title: MDM2 309 polymorphism predicts outcome in platinum-treated locally advanced head and neck cancer.
abstract: Chemo-radiotherapy (CRT) with cisplatin-based regimens is curative in a subset of patients with locally advanced (stage III and IV) squamous carcinomas of the head and neck (LAHNSCC), but causes considerable toxicity. To seek predictive biomarkers, we analysed single nucleotide polymorphisms (SNPs) in the p53 and MDM2 genes in LAHNSCC patients treated with cisplatin-based CRT. We analysed germ-line p53 72 Arg/Pro (R/P) and MDM2 309 SNPs and somatic p53 mutational status in 140 LAHNSCC and determined their utility as predictive biomarkers. In cases with wild-type p53, overall survival (OS) was longest in 72RR (median OS=60.8 months) and less favourable in 72PP (median OS=6.7 months, p<0.0001). OS in individuals with 72RP was intermediate between 72RR and 72PP, while in patients with missense p53 mutations, median OS did not reach statistical significance. Median OS was significantly shorter in patients with MDM2 309 SNP genotypes GG or GT, compared to TT (15 vs. 86 months; p<0.0001). The predictive effect of the G allele was maintained independent of age, gender, stage, primary site, nodal status, performance status, EGFR grade, HPV status, p53 mutation and p53 SNP (HR for death 3.241; 95% CI 1.90-5.52, p<0.001). The predictive utility of the MDM2 germ-line 309 SNP, which can be easily determined from peripheral blood, implies that it may be of value in the objective selection of patients for radical CRT. In contrast, the predictive utility of the 72 Arg/Pro SNP in p53 requires mutational analysis of p53, limiting its routine clinical use.
authors.affiliation: Laboratory of Cancer Genetics and Translational Oncology, Oncology Department, S. Croce General Hospital, via Carle 25, Cuneo, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vivenza
authors.forename: Milena
authors.initials: M
authors.lastname: Gasco
authors.forename: Martino
authors.initials: M
authors.lastname: Monteverde
authors.forename: Laura
authors.initials: L
authors.lastname: Lattanzio
authors.forename: Nelofer
authors.initials: N
authors.lastname: Syed
authors.forename: Ida
authors.initials: I
authors.lastname: Colantonio
authors.forename: Nerina
authors.initials: N
authors.lastname: Denaro
authors.forename: Guido
authors.initials: G
authors.lastname: Natoli
authors.forename: Alberto
authors.initials: A
authors.lastname: Comino
authors.forename: Elvio
authors.initials: E
authors.lastname: Russi
authors.forename: Marco
authors.initials: M
authors.lastname: Merlano
authors.forename: Tim
authors.initials: T
authors.lastname: Crook
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000628:therapy; D000068818:Cetuximab; D002945:Cisplatin / Q000627:therapeutic use; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D016158:Genes, p53 / Q000235:genetics*; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000628:therapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D017239:Paclitaxel / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D003841:Deoxycytidine; D051736:Proto-Oncogene Proteins c-mdm2; D017239:Paclitaxel; D000068818:Cetuximab; D002945:Cisplatin; D005472:Fluorouracil; D000093542:Gemcitabine