期刊
AMERICAN JOURNAL OF CANCER RESEARCH
卷 11, 期 4, 页码 1522-+出版社
E-CENTURY PUBLISHING CORP
关键词
SLF1; marker; oxaliplatin-based adjuvant chemotherapy; colon cancer
类别
资金
- International Science & Technology Cooperation Program of China [2013DFE33110]
- China National Major Project for New Drug Innovation [2017ZX09304015]
A three-stage study framework identified a stable association of rs6891545C > A polymorphism in the SLF1 gene with the response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, suggesting that patients carrying the A allele had better treatment response.
Response to oxaliplatin-based adjuvant chemotherapy varies among patients with stage II and III colon cancer; however, genetic alterations associated with this response remain incompletely characterized. A three-stage analytical framework, including the discovery, validation, and replication stages, was designed to explore genetic alterations modulating response to oxaliplatin-based chemotherapy in adjuvant setting among patients with stage II and III colon cancer receiving complete resection of tumor. Except for several somatic mutated genes, such as ARSD and ACE, showing less definitive associations with response to oxaliplatin-based adjuvant chemotherapy, we found stable associations of rs6891545C > A polymorphism in SLF1 gene, a key component of DNA damage response system, with the response across all three stages. Patients with rs6891545 A allele had significantly lower risk of poor responsiveness to oxaliplatin-based adjuvant chemotherapy at both discovery and validation stages, compared with ones possessing wild homozygous genotype CC (discovery stage: odds ratio, 0; 95% CI, 0-0.48; P = .005; validation stage: odds ratio, 0.33; 95% CI, 0.11-0.99; P=.048). In the replication cohort, rs6891545 A allele was confirmed to be strongly associated with improved DFS (hazard ratio, 0.43; 95% CI, 0.23-0.81; P=.007). Notably, the improvement persisted after controlling for sex, age, tumor location, differentiation, and stage (hazard ratio, 0.42; 95% CI, 0.22-0.80; P=.009). Moreover, in silico analysis unraveled strong impact of rs6891545 A allele on local secondary structure of SLF1 mRNA, possibly leading to low SLF1 protein expression. We conclude that the rs6891545C > A polymorphism may serve as an independent marker of response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, with improved clinical benefit observed in patients with the A allele possibly attributable to low expression of SLF1 protein resulting in deficient DNA repair capacity.
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