GENETIC VARIABILITY IN DISTINCT CISPLATIN AND RADIOTHERAPY METABOLIC PATHWAYS AND PROGNOSIS OF HEAD AND NECK SQUAMOUS CELL CARCINOMA PATIENTS

Introduction: Locally advanced head and neck squamous cell carcinoma (HNSCC) patients have been treated with cisplatin (CDDP) associated with radiotherapy (RT). The sensitivity and toxicity to CDDP and RT have been associated with single nucleotide polymorphisms (SNPs) in genes that operate in distinct metabolic pathways. Objective: This prospective study aimed to investigate the roles of GSTM1, GSTT1, GSTP1 c.313A > G (rs1695), XPC c.2815A > C (rs2228001), XPD c.934G > A and c.2251A > C (rs1799793 and rs13181), XPF c.2505T > C (rs1799801), ERCC1 c.354C > T (rs11615), MLH1 c.-93G > A (rs1800734), MSH2 c.211+9C > G (rs2303426), MSH3 c. c.3133G > A (rs26279), EXO1 c.1762G > A (rs1047840), TP53 c.215G > C (rs1042522), CASP3 c.-1191A > G and c.-182-247G > T (rs12108497 and rs4647601), FAS c.-1378G > A and c.-671A > G (rs2234767 and rs1800682) and FASL c.-844C > T (rs763110) SNPs genotypes, enrolled in CDDP and RT metabolism, in prognosis of 109 HNSCC patients treated with CDDP and RT. Methods: Genotypes were analyzed in genomic DNA by polymerase chain reaction based methods. Event-free survival (EFS) and overall survival (OS) were estimated by the Kaplan-Meier method, log-rank test and Cox hazards models. Results: At 24-months of follow-up, the EFS and OS were shorter in patients with GSTM1 null plus FAS GG (30.0% vs. 52.1%, P = 0.01; 30.0% vs. 57.9%, P = 0.03), GSTP1 AA plus ERCC1 CC (23.1% vs. 41.6%, P = 0.02; 30.8% vs. 49.6%, P = 0.008), XPD AC or CC plus FAS GG (29.1% vs. 50.6%, P = 0.003; 28.9% vs. 55.3%, P = 0.02), MSH2 CC or CG plus FAS GG (24.1% vs. 36.8%, P = 0.03; 23.9% vs. 45.9%, P = 0.02) and FAS GG plus FASL CC (12.5% vs. 36.6%, P = 0.01; 12.5% vs. 47.0%, P = 0.001) SNPs genotypes, respectively. The patients with GSTM1 null plus FAS GG, GSTP1 AA plus ERCC1 CC, XPD AC or CC plus FAS GG, MSH2 CC or CG plus FAS GG and FAS GG plus FASL CC SNPs genotypes had 2.55, 2.32, 2.89, 4.26 and 3.22 more risks of progression, relapse or death by disease, and 2.42, 2.49, 2.17, 4.52 and 4.69 more risks of evolving to death, respectively. Conclusion: Our data present, for the first time, preliminary evidence that combined inherited abnormalities in intracellular detoxification, DNA repair and apoptosis of damage cells modulate prognosis of HNSCC patients treated with CDDP and RT. Financial support: FAPESP and CAPES.