title: Genetic Association of Curative and Adverse Reactions to Tyrosine Kinase Inhibitors in Chinese advanced Non-Small Cell Lung Cancer patients.
abstract: Epidermal growth factor receptor (EGFR) Tyrosine kinase inhibitor (TKI) is an effective targeted therapy for advanced non-small cell lung cancer (NSCLC) but also causes adverse drug reactions (ADRs) e.g., skin rash and diarrhea. SNPs in the EGFR signal pathway, drug metabolism/ transport pathways and miRNA might contribute to the interpersonal difference in ADRs but biomarkers for therapeutic responses and ADRs to TKIs in Chinese population are yet to be fully investigated. We recruited 226 Chinese advanced NSCLC patients who received TKIs erlotinib, gefitinib and icotinib hydrochloride and systematically studied the genetic factors associated with therapeutic responses and ADRs. Rs884225 (T > C) in EGFR 3' UTR was significantly associated with lower risk of ADRs to erlotinib (p value = 0.0010, adjusted p value = 0.042). A multivariant interaction four-SNP model (rs884225 in EGFR 3'UTR, rs7787082 in ABCB1 intron, rs38845 in MET intron and rs3803300 in AKT1 5'UTR) was associated with ADRs in general and the more specific drug induced skin injury. The SNPs associated with both therapeutic responses and ADRs indicates they might share a common genetic basis. Our study provided potential biomarkers and clues for further research of biomarkers for therapeutic responses and ADRs in Chinese NSCLC patients.
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Ruan
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.affiliation: The Fourth Hospital of Jinan City, Taishan Medical College, Jinan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Centre for Genomic Sciences, the University of Hong Kong, Hong Kong, SAR, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02142, U.S.A.|Broad Institute of Harvard and MIT, Cambridge, MA 02142, U.S.A.
authors.forename: Hailiang
authors.initials: H
authors.lastname: Huang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Shen
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Mengqi
authors.initials: M
authors.lastname: Luan
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Mo
authors.initials: M
authors.lastname: Li
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Du
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ma
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.
authors.forename: Lin
authors.initials: L
authors.lastname: He
authors.affiliation: Department of Pharmacy, Shanghai pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China.|Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shengying
authors.initials: S
authors.lastname: Qin
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D044466:Asian People / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D002681:China; D043844:Crown Ethers / Q000008:administration & dosage / Q000009:adverse effects; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011506:Proteins / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D043844:Crown Ethers; D047428:Protein Kinase Inhibitors; D011506:Proteins; D011799:Quinazolines; C103637:mesoderm specific transcript protein; C531470:icotinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib