Genetic Variations Associated With Colorectal Cancer And Non-Hodgkin Lymphoma Susceptibility And Adverse Events In Rectal Cancer Patients Treated With Adjuvant Concurrent Chemoradiotherapy

The incidences of colorectal cancer (CRC) and non-Hodgkin lymphoma (NHL) have been increasing in China in recent years. It has been recognized that genetic variations including single nucleotide polymorphisms (SNPs) are important factors contributing to the individual susceptibility to cancer and adverse events (AEs) in chemoradiotherapy (CRT). This study sought to identify genetic variations that may be associated with susceptibility to CRC and NHL, acute AEs during the treatment of rectal cancer.SNPs located at3’untranslated region of genes which modulate gene expression by affecting certain microRNA’s binding ability to their transcripts, might have effect on the expression of target gene and therefore influencing individual susceptibility to cancer. Based on this hypothesis, we selected five SNPs within microRNA target sites of genes dysregulated in CRC, and then investigated their associations with CRC susceptibility in2003patients and2016controls. Genotypes were detected by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). The associations between the SNPs and CRC susceptibility were indicated by odds ratios (ORs) and95%confidence intervals (CIs), which were estimated by multivariate logistic regression. Luciferase reporter assay and real-time PCR analysis were conducted to investigate the function of SNPs. We identified5SNPs (KRAS rs1137188, KRAS rs7973450, KRAS rs9266, KRAS rs712and TLR4rs7873784) that might affect the binding ability to microRNA. Case-control study showed that TLR4rs7873784C allele was associated with significantly decreased risk for CRC, compared with the GG genotype. Individuals carrying at least one C allele (CC or GC genotype) showed a decreased risk for CRC (OR=0.70,95%CI,0.59-0.84; P=1.35×10-4). Biochemical assays indicated TLR4as a target of hsa-let-7d-3p and hsa-let-7e-3p, rs7873784G>C change resulted in altered regulation of TLR4expression. These consistant results support that TLR4rs7873784G>C variation was associated with susceptibility to CRC.Postoperative concomitant CRT is the standard of care for stage II and III rectal cancer patients, which can improve the local control rate and long-term survival rate. Clinical studies found variations of benefits and AEs in patients of this treatment option. Hence, identification of biomarkers that distinguish patients who respond to CRT and benefit from more aggressive treatments is required. Evidence has been accumulated to show that genetic variations may also play important roles in the occurrence of AEs. We selected45tag SNPs in12genes involved in capecitabine metabolism and DNA damage response, and then examined their associations with occurrence of acute AEs in rectal cancer patients treated with capecitabine-based CRT. Four hundred and seventy-seven patients with stage Ⅱ and Ⅲ rectal cancer involved in prospective, non-randomize phase Ⅲ trials received postoperative CRT of capecitabine with or without oxaliplatin. AEs were graded according to the Common Terminology Criteria for Adverse Events v3.0. Genotypes were detected by the Sequenom MassARRAY system. The associations between the SNPs and occurrence of acute AEs were indicated by ORs and95%CIs, which were estimated by multivariate logistic regression. With false discovery rate correction,3SNPs (TP rs11479, ATM rs189037and ATM rs227092) were associated with decreased risk of leukopenia (grade>2), with the ORs of0.56(95%CI,0.38-0.81; P=0.003),0.62(95%CI,0.46-0.85; P=0.003) and0.57(95%CI,0.42-0.78; P<0.001) for rs11479, rs189037and rs227092, respectively, calculated using an additive model. Furthermore, TP rs11479was associated with decreased risk of leukopenia only in patients with capecitabine CRT treatment.The incidence and subtype proportion of NHL between Chinese population and Caucasian populations are substantially different. We evaluated the effects of genome-wide association study (GWAS)-identified genetic variants for NHL in a Chinese population. Previous GWAS have identified that fifteen SNPs were associated with risk of NHL subtypes. We assessed the associations of these SNPs with NHL risk in a case-control study consisting of792cases and1542controls derived from Chinese Han population. Genotypes were detected by PCR-RFLP. The associations between the SNPs and NHL susceptibility were indicated by ORs and95%CIs, which were estimated by multivariate logistic regression. We found that the allele frequencies of the15SNPs in our study population significantly differed from those in Caucasian populations, with rs13397985, rs735665and rs11083846being extremely rare in Chinese Han population. Only two variants (IRF4rs872071and HLA-DQB1rs2647012) were significantly associated with NHL risk in Chinese, with the ORs of1.20(95%CI,1.05-1.38;P=0.009) and1.20(95%CI,1.03-1.39; P=0.018) for rs872071and rs2647012, respectively, calculated using an additive model.In conclusion, the genetic variation in TLR4rs7873784G>C influences TLR4expression by affecting the binding ability of microRNA, and may be associated with individual susceptibility to CRC. The genetic variations of ATM and. TP influence the occurrence of leukopenia during the treatment of capecitabine-based postoperative CRT in the rectal cancer patients. IRF4rs872071and HLA-DQB1rs2647012were significantly associated with NHL risk in Chinese. The results of NHL susceptibility indicate a substantial different genetic background for susceptibility to NHL among the different ethnic populations. Our findings may contribute to better understanding the development of CRC and NHL. This study might be helpful to clarify the effects of genetic variants on the individual’s variation of the AEs of CRT, which in turn might provide evidence for future studies on individualized CRT of rectal cancer.