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Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer.

ABSTRACT: Colorectal cancer (CRC) is a common malignant tumor of the digestive system worldwide, associated with hereditary genetic features. CRC with a Mendelian genetic predisposition accounts for approximately 5-10% of total CRC cases, mainly caused by a single germline mutation of a CRC susceptibility gene. The main subtypes of hereditary CRC are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). With the rapid development of genetic testing methods, especially next-generation sequencing technology, multiple genes have now been confirmed to be pathogenic, including DNA repair or DNA mismatch repair genes such as APC, MLH1, and MSH2. Since familial CRC patients have poor clinical outcomes, timely clinical diagnosis and mutation screening of susceptibility genes will aid clinicians in establishing appropriate risk assessment and treatment interventions at a personal level. Here, we systematically summarize the susceptibility genes identified to date and the potential pathogenic mechanism of HNPCC and FAP development. Moreover, clinical recommendations for susceptibility gene screening, diagnosis, and treatment of HNPCC and FAP are discussed.

SUBMITTER: Liu Q

PROVIDER: S-EPMC6360424 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer.

Liu Qiang Q Tan Yue-Qiu YQ

Journal of Cancer 20190101 3

Colorectal cancer (CRC) is a common malignant tumor of the digestive system worldwide, associated with hereditary genetic features. CRC with a Mendelian genetic predisposition accounts for approximately 5-10% of total CRC cases, mainly caused by a single germline mutation of a CRC susceptibility gene. The main subtypes of hereditary CRC are hereditary non-polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). With the rapid development of genetic testing methods, especiall ...[more]

PMID: 30719162

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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

Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer.

Publications

Advances in Identification of Susceptibility Gene Defects of Hereditary Colorectal Cancer.

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