title: Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy.
abstract: Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60-80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin.
  
  
  
  Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: "cases" developed oxaliplatin-induced grade 3-4 neuropathy (n = 48), and "controls" (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated.
  
  
  
  We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16-0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673.
  
  
  
  SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain. mariasereno75@gmail.com.
authors.forename: María
authors.initials: M
authors.lastname: Sereno
authors.affiliation: Neurology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gutiérrez-Gutiérrez
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Juan Moreno
authors.initials: JM
authors.lastname: Rubio
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Apellániz-Ruiz
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Lara
authors.initials: L
authors.lastname: Sánchez-Barroso
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Enrique
authors.initials: E
authors.lastname: Casado
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Falagan
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: López-Gómez
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Merino
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: César
authors.initials: C
authors.lastname: Gómez-Raposo
authors.affiliation: Medical Oncologist, Medical Oncology Department, La Paz University Hospital, Madrid, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Rodriguez-Salas
authors.affiliation: Medical Oncology Department, Infanta Sofía University Hospital, SS de los Reyes, Madrid, Spain.
authors.forename: Francisco Zambrana
authors.initials: FZ
authors.lastname: Tébar
authors.affiliation: Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Center (CNIO), Madrid, Spain.|ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000235:genetics*; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics*; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000175:diagnosis* / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics*; D011379:Prognosis; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D062556:NAV1.7 Voltage-Gated Sodium Channel; D009944:Organoplatinum Compounds; C486866:SCN9A protein, human; D000077150:Oxaliplatin
keywords: Calcium channel; Oxaliplatin neuropathy; SCN9A