Single Nucleotide Polymorphisms In The Tumor Progression Related Genes Are Associated With Prognosis In Colorectal Cancer And Late-stage Non-small Cell Lung Cancer

Single nucleotide polymorphism (SNP) is widely and stably distributed inhuman genome. SNP can reflect the genetic background of patients andindentify the difference of individuals. Meanwhile, SNP can achieve rapid,automatic and large-scale detection, which has broad prospects for theapplication of tumor prognosis evaluation.Colorectal cancer (CRC) is the third most commonly diagnosed cancer andthe fourth leading cause of cancer death, which is a serious threat to publichealth. Recent genome-wide association studies (GWAS) have identified severalcommon susceptibility loci associated with the risk of colorectal cancer (CRC).However, whether these loci affect clinical outcomes of CRC is not clear. In thisstudy, we genotyped26single nucleotide polymorphisms (SNPs) in tenGWAS-identified CRC susceptibility regions in510CRC patients and evaluatedtheir associations with survival and recurrence of CRC patients. Only one SNP,rs10318(15q13.3), was significantly associated with recurrence for patients withstage II disease. Three SNPs: rs10749971(11q23.1), rs961253(20p12.3), and rs355527(20p12.3) in two regions were significantly associated with recurrencefor patients with stage III disease. Five SNPs: rs961253(20p12.3),rs355527(20p12.3), rs4464148（18q21.1), rs6983267（8q24.21), and rs10505477(8q24.21) in three regions were significantly associated with survival forpatients with stage III disease. Cumulative effects of multiple unfavorablegenotypes were observed for recurrence and survival in patients with stage IIICRC. Interestingly，the host genes of rs10318(GREM1), rs961253(BMP2),rs355527(BMP2), and rs4464148(SMAD7) are all belong to the TGF-β signalingpathway, which suggested that gentic variations in the TGF-β signaling genesare associated with the survival of CRC patients who treated with5-FU basedchemotherapy. Our results suggest that cancer susceptibility loci may also affectthe prognosis and/or treatment response of patients with CRC.The VEGF-independent angiogenic signaling plays an important role in thedevelopment of colorectal cancer (CRC). However, their implication in theclinical outcome of CRC has not been reported. This study aimed to investigatethe association between genetic variations in several major VEGF-independentsignaling pathway genes and the overall survival of CRC patients. Wegenotyped seven single nucleotide polymorphisms (SNPs) in four importantVEGF-independent angiogenic genes (ANGPT1, AMOT, DLL4and ENG) in aChinese population with408CRC patients. One SNP, rs1954727in ANGPT1,was significantly associated with CRC overall survival. Compared to patientswith the homozygous wild-type genotype of rs1954727, those withheterozygous and homozygous variant genotypes exhibited a favorable overallsurvival with a hazard ratio (HR) of0.89(95%confidence interval [CI]0.55-1.43, p=0.623), and0.32(95%CI0.15-0.71, p=0.005), respectively (ptrend=0.008). In stratified analysis, this association remained significant inpatients receiving chemotherapy (p for trend=0.012), but not in those withoutchemotherapy. We further evaluated the effects of chemotherapy on CRCsurvival that was stratified by rs1954727genotypes. We found that chemotherapy resulted in a significantly better overall survival in the CRCpatients (HR=0.44,95%CI0.26-0.75, p=0.002), which was especiallyprominent in those patients with the heterozygous genotype of rs1954727(HR=0.45,95%CI0.22-0.92, p=0.028). In all, our data suggest that rs1954727in ANGPT1gene might be a prognostic biomarker for the overall survival ofCRC patients, especially in those receiving chemotherapy.Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortalityworldwide. Almost half NSCLC patients present with unresectable late-stage(stage IIIA/B or stage IV) disease in the United States. Regulator of G-proteinsignaling (RGS) plays an important role in the NSCLC progression. It isreported that some RGS polymorphisms are associated with familial lung cancersusceptibility. However, whether SNPs in RGS are associated with clinicaloutcome of NSCLC is still unknown. We selected95tagging single nucleotidepolymorphisms (SNPs) in17RGS genes and genotyped them in598late-stageNSCLC patients. Thirteen SNPs were significantly associated with overallsurvival. Among them, rs2749786of RGS12was most significant. Stratifiedanalysis by chemotherapy or chemoradiation further identified SNPs that wereassociated with overall survival in subgroups. Rs2816312of RGS1andrs6689169of RGS7were most significant in chemotherapy group andchemoradiotherapy group, respectively. A significant cumulative effect wasobserved when these SNPs were combined. Survival tree analyses identifiedpotential interactions between rs944343, rs2816312, and rs1122794in affectingsurvival time in patients treated with chemotherapy, while the genotype ofrs6429264affected survival in chemoradiation-treated patients. To ourknowledge, this is the first study to reveal the importance of RGS gene family inthe survival of late-stage NSCLC patients.