A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma

Wang, Yang1,2,3,4; Xiao, Fan1,2,3,4; Zhao, Yi1,2,3,4,5; Mao, Chen-Xue1,2,3,4; Yu, Lu-Lu1,2,3,4; Wang, Lei-Yun1,2,3,4; Xiao, Qi1,2,3,4; Liu, Rong1,2,3,4; Li, Xi1,2,3,4; McLeod, Howard L.1,2,3,4,6,7; Hu, Bi-Wen8; Huang, Yu-Ling9,10; Lv, Qiao-Li9,10; Xie, Xiao-Xue11,12; Huang, Wei-Hua1,2,3,4; Zhang, Wei1,2,3,4; Guo, Cheng-Xian8; Li, Jin-Gao9,10; Yin, Ji-Ye1,2,3,4,13

2022-08-23

10.1186/s12943-022-01631-8

MOLECULAR CANCER   Impact Factor & Quartile

1476-4598

Background Genetic variants associated with acute side effects of radiotherapy in nasopharyngeal carcinoma (NPC) remain largely unknown. Methods We performed a two-stage genome-wide association analysis including a total of 1084 patients, where 319 individuals in the discovery stage were genotyped for 688,783 SNPs using whole genome-wide screening microarray. Significant variants were then validated in an independent cohort of 765 patients using the MassARRAY system. Gene mapping, linkage disequilibrium, genome-wide association analysis, and polygenic risk score were conducted or calculated using FUMA, LDBlockShow, PLINK, and PRSice software programs, respectively. Results Five SNPs (rs6711678, rs4848597, rs4848598, rs2091255, and rs584547) showed statistical significance after validation. Radiotherapy toxicity was more serious in mutant minor allele carriers of all five SNPs. Stratified analysis further indicated that rs6711678, rs4848597, rs4848598, and rs2091255 correlated with skin toxicity in patients of EBV positive, late stage (III and IV), receiving both concurrent chemoradiotherapy and induction/adjuvant chemotherapy, and with OR values ranging from 1.92 to 2.66. For rs584547, high occurrence of dysphagia was found in A allele carriers in both the discovery (P = 1.27 x 10(- 6), OR = 1.55) and validation (P = 0.002, OR = 4.20) cohorts. Furthermore, prediction models integrating both genetic and clinical factors for skin reaction and dysphagia were established. The area under curve (AUC) value of receiver operating characteristic (ROC) curves were 0.657 (skin reaction) and 0.788 (dysphagia). Conclusions Rs6711678, rs4848597, rs4848598, and rs2091255 on chromosome 2q14.2 and rs584547 were found to be novel risk loci for skin toxicity and dysphagia in NPC patients receiving radiotherapy.

Nasopharyngeal carcinoma GWAS Radiogenomics Radiotherapy toxicity Skin reaction Dysphagia INHBB STY8

SCI

English

Others

National Natural Science Foundation of China["82073943","81773823","81974511"] ; Scientific and Technological Project of Changsha[kq2004147] ; Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University[YX202110] ; Open Fund for Scientific Research of NHC Key Laboratory of Personalized Diagnosis and Treatment of Nasopharyngeal Carcinoma[2021NPCK01] ; Hunan Cancer Hospital Climb Plan[YF2020011]

Biochemistry & Molecular Biology ; Oncology

Biochemistry & Molecular Biology ; Oncology

WOS:000843507600001

BMC

Web of Science

1.Cent South Univ, Xiangya Hosp, Dept Clin Pharmacol, Changsha 410078, Peoples R China
2.Cent South Univ, Inst Clin Pharmacol, Hunan Key Lab Pharmacogenet, Changsha 410078, Peoples R China
3.Minist Educ, Engn Res Ctr Appl Technol Pharmacogen, 110 Xiangya Rd, Changsha 410078, Peoples R China
4.Natl Clin Res Ctr Geriatr Disorders, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China
5.Southern Univ Sci & Technol, Dept Gen Practice, Shenzhen Peoples Hosp, Clin Med Coll 2,Affiliated Hosp 1,Jinan Univ, Shenzhen 518020, Guangdong, Peoples R China
6.Geriatr Oncol Consortium, Tampa, FL 33612 USA
7.USF Taneja Coll Pharm, Tampa, FL 33612 USA
8.Cent South Univ, Xiangya Hosp 3, Ctr Clin Pharmacol, Changsha 410013, Hunan, Peoples R China
9.Nanchang Univ, Dept Radiat Oncol, Jiangxi Canc Hosp, Nanchang 330029, Jiangxi, Peoples R China
10.Nanchang Univ, Natl Hlth Commiss NHC, Key Lab Personalized Diag & Treatment Nasopharyng, Jiangxi Canc Hosp, Nanchang 330029, Jiangxi, Peoples R China
11.Cent South Univ, Hunan Prov Tumor Hosp, Dept Radiotherapy, Xiangya Med Sch, Changsha 410013, Peoples R China
12.Cent South Univ, Affiliated Tumor Hosp, Xiangya Med Sch, Changsha 410013, Peoples R China
13.Hunan Key Lab Precise Diag & Treatment Gastrointe, Changsha 410078, Peoples R China

Wang, Yang,Xiao, Fan,Zhao, Yi,et al. A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma[J]. MOLECULAR CANCER,2022,21(1).

Wang, Yang.,Xiao, Fan.,Zhao, Yi.,Mao, Chen-Xue.,Yu, Lu-Lu.,...&Yin, Ji-Ye.(2022).A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma.MOLECULAR CANCER,21(1).

Wang, Yang,et al."A two-stage genome-wide association study to identify novel genetic loci associated with acute radiotherapy toxicity in nasopharyngeal carcinoma".MOLECULAR CANCER 21.1(2022).