The Largest Chinese Cohort Study Indicates Homologous Recombination Pathway Gene Mutations as Another Major Genetic Risk Factor for Colorectal Cancer with Heterogeneous Clinical Phenotypes  

作　　者：Yun Xu Kai Liu Cong Li Minghan Li Fangqi Liu Xiaoyan Zhou Menghong Sun Megha Ranganathan Liying Zhang Sheng Wang Xin Hu Ye Xu 

机构地区：[1]Department of Colorectal Surgery,Fudan University Shanghai Cancer Center,Shanghai,P.R.China [2]Department of Pathology,Fudan University Shanghai Cancer Center,Shanghai,P.R.China [3]Department of Pathology,Tissue Bank,Fudan University Shanghai Cancer Center,Shanghai,P.R.China [4]Department of Medicine,Memorial Sloan Kettering Cancer Center,New York,NY,USA [5]Department of Pathology and Laboratory Medicine,David Geffen School of Medicine,University of California,Los Angeles,CA,USA [6]Precision Cancer Medical Center,Fudan University Shanghai Cancer Center,Shanghai,P.R.China

出　　处：《Research》2024年第3期191-203,共13页研究（英文）

基　　金：the Science and Technology Commission of Shanghai Municipality(20DZ1100101).

摘　　要：While genetic factors were associated with over 30% of colorectal cancer (CRC) patients, mutations in CRC-susceptibility genes were identified in only 5% to 10% of these patients. Besides, previous studies on hereditary CRC were largely designed to analyze germline mutations in patients with single genetic high-risk factor, which limited understanding of the association between genotype and phenotypes. From January 2015 to December 2018, we retrospectively enrolled 2,181 patients from 8,270 consecutive CRC cases, covering 5 categories of genetic high-risk factors. Leukocyte genomic DNA was analyzed for germline mutations in cancer predisposition genes. The germline mutations under each category were detected and analyzed in association with CRC susceptibility, clinical phenotypes, and prognoses. A total of 462 pathogenic variants were detected in 19.3% of enrolled CRC patients. Mismatch repair gene mutation was identified in 9.1% of patients, most prevalent across all high-risk groups. Homologous recombination (HR) gene mutations were detected in 6.5% of cases, penetrated in early-onset and extra-colonic cancer risk groups. Mutations in HR genes, including BARD1, RAD50, and ATM, were found to increase CRC risk with odds ratios of 2.8-, 3.1-, and 3.1-fold, respectively. CRC patients with distinct germline mutations manifested heterogeneous phenotypes in clinicopathology and long-term prognoses. Thus, germline mutation screenings should be performed for CRC patients with any of those genetic risk factors. This study also reveals that HR gene mutations may be another major driver for increased CRC risk.

关 键 词：SUSCEPTIBILITY CATEGORY MAJOR 

分 类 号：R735.34[医药卫生—肿瘤]