title: TNFRSF10B polymorphisms and haplotypes associated with increased risk of death in non-small cell lung cancer.
abstract: Presently, there are few validated biomarkers that can predict survival or treatment response for non-small cell lung cancer (NSCLC) and most are based on tumor markers. Biomarkers based on germ line DNA variations represent a valuable complementary strategy, which could have translational implications by subclassifying patients to tailored, patient-specific treatment. We analyzed single nucleotide polymorphisms (SNPs) in 53 inflammation-related genes among 651 NSCLC patients. Multivariable Cox proportional hazard models, adjusted for lung cancer prognostic factors, were used to assess the association of genotypes and haplotypes with overall survival. Four of the top 15 SNPs associated with survival were located in the TNF-receptor superfamily member 10b (TNFRSF10B) gene. The T-allele of the top ranked SNP (rs11785599) was associated with a 41% increased risk of death (95% confidence interval [CI] = 1.16-1.70) and the other three TNFRSF10B SNPs (rs1047275, rs4460370 and rs883429) exhibited a 35% (95% CI = 1.11-1.65), 29% (95% CI = 1.06-1.57) and 24% (95% CI = 0.99-1.54) increased risk of death, respectively. Haplotype analyses revealed that the most common risk haplotype (TCTT) was associated with a 78% (95% CI = 1.25-2.54) increased risk of death compared with the low-risk haplotype (CGCC). When the data were stratified by treatment, the risk haplotypes exhibited statistically significantly increased risk of death among patients who had surgery only and no statistically significant effects among patients who had surgery and adjuvant chemotherapy. These data suggest that possessing one or more risk alleles in TNFRSF10B is associated with an increased risk of death. Validated germ line biomarkers may have potential important clinical implications by optimizing patient-specific treatment.
authors.affiliation: Department of Cancer Epidemiology.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.forename: Anna R
authors.initials: AR
authors.lastname: Giuliano
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Thompson
authors.forename: Ernest K
authors.initials: EK
authors.lastname: Amankwah
authors.forename: Jhanelle E
authors.initials: JE
authors.lastname: Gray
authors.forename: David A
authors.initials: DA
authors.lastname: Fenstermacher
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Jonathan
authors.forename: Amer A
authors.initials: AA
authors.lastname: Beg
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000235:genetics / Q000401:mortality / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D018287:Carcinoma, Large Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D011446:Prospective Studies; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics*; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human