Head and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy responsible for approximately 5.0% of global cancer deaths. The standard treatment for locally advanced HNSCC involves cisplatin (CDDP)-based chemotherapy and radiotherapy, which can lead to significant adverse effects, particularly nephrotoxicity. It is already well known that the efficacy of CDDP as well as its side effects vary in distinct patients with HNSCC, and single nucleotide variants (SNVs) in genes that act in CDDP metabolism constitute a plausible explanation for this finding.

To investigate the roles of SNVs GSTM1, GSTT1, 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.3133A>G, EXO1 c.1765G>A, TP53 c.215G>C, CASP3 c.-1191A>G and c.-182-247G>T, FAS c.-1378G>A and c.-671A>G, and FASL c.-844C>T SNVs on kidney function outcomes in HNSCC patients undergoing CDDP treatment.

A total of 109 patients with locally advanced HNSCC treated with CDDP were included in the study. Genotypes were determined using polymerase chain reaction (PCR). Renal function was assessed by calculating estimating glomerular filtration rate (eGFR) using the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, before treatment initiation and 30 days post-treatment. The percentage variation in kidney function was calculated by determining the difference between baseline (pre-chemotherapy) and follow-up (post-chemotherapy) values for eGFR divided by the pre-chemotherapy value and represented as ΔeGFR.

Patients with the GSTT1 present and ERCC1 c.354CT or TT isolated genotypes presented a decline in kidney function of 4.94% and 8.94%, respectively. A decline of 17.67% in renal function post-CDDP treatment was observed in patients with the GSTT1 present combined with TP53 c.215CC genotype. Patients with the GSTP1 c.313AG or GG and ERCC1 c.354CT or TTC>T (17.57%), MLH1 c.93GA or A (12.49%), or MSH3 c.3133AG or GG (12.19%) combined genotypes showed a reduction in renal function after CDDP treatment. Renal function declines of 18.85% and 13.38% were observed in patients with ERCC1 c.354CT or TT and MLH1 c.93GA or AA or MSH3 c.3133AG or GG combined genotypes, respectively.

Our data indicates, for the first time, preliminary evidence that combined inherited abnormalities, SNVs that act in CDDP metabolism, act as independent factors for nephrotoxicity in HNSCC patients and can be used to select patients for personalized treatments that promote renal protection and reduced nephrotoxicity.

The study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (grant number 88887.513947/2020-00), the Postdoctoral Program (PPPD) at the University of Campinas (UNICAMP) (Postdoctoral ID number: 326285), and the Fundação de Apoio ao Ensino e à Pesquisa do Estado de São Paulo (FAPESP) Cancer Theranostics Innovation Center (CancerThera) (FAPESP 2021/10265-8).