Association of MLH1 single nucleotide polymorphisms with clinical outcomes of first-line irinotecan-based chemotherapy in colorectal cancer.
ABSTRACT: Purpose:Several studies have proved that single nucleotide polymorphisms (SNPs) of mismatch repair system genes are closely related to the development of colorectal cancer (CRC) by causing microsatellite instability, while effects of the SNPs of MMR system-related genes on the clinical outcomes of cytotoxic chemotherapy are less understood. The aim of this study explored the influence of MLH1 SNPs on clinical outcomes of first-line irinotecan-based chemotherapy in CRC. Patients and methods:A total of 125 metastatic colorectal cancer (mCRC) patients who received first-line irinotecan-based chemotherapy (none of them combined with bevacizumab or cetuximab) were enrolled in this study. Blood samples or formalin-fixed paraffin-embedded tissues of study population were taken. DNA isolation and genotyping analyzed were obtained for potential functional polymorphisms of MLH1 rs1800734 by real-time PCR. Progression-free survival (PFS) was the primary endpoint and tumor response rate (RR) was the secondary endpoint of this study. Results:Of all the assessable population, the result showed no statistical difference among the three types SNPs of MLH1 rs1800734 (AA, AG, GG) for RR (P=0.859), and also without significant difference for AA + AG combined variants vs GG variant (P=0.849). The median PFS for AA, AG, and GG variants of MLH1 rs1800734 SNPs were 9.4 months, 7.0 months, and 6.9 months, respectively (log-rank P=0.031). Interestingly, compared with AA variant of MLH1 rs1800734 SNPs, GG variant showed a shorter PFS (HR: 3.49; 95 CI: 1.02-11.94; P=0.046). Furthermore, the median PFS of AA + AG combined variants and GG variant were 8.3 months and 6.9 months (log-rank P=0.037), and GG variant have a decreased trend with no significant difference (HR: 1.57; 95 CI: 0.98-2.53; P=0.061). Conclusion:The AA variant of MLH1 rs1800734 SNPs has a longer PFS in first-line irinotecan-based chemotherapy for mCRC patients, and the result needs to be further confirmed by prospective studies in the future.
Project description:Hepatocellular carcinoma (HCC) is a malignant cancer causing deleterious health effect worldwide, especially in China. So far clinical cure rate and long-term survival rate of HCC remains low. Most HCC patients after cancer resection have recurrence or metastasis within 5 years. This study aims to explore the genetic association of mutL homolog 1 (MLH1) polymorphisms with HCC risk and prognosis. Four candidate MLH1 polymorphisms, rs1800734, rs10849, rs3774343 and rs1540354 were studied from a hospital-based case-control study including 1,036 cases (HCC patients) and 1,036 controls (non-HCC patients) in Guangxi, China. All these SNPs interacted with environmental risk factors, such as HBV infection, alcohol intake and smoking in the pathogenesis of HCC. However, only rs1800734 had significant difference between cases and controls. Compared to the AA genotype, patients with AG, GG and AG/GG genotype of rs1800734 had an increased risk of HCC [ORs (95% CI) = 1.217 (1.074∼1.536), 1.745 (1.301∼2.591) and 1.291 (1.126∼1.687)] and a decreased survival time [co-dominant, HR (95% CI) = 1.553 (1.257∼1.920); dominant, HR (95% CI) = 2.207 (1.572∼3.100)]. Furthermore, we found that tumor number, tumor staging, metastasis and rs1800734 were associated with the overall survival of HCC patients by multivariate COX regression analysis. No significant difference was found between the other three MLH1 polymorphisms with HCC risk and prognosis. Our study suggests MLH1 SNP, rs1800734 as a new predictor for poor prognosis of HCC patients.
Project description:The MLH1 promoter polymorphism rs1800734 is associated with MLH1 CpG island hypermethylation and expression loss in colorectal cancer (CRC). Conversely, variant rs1800734 is associated with MLH1 shore, but not island, hypomethylation in peripheral blood mononuclear cell DNA. To explore these distinct patterns, MLH1 CpG island and shore methylation was assessed in CRC cell lines stratified by rs1800734 genotype. Cell lines containing the variant A allele demonstrated MLH1 shore hypomethylation compared to wild type (GG). There was significant enrichment of transcription factor AP4 at the MLH1 promoter in GG and GA cell lines, but not the AA cell line, by chromatin immunoprecipitation studies. Preferential binding to the G allele was confirmed by sequencing in the GA cell line. The enhancer-associated histone modification H3K4me1 was enriched at the MLH1 shore; however, H3K27ac was not, indicating the shore is an inactive enhancer. These results demonstrate the role of variant rs1800734 in altering transcription factor binding as well as epigenetics at regions beyond the MLH1 CpG island in which it is located.
Project description:Tumor hypoxia is common in a number of solid tumor types including gastric cancer, and is associated with treatment resistance and poor prognosis. The present study aimed to investigate the function of hypoxia-associated genetic polymorphisms in predicting treatment response and survival in patients with metastatic gastric cancer (MGC) treated with EOF (oxaliplatin and 5-fluorouracil combined with epirubicin) as first-line chemotherapy. The present retrospective study enrolled 108 Chinese patients with MGC receiving EOF as first-line chemotherapy, and genotyped six single nucleotide polymorphisms (SNPs) in four hypoxia-associated genes [myoglobin (MB) rs7292 and rs7293, ATP Binding Cassette Subfamily G Member 2 rs2231142, MutL homolog 1 (MLH1) rs1800734 and rs9852810, and Poly(ADP-Ribose) Polymerase 1 rs1136410]. The results of the present study indicated that the CT/TT genotype of MB rs7292, as well as the GG genotype of MLH1 rs9852810, were independent favorable predictive factors of progression-free survival [PFS; MB rs7292: hazard ratio (HR)=0.135, 95% confidence interval (CI)=0.057-0.321, P<0.001; MLH1 rs9852810: HR=0.494, 95% CI=0.267-0.913, P=0.024). Using a prognostic index based on the favorable SNPs for PFS (MB rs7292 CT/TT genotype, and MLH1 rs9852810 GG genotype), patients were classified into a low-risk group (involving one or two of the two SNPs) and a high-risk group (involving neither of the two SNPs), with a PFS of 180.0 and 117.0 days, respectively (P=0.002). The results of the present study demonstrated that the CT/TT genotype of MB rs7292 and the GG genotype of MLH1 rs9852810 were independent favorable predictive factors of PFS in patients with MGC treated with EOF. Identification of those SNPs in blood samples may allow for the prediction of the short-term efficacy of first-line EOF treatment in patients with MGC.
Project description:<h4>Background</h4>Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens.<h4>Materials and methods</h4>Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing.<h4>Results</h4>Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival.<h4>Conclusions</h4>Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.
Project description:Head and neck squamous cell carcinoma (HNSCC) is treated with cisplatin (CDDP) and radiotherapy (RT), and distinct results are observed among patients with similar clinicopathological aspects. This prospective study aimed to investigate whether MLH1 c.-93G>A (rs1800734), MSH2 c.211+9C>G (rs2303426), MSH3 c.3133G>A (rs26279), EXO1 c.1765G>A (rs1047840), and EXO1 c.2270C>T (rs9350) single nucleotide polymorphisms (SNPs) of the mismatch repair (MMR) pathway change side effects and response rate of 90 HNSCC patients treated with CDDP and RT. DNA from peripheral blood was analyzed by PCR-based methods to obtain genotypes. It was observed 4.27-fold and 4.69-fold increased risks of presenting pronounced nephrotoxicity with treatment in patients with MSH3 GG and EXO1 rs9350 CC genotypes compared with patients with GA or AA and CT or TT genotypes, respectively. MSH3 GG or GA and GT haplotype of EXO1 rs1047840 and rs9350 SNPs conferred to patients 10.29 and 4.00 more chances of presenting pronounced ototoxicity after treatment than MSH3 AA genotype and other EXO1 haplotypes, respectively. Patients with EXO1 rs1047840 GA or AA genotype and AC haplotype of EXO1 rs1047840 and rs9350 SNPs had both 9.55-fold increased risks of achieving partial response or stable disease instead of complete remission after treatment than patients with EXO1 GG genotype and other EXO1 haplotypes, respectively. For the first time, our data show preliminary indication that inherited alterations of DNA MMR pathway, related to MSH3 rs26279, EXO1 rs1047840 and EXO1 rs9350 SNPs, modify toxicity and response to chemoradiation in HNSCC, and may contribute to future personalized treatment of patients.
Project description:OBJECTIVE:Polymorphisms in XPG were considered to contribute to the clinical outcome of patients receiving platinum drug chemotherapy. We investigated the impact of several potential SNPs of XPG on the efficacy of platinum-based chemotherapy in NSCLC patients. METHODS:A total of 433 patients were consecutively selected between Nov. 2006 and Dec. 2007, and were followed-up up to Nov. 2011. The genotyping of six SNPs (rs2296147, rs751402, rs873601, rs4150375, rs17655 and rs2094258) were genotyped using the Taqman real-time PCR method with a 7900 HT sequence detector system. RESULTS:Patients carrying CT+TT genotype of rs2296147 had a significantly longer median PFS (17.5 months) and OS (26.8 months) than CC genotype. Hazard ratio (HR) for PFS and OS in patients with CT+TT genotype of rs2296147 was respectively 0.73(0.51-0.97) and 0.66(0.48-0.99) when compare CC genotype, respectively. Similarly, patients with rs2094258 AG+GG genotype had a longer median progression time (18.4 months) and overall survival time (27.3 months) when compared with those with AA genotype, and HRs(95% CI) for PFS and OS were 0.44(0.34-0.78) and 0.51(0.39-0.82), respectively. CONCLUSIONS:Our study suggests rs2296147 CT+TT and rs2094258 AG+GG genotypes contribute to the better survival of NSCLC. Our study provides significant information on role of prognostic value of XPG SNPs, and detecting of XPG could be used as predictive markers toward individualizing NSCLC treatment strategies.
Project description:Platinum agents induce cancer cell death through BCL2-dependent intrinsic apoptotic pathway and are commonly used as anti-tumor drug. In this study, we evaluated whether single nucleotide polymorphism (SNPs) of BCL2 can affect the overall survival (OS) and progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy. We genotyped 48 SNPs of BCL2 gene by Illumina Custom Designed Chip in 972 advanced NSCLC patients treated with platinum-based chemotherapy. We evaluated the relationship between genotype/haplotype/diplotype and OS/PFS by COX regression analysis. As a result, five SNPs, rs949037, rs3810027, rs4987739, rs4987726 and rs7226979, were significantly associated with overall survival time in 972 NSCLC patients after platinum-based chemotherapy. rs1381547 and rs8083946 were associated with progression-free survival. As representative, the G allele of rs949037 was associated with longer OS in NSCLC patients with platinum-based chemotherapy. Patients with GG or AG genotype showed a 19.9 months mOS vs AA genotype 14.2 months mOS (HR: 1.38, 95% CI: 1.11-1.72, p=0.004). In further analysis, rs949037 was found to predominantly contribute to the OS of patients with platinum-tubulin-targeting drugs, moreover, the GG genotype of rs949037 showed an 8.5 months longer OS compared with the unfavorable AA genotype (mOS: 21.36 vs 12.83, HR=0.70, 95% CI: 0.52-0.94, p=0.000). To conclude, polymorphisms of BCL2 gene may have an impact on the OS of platinum-based chemotherapy in NSCLC patients, which may be prognostic biomarkers of chemotherapy if validated in larger studies.
Project description:Both colorectal (CRC, 15%) and endometrial cancers (EC, 30%) exhibit microsatellite instability (MSI) due to MLH1 hypermethylation and silencing. The MLH1 promoter polymorphism, rs1800734 is associated with MSI CRC risk, increased methylation and reduced MLH1 expression. In EC samples, we investigated rs1800734 risk using MSI and MSS cases and controls. We found no evidence that rs1800734 or other MLH1 SNPs were associated with the risk of MSI EC. We found the rs1800734 risk allele had no effect on MLH1 methylation or expression in ECs. We propose that MLH1 hypermethylation occurs by different mechanisms in CRC and EC.
Project description:PURPOSE: ERCC1 and ERCC2 play critical roles in the nucleotide excision repair pathway that effectively repairs DNA damage induced by chemotherapeutic agents. Therefore, functional single nucleotide polymorphisms (SNPs) in these genes could have an impact on clinical outcomes in cancer patients who received chemotherapy. However, few studies have simultaneously investigated the roles of ERCC1 and ERCC2 SNPs in clinical outcomes in gastric cancer patients. EXPERIMENTAL DESIGN: We genotyped by the TaqMan assay three common, potentially functional ERCC1 (rs3212986) and ERCC2 SNPs (rs13181 and rs1799793) in 360 gastric cancer patients. We used both Kaplan-Meier tests and Cox proportional hazards models to evaluate the effects of ERCC1 and ERCC2 genotypes and haplotypes on clinical outcomes. RESULTS: We found that, compared with ERCC2 rs1799793 GG+AG genotypes, the homozygous variant AA genotype was associated with significantly poorer overall survival (OS) (AA vs. GG+AG, log-rank P=0.012) and significantly higher risk of death (AA vs. GG+AG, Adjusted hazards ratio [HR] 2.13; 95% CI, 1.28 to 3.56; P=0.004). In combined analyses, patients with any one of the three unfavorable genotypes (i.e. ERCC1 rs3212986 TT, ERCC2 rs13181 GG and rs1799793 AA) had statistically significant hazards of poor prognosis (Adjusted HR, 1.54; 95% CI, 1.06 to 2.25; P=0.025), compared with those without any unfavorable genotypes. Furthermore, the haplotype A-G-G (rs1799793/rs13181/rs3212986) had a significant impact on OS (Adjusted HR, 1.57; 95% CI, 1.11 to 2.21; P=0.011), compared with the common haplotype G-T-G. CONCLUSION: ERCC1 and ERCC2 functional SNPs may jointly affect OS in Caucasian gastric cancer patients. Additional large prospective studies are essential to confirm our findings.
Project description:BACKGROUND:We aimed to investigate the association between single-nucleotide polymorphisms (SNP) in mismatch repair (MMR) pathway genes and survival in patients with oral squamous cell carcinoma (OSCC) who received adjuvant concurrent chemoradiotherapy (CCRT). METHODS:Using the Sequenom iPLEX MassARRAY system, five SNPs in four major MMR genes were genotyped in 319 patients with OSCC who received CCRT treatment. Kaplan-Meier survival curves and Cox proportional hazard regression models were used to assess overall survival (OS) and disease-free survival (DFS) among MMR genotypes. RESULTS:The results of Kaplan-Meier survival analysis revealed that the MutS homolog 2 (MSH2) rs3732183 polymorphism showed a borderline significant association with DFS (log-rank p = 0.089). Participants with the MSH2 rs3732183 GG genotype exhibited a relatively low risk of recurrence (hazard ratio (HR) = 0.45; 95% confidence interval (CI) = 0.22-0.96; p = 0.039). In addition, the MutL homolog 1 (MLH1) rs1800734 GG genotype carriers exhibited higher OS (HR = 0.52, 95% CI = 0.27-1.01; p = 0.054) and DFS (HR = 0.49, 95% CI = 0.26-0.92; p = 0.028) rates. CONCLUSIONS:Our results indicated that the GG genotypes of MSH2 rs3732183 and MLH1 rs1800734 are associated with relatively high survival in OSCC patients treated using adjuvant CCRT. These polymorphisms may serve as prognosis predictors in OSCC patients.