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Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

ABSTRACT: Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.

SUBMITTER: Sunakawa Y

PROVIDER: S-EPMC7507965 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Sunakawa Y Y Cao S S Volz N B NB Berger M D MD Yang D D Parekh A A Zhang W W Matsusaka S S Ning Y Y Stremitzer S S Stintzing S S Sebio A A Okazaki S S Wakatsuki T T Azuma M M Watanabe M M Koizumi W W Wu A H AH Lenz H-J HJ

The pharmacogenomics journal 20160531 6

Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients ...[more]

PMID: 27241062

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Project description:AimTo investigate the role of single nucleotide polymorphisms (SNPs) in CD24 gene in susceptibility and overall survival of gastric cancer (GC).MethodsWe genotyped 3 tagging SNPs of CD24-P-534 in the promoter region, P170 in the coding region of exon 2 and P1527 in the 3' untranslated region - using polymerase chain reaction-restriction fragment length polymorphism in specimens from 679 histologically-confirmed GC cases, 111 gastric atrophy (GA) cases and 976 tumor-free controls. Serum immunoglobulin G antibodies to Helicobacter pylori (H. pylori) of all subjects were detected by enzyme-linked immunosorbent assay. CD24 expression was evaluated by immunohistochemistry in 131 GC specimens. Correlations between SNPs and risk of GC or GA were shown by P values and odd ratios (ORs) with 95% confidence intervals (95%CI) compared with the most common genotype of each SNP using the unconditional logistic regression model after adjusting for age, sex and H. pylori infection. Survival within each SNP group was plotted by Kaplan-Meier method and compared by log-rank test (recessive model). Hazard ratios with 95%CIs were computed by Cox regression model after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy.ResultsAll of the three loci were in Hardy-Weinberg equilibrium in the control group. Median follow-up time for the 600 GC patients included in the survival analysis was 36.2 mo (range, 2.1-66.7 mo; 95%CI: 34.3-36.5 mo). Patients with the P-534 A/A genotype had significantly shorter survival (HR = 1.38, 95%CI: 1.01-1.88, P = 0.042) than did the C/C or C/A genotype carriers after adjusting for age, sex, histological type, tumor differentiation, clinical stage and post-operational chemotherapy. This trend was more evident in patients who lived longer than 2.5 years (HR = 7.55, 95%CI: 2.16-26.32, P = 0.001). The P170 T/T genotype was associated with a shorter lifespan than the non-T/T genotypes, but not significantly so. None of the three genetic variants was found to be associated with risk of GC (including tumor stage, grade and distant metastasis) or with risk of gastric atrophy. Furthermore, no difference of CD24 expression was found among the genotypes.ConclusionThe P-534 site in CD24 gene affects the overall survival of gastric cancer and may serve as a prognostic marker for gastric cancer.

Project description:BackgroundGastric cancer (GC) is common and its prognosis is often poor due to difficulties in early diagnosis and optimal treatment strategies. TNM staging system is useful in predicting prognosis but only possible after surgery. Therefore, it is desirable to investigate prognostic factors/markers that may predict prognosis before surgery by which helps appropriate management decisions preoperatively.MethodsA total of 320 GC patients were consecutively recruited from 2004 to 2013 and followed up for 127 months (10.6 years) after surgery. These patients' were examined for body mass index (BMI) and blood levels of albumin, triglyceride, total cholesterol, low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C). Kaplan-Meier method and log rank test were used to analyze long-term survival using the above potential risk markers. We first employed medians of these variables to reveal maximal potentials of the above prognostic predictors.ResultsThree major findings were obtained: (1) Preoperative BMI was positively correlated with albumin (r = 0.144, P<0.05) and triglyceride (r = 0.365, P<0.01), but negatively correlated with TNM staging (r = -0.265, P<0.05). Preoperative albumin levels were positively correlated with triglyceride (r = 0.173, P<0.05) but again, negatively correlated with TNM staging (r = -0.137, P<0.05); (2) Poor survival was observed in GC patients with lower levels of BMI (P = 0.028), albumin (P = 0.004), and triglyceride (P = 0.043), respectively. Receiver operating characteristic (ROC) curve analyses suggested BMI, albumin and triglyceride to have survival-predictor powers similar to TNM system; and (3) Cox multi-factorial analyses demonstrated that age (P = 0.049), BMI (P = 0.016), cell differentiation (P = 0.001), and TNM staging (P = 0.011) were independent overall survival-predictors for GC patients.ConclusionsPreoperative BMI, albumin, and triglyceride levels are capable of predicting survival for GC patients superior to postoperative TNM system in terms of timing for management. As potential survival-predictors, preoperative tests of BMI, albumin and triglyceride, combined with clinical imaging, may help personalized management for GC patients including planning surgical strategy, optimal radio-chemotherapy and appropriate follow-up intervals after surgery.

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Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Publications

Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

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