carcinoma sequence

cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue

Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes

Colorectal cancer microsatellite instability

grantor: University of Toronto'Background'. Colorectal cancer is the third most common cancer in both sexes and the second leading cause of cancer-related deaths in Canada. Microsatellite DNA sequences, common throughout the human genome, are subject to high rates of mutation in approximately 15% of colorectal cancers due to deficiency in DNA mismatch repair. Mutations of the 'Adenomatous Polyposis Coli' ('APC') gene are thought to initiate colorectal neoplasia. The 'APC I1307K' polymorphism, common in the Ashkenazi Jewish population, contains an (A)8 microsatellite repeat. The clinical relevance of mismatch repair deficiency and microsatellite instability in colorectal cancer is incompletely understood, as is the cancer risk of the 'APC I1307K' polymorphism. 'Methods'. Tumors from a population-based series of 607 young patients with colorectal cancer from were screened for microsatellite instability and 476 Ashkenazi Jewish patients with colorectal neoplasms were screened for the 'APC I1307K ' polymorphism. 'Results'. High-frequency microsatellite instability (MSI-H) was observed in 17% of the cancers from the population-based series. Patients with MSI-H colorectal cancers were found to have significantly better survival in multivariate analysis and MSI-H cancers were less likely to metastasize after controlling for the extent of tumor invasion. The ' APC I1307K' polymorphism was present in more than 10% of Ashkenazi Jewish patients with colorectal neoplasia. The (A)8 microsatellite sequence of the 'APC I1307K' polymorphism was subject to a very high rate of somatic mutation by a mechanism apparently not related to mismatch repair deficiency. An additional polymorphism, 'APC E1317Q ', was identified in this series, but did not appear to be associated with a significant risk for colorectal neoplasia. 'Conclusions'. MSI-H is relatively common in colorectal cancers and defines a distinct disease subtype with an improved survival and a decreased risk of metastasis. The ' APC I1307K' polymorphism is a risk factor for colorectal neoplasia due to somatic mutation of the (A)8 polymorphic microsatellite sequence.Ph.D

Inherited Colorectal Cancer Syndromes

Colorectal cancer is common in the Western world; ~5% of individuals diagnosed with colorectal cancer have an identifiable inherited genetic predisposition to this malignancy. Genetic testing and rational clinical management recommendations currently exist for the management of individuals with a variety of colorectal cancer syndromes, including hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome), familial adenomatous polyposis (FAP), MYH-associated polyposis (MAP), and the hamartomatous polyposis syndromes (Peutz–Jeghers, juvenile polyposis, and Cowden disease). In addition to colorectal neoplasia, these syndromes frequently predispose carriers to a variety of extracolonic cancers. The elucidation of the genetic basis of several colorectal cancer predisposition syndromes over the past two decades has allowed for better management of individuals who are either affected with, or at-risk for inherited colorectal cancer syndromes. Appropriate multidisciplinary management of these individuals includes genetic counseling, genetic testing, clinical screening, and treatment recommendations