Identification of specific susceptibility loci for the early-onset colorectal cancer
Abstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Metho...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-03-01
|
| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-023-01163-w |
| _version_ | 1797863921635295232 |
|---|---|
| author | Haoxue Wang Yimin Cai Meng Jin Chao Qun Huang Caibo Ning Siyuan Niu Linyun Fan Bin Li Ming Zhang Zequn Lu Xuesi Dong Zilin Luo Rong Zhong Heng Li Ying Zhu Xiaoping Miao Xiaojun Yang Jiang Chang Ni Li Jianbo Tian |
| author_facet | Haoxue Wang Yimin Cai Meng Jin Chao Qun Huang Caibo Ning Siyuan Niu Linyun Fan Bin Li Ming Zhang Zequn Lu Xuesi Dong Zilin Luo Rong Zhong Heng Li Ying Zhu Xiaoping Miao Xiaojun Yang Jiang Chang Ni Li Jianbo Tian |
| author_sort | Haoxue Wang |
| collection | DOAJ |
| description | Abstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Methods Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant. Results We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10−4), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32–2.02, P = 7.67×10−6). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2. Conclusions These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention. Graphical Abstract |
| first_indexed | 2024-04-09T22:43:24Z |
| format | Article |
| id | doaj.art-1609588152ef48cd85729c6ee2a228fb |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-09T22:43:24Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-1609588152ef48cd85729c6ee2a228fb2023-03-22T11:58:26ZengBMCGenome Medicine1756-994X2023-03-0115111910.1186/s13073-023-01163-wIdentification of specific susceptibility loci for the early-onset colorectal cancerHaoxue Wang0Yimin Cai1Meng Jin2Chao Qun Huang3Caibo Ning4Siyuan Niu5Linyun Fan6Bin Li7Ming Zhang8Zequn Lu9Xuesi Dong10Zilin Luo11Rong Zhong12Heng Li13Ying Zhu14Xiaoping Miao15Xiaojun Yang16Jiang Chang17Ni Li18Jianbo Tian19Department of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan UniversityDepartment of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyOffice of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeOffice of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Urology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan UniversityDepartment of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Wuhan UniversityDepartment of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and TechnologyOffice of Cancer Screening, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Epidemiology and Biostatistics, School of Public Health, TaiKang Center for Life and Medical Sciences, Wuhan University, Research Center of Public Health, Renmin Hospital of Wuhan UniversityAbstract Background The incidence of early-onset colorectal cancer (EOCRC; patients < 50 years old) has been rising rapidly, whereas the EOCRC genetic susceptibility remains incompletely investigated. Here, we aimed to systematically identify specific susceptible genetic variants for EOCRC. Methods Two parallel GWASs were conducted in 17,789 CRC cases (including 1490 EOCRC cases) and 19,951 healthy controls. A polygenic risk score (PRS) model was built based on identified EOCRC-specific susceptibility variants by using the UK Biobank cohort. We also interpreted the potential biological mechanisms of the prioritized risk variant. Results We identified 49 independent susceptibility loci that were significantly associated with the susceptibility to EOCRC and the diagnosed age of CRC (both P < 5.0×10−4), replicating 3 previous CRC GWAS loci. There are 88 assigned susceptibility genes involved in chromatin assembly and DNA replication pathways, mainly associating with precancerous polyps. Additionally, we assessed the genetic effect of the identified variants by developing a PRS model. Compared to the individuals in the low genetic risk group, the individuals in the high genetic risk group have increased EOCRC risk, and these results were replicated in the UKB cohort with a 1.63-fold risk (95% CI: 1.32–2.02, P = 7.67×10−6). The addition of the identified EOCRC risk loci significantly increased the prediction accuracy of the PRS model, compared to the PRS model derived from the previous GWAS-identified loci. Mechanistically, we also elucidated that rs12794623 may contribute to the early stage of CRC carcinogenesis via allele-specific regulating the expression of POLA2. Conclusions These findings will broaden the understanding of the etiology of EOCRC and may facilitate the early screening and individualized prevention. Graphical Abstracthttps://doi.org/10.1186/s13073-023-01163-wGWASEarly-onset CRCGenetic variantsPRSPOLA2 |
| spellingShingle | Haoxue Wang Yimin Cai Meng Jin Chao Qun Huang Caibo Ning Siyuan Niu Linyun Fan Bin Li Ming Zhang Zequn Lu Xuesi Dong Zilin Luo Rong Zhong Heng Li Ying Zhu Xiaoping Miao Xiaojun Yang Jiang Chang Ni Li Jianbo Tian Identification of specific susceptibility loci for the early-onset colorectal cancer Genome Medicine GWAS Early-onset CRC Genetic variants PRS POLA2 |
| title | Identification of specific susceptibility loci for the early-onset colorectal cancer |
| title_full | Identification of specific susceptibility loci for the early-onset colorectal cancer |
| title_fullStr | Identification of specific susceptibility loci for the early-onset colorectal cancer |
| title_full_unstemmed | Identification of specific susceptibility loci for the early-onset colorectal cancer |
| title_short | Identification of specific susceptibility loci for the early-onset colorectal cancer |
| title_sort | identification of specific susceptibility loci for the early onset colorectal cancer |
| topic | GWAS Early-onset CRC Genetic variants PRS POLA2 |
| url | https://doi.org/10.1186/s13073-023-01163-w |
| work_keys_str_mv | AT haoxuewang identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT yimincai identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT mengjin identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT chaoqunhuang identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT caiboning identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT siyuanniu identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT linyunfan identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT binli identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT mingzhang identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT zequnlu identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT xuesidong identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT zilinluo identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT rongzhong identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT hengli identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT yingzhu identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT xiaopingmiao identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT xiaojunyang identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT jiangchang identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT nili identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer AT jianbotian identificationofspecificsusceptibilitylocifortheearlyonsetcolorectalcancer |