Value Of Single Nucleotide Polymorphisms Research Articles

Preoperative chemosensitivity testing as Predictor of Treatment benefit in Adjuvant stage III colon cancer (PePiTA): Protocol of a prospective BGDO (Belgian Group for Digestive Oncology) multicentric study

BackgroundSurgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available.Identifying which patients are unlikely to respond to adjuvant chemotherapy from among those who are eligible for such treatment would be a major step towards treatment personalization. It would spare such patients from unnecessary toxicities and would improve the allocation of societal healthcare resources.Methods/designPePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer.The study’s primary objective is to examine the ability of PET/CT-assessed tumor FDG uptake after one course of preoperative chemotherapy to predict the outcome of adjuvant therapy, as measured by 3-year disease-free survival.Secondary objectives are to examine the predictive value of changes in PET/CT-assessed tumor FDG uptake on overall survival, to define the best cut-off value of FDG uptake for predicting treatment outcome, and to analyse the cost-effectiveness of such preoperative chemo-sensitivity testing.At study planning, exploratory translational research objectives were 1) to assess the predictive value of circulating tumor cells for disease-free survival, 2) to examine the predictive value of single nucleotide polymorphisms for disease-free survival with respect to genes related either to toxicity or to drug targets, 3) to assess genomic rearrangements associated with response or resistance to FOLFOX treatment, 4) to identify an immunologic signature associated with metabolic tumor response to FOLFOX therapy and, finally, 5) to create a bank of frozen tumor samples for future studies.DiscussionPePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer.EudraCT number2009-011445-13Trial registrationClinicalTrials.gov number, NCT00994864

Prognostic value of single nucleotide polymorphisms of candidate genes associated with inflammation in early stage breast cancer

To examine the role of germline genetic variations in inflammatory pathways as modifiers of time to recurrence (TTR) in patients with early stage breast cancer (BC), DNA from 997 early stage BC patients was genotyped for 53 tagging single nucleotide polymorphisms (SNPs) in 12 genes involved in inflammation. SNPs were analyzed separately for Caucasians versus African-Americans and Hispanics. Cox proportional hazards models were used to evaluate the association between SNPs in the inflammatory genes and TTR, adjusted for clinical and pathologic covariates. In univariable analyses of Caucasian women, the homozygous genotype of 12 SNPs, including 6 NFKB1 SNPs, 4 IL4 SNPs, and 2 IL13 SNPs, were significantly associated with a decrease in TTR compared with the heterozygous and/or corresponding homozygous genotype (P < 0.05). The significant NFKB1 and IL4 SNPs were in an area of high linkage disequilibrium (D' > 0.8). After adjusting for stage, age, and treatment, carriage of the homozygous genotypes for NFKB1 rs230532 and IL13rs1800925 were independently associated with a shorter TTR (P = 0.001 and P = 0.034, respectively). In African-American and Hispanic patients, expression of NFKB1 rs3774932, TNFrs1799964, and IL4rs3024543 SNPs were associated with a shorter TTR in univariable model. Only NFKB1 rs3774932 (P = 0.02) and IL4Rrs3024543 (P = 0.03) had independent prognostic value in the multivariable model These data support the existence of host genetic susceptibility as a component in recurrence risk mediated by pro-inflammatory and immune factors, and suggest the potential for drugs which modify immune responses and inflammatory genes to improve prognosis in early stage BC.

Evaluation of Clinical Value of Single Nucleotide Polymorphisms of Dihydropyrimidine Dehydrogenase Gene to Predict 5-Fluorouracil Toxicity in 60 Colorectal Cancer Patients in China

Dihydropyrimidine dehydrogenase (DPD) activity could be affected by single nucleotide polymorphisms (SNPs), resulting in either no effect, partial or complete loss of DPD activity. To evaluate if SNPs of DPD can be used to predict 5-FU toxicity, we evaluated five SNPs of DPD (14G1A, G1156T, G2194A, T85C and T464A) by TaqMan real time PCR in 60 colorectal cancer patients. Clinical data demonstrated that there was higher correlation between DPD activity and toxic effects of 5-FU (p<0.05). Six patients were positive for G2194A detection, which were all heterozygous. Two patients had lower DPD activities (< 3) with higher toxic effects (≥stage III) while one patient was also positive for T85C detection. Ten patients were positive for T85C detection. Two patients were homozygous with lower DPD activities and higher toxic effects. Two patients were positive for the T464A detection, which were heterozygous with lower DPD activity and higher toxic effects and also positive for T85C detection. These data clearly indicated that the T464A and homozygous of the T85C are stronger biomarkers to predict the 5-FU toxicity. Our study significantly indicated that the detection for G2194A, T85C and T464A could predict ~13% of 5-FU severe toxic side effects.

Histone deacetylase gene variants predict brain volume changes in multiple sclerosis

Neuroimaging measures hold promise for enhancing the detection of disease-related genetic variants. In this study, we use advanced multivariate regression methods to assess the predictive value of single nucleotide polymorphisms (SNPs) on several brain volumetric- and lesion-related neuroimaging measures in a well-characterized cohort of 326 patients with multiple sclerosis (MS). SNP selection was constrained to key epigenetic regulatory genes to further explore the emerging role of epigenetics in MS. Regression models consistently identified rs2522129, rs2675231, and rs2389963 as having among the highest predictive values for explaining differences related to brain volume measures. These SNPs are all contained in genes from the same superfamily, histone deacetylases, which have biological functions that are relevant to MS, neurodegeneration, and aging. Our preliminary findings generate hypotheses for testing in future independent MS data sets as well as other neurodegenerative conditions.

Identifying disease related sub-pathways for analysis of genome-wide association studies

Most methods for genome-wide association studies (GWAS) focus on discovering a single genetic variant, but the pathogenesis of complex diseases is thought to arise from the joint effect of multiple genetic variants. Information about pathway structure, such as the interactions and distances between gene products within pathways, can help us learn more about the functions and joint effect of genes associated with disease risk. We developed a novel sub-pathway based approach to study the joint effect of multiple genetic variants that are modestly associated with disease. The approach prioritized sub-pathways based on the significance values of single nucleotide polymorphisms (SNPs) and the interactions and distances between gene products within pathways. We applied the method to seven complex diseases. The result showed that our method can efficiently identify statistically significant sub-pathways associated with the pathogenesis of complex diseases. The approach identified sub-pathways that may inform the interpretation of GWAS data.

The predictive value of single nucleotide polymorphisms in the VEGF system to the efficacy of first-line treatment with bevacizumab plus chemotherapy in patients with metastatic colorectal cancer

Bevacizumab and chemotherapy is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). So far, no predictive markers have been identified. The aim was to investigate the possible predictive value of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor (VEGF) system in this setting. Pre-treatment blood samples and response evaluations were available from 218 of the 249 included patients. All patients received bevacizumab and chemotherapy comprising fluorouracil and leucovorin or capecitabine combined with either oxaliplatin (FOLFOX or XELOX, n = 183) or irinotecan (FOLFIRI or XELIRI, n = 66). Germline DNA was isolated from whole blood, and five SNPs in the VEGF-A gene, one SNP in the VEGF receptor 1 (VEGFR-1) gene and three SNPs in the VEGFR-2 gene were analysed by polymerase chain reaction. Response was evaluated according to RECIST version 1.0, and the association to genotypes was analysed using Fisher's exact test. The VEGFR-1 319C/A SNP was significantly associated with response. Objective response was observed in 36% of the patients with CC genotype, 40% with CA and 56% with AA, p = 0.048. The response rates also differed significantly between patients with C-allele containing genotypes (CC + CA) (39%) and patients homozygous for the A-allele (AA) (56%), p = 0.015. There was no correlation between response rates and the remaining SNPs. The VEGFR-1 319C/A SNP is a potential predictive marker for bevacizumab plus chemotherapy in patients with mCRC. Patients with the A allele appeared to have increased response rates. The results call for validation.

The predictive value of single nucleotide polymorphisms in the vascular endothelial growth factor system in patients with metastatic colorectal cancer treated with bevacizumab plus chemotherapy as first-line treatment: Results of the phase III ACT trial NCT00598156 translational study.

3600 Background: The combination of bevacizumab and chemotherapy is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). So far, no predictive markers have been identifi...

Prognostic value of single nucleotide polymorphisms (SNPs) of candidate genes associated with inflammation in early-stage breast cancer.

1524 Background: Numerous studies have found little if any association between single nucleotide polymorphisms (SNPs) in genes associated with inflammation and breast cancer incidence. In contrast, the role of various inflammatory SNPs in predicting time to recurrence in early stage breast cancer (BC) patients has not been extensively examined. Methods: Genomic DNA from 1030 early stage BC patients was analyzed for 12 tagged SNPs of candidate genes involved in inflammation using the ILLUMINA Golden Gate platform. Cox proportional hazards models were used to evaluate the association between at risk alleles and breast cancer recurrence adjusted for clinical and pathologic covariates. Only SNPs with p values <0.1 were selected for the multivariable analysis using backward variable selection. Results: In univariable analyses 4 of 12 SNPs, NFKB1 (rs3774932), IL4(rs2243268), IL13(rs1800925) and IL10(rs1800896) were significantly associated with an increased time to recurrence (p< 0.1). In multivariable analyses NFkB (p = 0.02) and IL4 (p = 0.03) were independent predictors of longer time to recurrence compared to the dominant SNP when adjusted for stage, age and treatment. When number of at-risk alleles were counted for 4 significant SNPs, the presence of more risk alleles predicted for shorter disease free survival (Log-rank p value = 0.00079). Conclusions: These data suggest that individual and combined SNPs associated with inflammatory pathways are independent predictors of time to recurrence. This could have relevance towards the selection of drugs/immune modulators which targeting specific inflammatory pathways in an effort to prolong disease free survival in early stage BC patients.

The Value of Single Nucleotide Polymorphisms in TGFβ1, TPA and ACE in Survival Prediction in Patients with Non-small Cell Lung Cancer

Single nucleotide polymorphisms (SNPs) of transforming growth factor belta1 (TGFβ1) are known to be associated with the risk of radiation induced lung toxicities. Tissue plasminogen activator (TPA), and angiotensin-converting enzyme (ACE) are also related to radiation damage. We hypothesized that single nucleotide polymorphisms (SNPs) of the functional regions of these genes may also be associated with survival in patients with non-small cell lung cancer (NSCLC).

Predictive value of single nucleotide polymorphisms (SNPs) in DNA repair genes in non-selected advanced colorectal cancer (CRC) patients (p) treated with oxaliplatin (OXA) plus 5-Fluorouracil (5-FU) first-line chemotherapy (CT)

3680 Background: OXA cause DNA cross-linking and oxidative damage. SNPs in DNA repair genes are associated with inter-individual differences in DNA repair capacity and can explain the heterogeneity in OXA response. We assessed SNPs in four DNA repair genes belonging to three of the major DNA repair pathways: nucleotide excision repair (XPD Lys751Gln; ERCC1 C118T); base excision repair (XRCC1Arg399Gln) and homologous recombination repair (XRCC3Thr241Met) and correlated the results with outcome in OXA/5FU-treated advanced CRC p. Methods: 39 consecutive advanced CRC p were included. TaqMan 5' nuclease assay was used to examine SNPs from DNA isolated from peripheral blood lymphocytes. Results: p characteristics: median age: 59 years (33–72); 59% male. Overall outcome: median time to progression (TTP): 7 months (m); overall response rate (OR): 46%. Homozygosity for wild type alleles (Lys, C, Arg and Thr, respectively) was considered a favorable genotype for OXA response. OR according to genotype (favorable/unfavorable): XPD23 47.8/43.8%; ERCC1 33,3/47,2%; XRCC1 47.4/45% and XRCC3 44.4/38.1% (P=ns). No differences in TTP according to single genotype were observed. In contrast, when we analyzed the impact of allele combination, p carrying 4 or more unfavorable alleles (47% p) had a shorter TTP than those carrying less than 4 (53% p) (4.5m vs 7.5m; P=0.07). Conclusions: The impact of allele combination in DNA repair genes may be a key predictive marker of chemosensitivity. The prospective inclusion and genotyping of advanced CRC p is needed to clarify the role of these SNPs in predicting response to OXA/5FU. No significant financial relationships to disclose.

Predictive value of single nucleotide polymorphisms (SNPs) in DNA repair genes in non-selected advanced colorectal cancer (CRC) patients (p) treated with oxaliplatin (OXA) plus 5-Fluorouracil (5-FU) first-line chemotherapy (CT)

3680 Background: OXA cause DNA cross-linking and oxidative damage. SNPs in DNA repair genes are associated with inter-individual differences in DNA repair capacity and can explain the heterogeneity in OXA response. We assessed SNPs in four DNA repair genes belonging to three of the major DNA repair pathways: nucleotide excision repair (XPD Lys751Gln; ERCC1 C118T); base excision repair (XRCC1Arg399Gln) and homologous recombination repair (XRCC3Thr241Met) and correlated the results with outcome in OXA/5FU-treated advanced CRC p. Methods: 39 consecutive advanced CRC p were included. TaqMan 5' nuclease assay was used to examine SNPs from DNA isolated from peripheral blood lymphocytes. Results: p characteristics: median age: 59 years (33–72); 59% male. Overall outcome: median time to progression (TTP): 7 months (m); overall response rate (OR): 46%. Homozygosity for wild type alleles (Lys, C, Arg and Thr, respectively) was considered a favorable genotype for OXA response. OR according to genotype (favorable/unfavorable): XPD23 47.8/43.8%; ERCC1 33,3/47,2%; XRCC1 47.4/45% and XRCC3 44.4/38.1% (P=ns). No differences in TTP according to single genotype were observed. In contrast, when we analyzed the impact of allele combination, p carrying 4 or more unfavorable alleles (47% p) had a shorter TTP than those carrying less than 4 (53% p) (4.5m vs 7.5m; P=0.07). Conclusions: The impact of allele combination in DNA repair genes may be a key predictive marker of chemosensitivity. The prospective inclusion and genotyping of advanced CRC p is needed to clarify the role of these SNPs in predicting response to OXA/5FU. No significant financial relationships to disclose.