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Two novel colorectal cancer risk loci in the region on chromosome 9q22.32.

ABSTRACT: Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in the region, comparing Swedish CRC cases (2664) and controls (4782). Two overlapping haplotypes were suggested. One 10-SNP haplotype was indicated in familial CRC (OR 1.4, p = 0.00005) and one 25-SNP haplotype was indicated in sporadic CRC (OR 2.2, p = 0.0000012). The allele frequencies of the 10-SNP and the 25-SNP haplotypes were 13.7% and 2.5% respectively and both included one RNA, RP11-332M4.1 and RP11-l80l4.2, in the non-overlapping regions. The sporadic 25-SNP haplotype could not be studied further, but the familial 10-SNP haplotype was analyzed in 61 additional CRC families, and 6 of them were informative for all markers and had the risk haplotype. Targeted sequencing of the 10-SNP region in the linked families identified one variant in RP11-332M4.1, suggestive to confer the increased CRC risk on this haplotype. Our results support the presence of two loci at 9q22.32, each with one RNA as the putative cause of increased CRC risk. These RNAs could exert their effect through the same, or different, genes/pathways, possibly through the regulation of neighboring genes, such as PTCH1, FANCC, DKFZP434H0512, ERCC6L2 or the processed transcript LINC00046.

SUBMITTER: Thutkawkorapin J

PROVIDER: S-EPMC5834248 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Two novel colorectal cancer risk loci in the region on chromosome 9q22.32.

Thutkawkorapin Jessada J Mahdessian Hovsep H Barber Tom T Picelli Simone S von Holst Susanna S Lundin Johanna J Valle Laura L Kontham Vinaykumar V Liu Tao T Nilsson Daniel D Jiao Xiang X Lindblom Annika A

Oncotarget 20180129 13

Highly penetrant cancer syndromes account for less than 5% of all cases with familial colorectal cancer (CRC), and other genetic contribution explains the majority of the genetic contribution to CRC. A CRC susceptibility locus on chromosome 9q has been suggested. In this study, families where risk of CRC was linked to the region, were used to search for predisposing mutations in all genes in the region. No disease-causing mutation was found. Next, haplotype association studies were performed in ...[more]

PMID: 29541405

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Project description:BackgroundPrevious genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.MethodsWe conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.ResultsThe discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.ConclusionsThis study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Project description:Background & aimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10(-8) to 1.24 × 10(-12): 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%-18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

Dataset Information

Two novel colorectal cancer risk loci in the region on chromosome 9q22.32.

Publications

Two novel colorectal cancer risk loci in the region on chromosome 9q22.32.

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