GSTP1 c.313A>G, XPD c.934G>A, XPF c.2505T>C and CASP9 c.‐1339A>G Polymorphisms and Severity of Vomiting in Head and Neck Cancer Patients treated with Cisplatin Chemoradiation

Abstract

Cisplatin (CDDP) chemotherapy associated with radiation (RT) has been used in advanced head and neck squamous cell carcinoma (HNSCC) patients, and vomiting is a common side effect during treatment. This prospective study aimed to identify the roles of GSTM1 and GSTT1 (presents or nulls), GSTP1 c.313A>G, XPC c.2815A>C, XPD c.934G>A and c.2251A>C, XPF c.2505T>C, ERCC1 c.354C>T, MLH1 c.-93G>A, MSH2 c.211 + 9C>G, MSH3 c.3133G>A, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-1168G>T, CASP9 c.-1339A>G, CASP8 c.-937_-932delAGTAAG, FAS c.-1378G>A and c.-671A>G, and FASL c.-157-687C>T single nucleotide polymorphisms, involved in CDDP metabolism, in vomiting severity in 88 HNSCC patients treated with CDDP and RT. Ondansetron and dexamethasone were administered as anti-emetic therapy. Patients with GSTP1 c.313AG or GG genotype alone and combined with XPD c.934GA or AA, XPF c.2505TC or CC, and CASP9 c.-1339AG or GG genotypes had 4.28, 5.00, 5.45 and 5.38 more chances of presenting moderate/severe vomiting than patients with others genotypes. Our data suggest, for the first time, that inherited abnormality in apoptosis pathway alone or combined with inherited abnormalities in DNA repair pathway, is capable of modulating emesis in HNSCC patients under CDDP chemoradiation and may be used for selecting patients who should receive pre-emptive anti-emetic therapy.

Immunohistochemical expression of DNA repair proteins in oral tongue and lower lip squamous cell carcinoma

“…31 DNA damage is associated with an increased risk of cancer, in which the reduced capacity of DNA repair can accelerate changes and mutations in essential genes, triggering carcinogenesis. 13,20,29 In this study, we observed a significant difference in the cytoplasmic protein expression of XPF between the OTSCC and LLSCC groups, with higher expression in OTSCC cases; however, there was no association with the clinical parameters analyzed. This cytoplasmic expression of XPF may indicate deregulation of protein function in OTSCC, which could contribute to the more aggressive behavior of the tumor at this anatomical site.…”

“…Studies using cells from XPF-deficient patients and animal models have shown that low expression of XPF is associated with higher sensitivity to DNA-damaging agents. 21,29 Ang et al 21 observed high nuclear expression of protein XRCC1 in head and neck carcinomas, which was related to poor patient survival, especially among those undergoing chemotherapy. In the study of Mahjabeen et al, 14 expression of XRCC1 was associated with poor survival in a series of head and neck carcinomas and immunostaining for the protein was observed in both cytoplasm and nucleus.…”

“…27 The genes that encode these molecules involved in the repair of DNA damage have been studied as biological markers of cancer and might be associated with tumor development and patient prognosis. 14,28,29 OTSCC is frequently diagnosed in an advanced clinical stage and is associated with high rates of morbidity and mortality when compared to LLSCC. 30 Given the heterogeneity of head and neck cancers and their biological behavior and etiological factors, it is important to evaluate markers associated with DNA repair in SCC arising from different anatomical sites.…”

Cost-minimization analysis of GSTP1c.313A>G genotyping for the prevention of cisplatin-induced nausea and vomiting: A Bayesian inference approach

“…In this case, the observed data consist of a prospective non-interventional study performed in the same institution, where 88 patients were submitted to high-dose CDDP and radiotherapy without the use of fosaprepitant. [14] For the prior risk of the GSTP1 c.313 AG or GG genotype, we considered an additional prospective case-control study from a similar sample population of 229 patients. [28] The probability of grade 3 or 4 CINV was collected from a current meta-analysis (three-weekly CDDP arm), [29] while the chance of chemotherapy dropouts and suspensions was obtained from the intervention arm (N = 179) of a randomized clinical trial assessing high-dose CDDP and radiotherapy.…”

“…Recently, patients with head and neck cancer (HNC) under chemoradiation therapy with high-dose CDDP were prospectively evaluated in our institution, aiming to identify a possible correlation between single nucleotide polymorphisms (SNPs) involved in CDDP metabolism and the occurrence of CINV. [14] In this setting, the prophylaxis consisted of dexamethasone in combination with the 5-HT3 antagonist ondansetron, which is supported by the public health system in Brazil. Among the SNPs studied, the glutathione S-transferase P gene ( GSTP1 ) c.313 (NM_000852.3, rs1695) was highlighted.…”