A comprehensive risk score for effective risk stratification and screening of nasopharyngeal carcinoma
Xiang Zhou, Su-Mei Cao, Yong-Lin Cai, Xiao Zhang, Shanshan Zhang, Guo-Fei Feng, Yufeng Chen, Qi-Sheng Feng, Yijun Chen, Ellen T Chang, Zhonghua Liu, Hans-Olov Adami, Jianjun Liu, Weimin Ye, Zhe Zhang, Yi-Xin Zeng, Miao Xu, Xiang Zhou, Su-Mei Cao, Yong-Lin Cai, Xiao Zhang, Shanshan Zhang, Guo-Fei Feng, Yufeng Chen, Qi-Sheng Feng, Yijun Chen, Ellen T Chang, Zhonghua Liu, Hans-Olov Adami, Jianjun Liu, Weimin Ye, Zhe Zhang, Yi-Xin Zeng, Miao Xu
Abstract
Using Epstein-Barr virus (EBV)-based markers to screen populations at high risk for nasopharyngeal carcinoma (NPC) is an attractive preventive approach. Here, we develop a comprehensive risk score (CRS) that combines risk effects of EBV and human genetics for NPC risk stratification and validate this CRS within an independent, population-based dataset. Comparing the top decile with the bottom quintile of CRSs, the odds ratio of developing NPC is 21 (95% confidence interval: 12-37) in the validation dataset. When combining the top quintile of CRS with EBV serology tests currently used for NPC screening in southern China, the positive prediction value of screening increases from 4.70% (serology test alone) to 43.24% (CRS plus serology test). By identifying individuals at a monogenic level of NPC risk, this CRS approach provides opportunities for personalized risk prediction and population screening in endemic areas for the early diagnosis and secondary prevention of NPC.
Conflict of interest statement
The authors declare no competing interests.
© 2021. The Author(s).
Figures
References
- Bray F, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J. Clin. 2018;68:394–424.
- Cao S-M, Simons MJ, Qian C-N. The prevalence and prevention of nasopharyngeal carcinoma in China. Chin. J. Cancer. 2011;30:114. doi: 10.5732/cjc.010.10377.
- Xu M, et al. Genome sequencing analysis identifies Epstein–Barr virus subtypes associated with high risk of nasopharyngeal carcinoma. Nat. Genet. 2019;51:1131–1136. doi: 10.1038/s41588-019-0436-5.
- Tsao SW, et al. Etiological factors of nasopharyngeal carcinoma. Oral. Oncol. 2014;50:330–338. doi: 10.1016/j.oraloncology.2014.02.006.
- Liu Z, et al. Quantification of familial risk of nasopharyngeal carcinoma in a high‐incidence area. Cancer. 2017;123:2716–2725. doi: 10.1002/cncr.30643.
- Bei J-X, et al. A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. Nat. Genet. 2010;42:599. doi: 10.1038/ng.601.
- Cui Q, et al. An extended genome-wide association study identifies novel susceptibility loci for nasopharyngeal carcinoma. Hum. Mol. Genet. 2016;25:3626–3634. doi: 10.1093/hmg/ddw200.
- Bei J-X, et al. A GWAS meta-analysis and replication study identifies a novel locus within CLPTM1L/TERT associated with nasopharyngeal carcinoma in individuals of Chinese ancestry. Cancer Epidemiol. Prev. Biomark. 2016;25:188–192. doi: 10.1158/1055-9965.EPI-15-0144.
- Chang ET, Adami HO. The enigmatic epidemiology of nasopharyngeal carcinoma. Cancer Epidemiol. Biomark. Prev. 2006;15:1765–1777. doi: 10.1158/1055-9965.EPI-06-0353.
- Chan KCA, et al. Analysis of plasma Epstein–Barr virus DNA to screen for nasopharyngeal cancer. N. Engl. J. Med. 2017;377:513–522. doi: 10.1056/NEJMoa1701717.
- Chien Y-C, et al. Serologic markers of Epstein–Barr virus infection and nasopharyngeal carcinoma in Taiwanese men. N. Engl. J. Med. 2001;345:1877–1882. doi: 10.1056/NEJMoa011610.
- Liu Z, et al. Two Epstein-Barr virus-related serologic antibody tests in nasopharyngeal carcinoma screening: results from the initial phase of a cluster randomized controlled trial in southern China. Am. J. Epidemiol. 2012;177:242–250. doi: 10.1093/aje/kws404.
- Ji M, et al. Incidence and mortality of nasopharyngeal carcinoma: interim analysis of a cluster randomized controlled screening trial (PRO-NPC-001) in southern China. Ann. Oncol. 2019;30:1630–1637. doi: 10.1093/annonc/mdz231.
- Liu Y, et al. Establishment of VCA and EBNA1 IgA-based combination by enzyme-linked immunosorbent assay as preferred screening method for nasopharyngeal carcinoma: a two-stage design with a preliminary performance study and a mass screening in southern China. Int. J. Cancer. 2012;131:406–416. doi: 10.1002/ijc.26380.
- Xu F-H, et al. An epidemiological and molecular study of the relationship between smoking, risk of nasopharyngeal carcinoma, and Epstein–Barr virus activation. JNCI: J. Natl Cancer Inst. 2012;104:1396–1410. doi: 10.1093/jnci/djs320.
- He Y-Q, et al. Association between environmental factors and oral Epstein-Barr virus DNA loads: a multicenter cross-sectional study in China. J. Infect. Dis. 2019;219:400–409. doi: 10.1093/infdis/jiy542.
- Chen Y-P, et al. Nasopharyngeal carcinoma. Lancet. 2019;394:64–80. doi: 10.1016/S0140-6736(19)30956-0.
- Cao, S.-M. et al. Fluctuations of Epstein-Barr virus serological antibodies and risk for nasopharyngeal carcinoma: a prospective screening study with a 20-year follow-up. PloS ONE6, e19100 (2011).
- Zeng Y, et al. Serological mass survey for early detection of nasopharyngeal carcinoma in Wuzhou City, China. Int. J. Cancer. 1982;29:139–141. doi: 10.1002/ijc.2910290204.
- Yong‐Sheng Z, et al. Immunoglobulin A against viral capsid antigen of Epstein‐Barr virus and indirect mirror examination of the nasopharynx in the detection of asymptomatic nasopharyngeal carcinoma. Cancer. 1992;69:3–7. doi: 10.1002/1097-0142(19920101)69:1<3::AID-CNCR2820690104>;2-7.
- Lam WKJ, et al. Sequencing-based counting and size profiling of plasma Epstein–Barr virus DNA enhance population screening of nasopharyngeal carcinoma. Proc. Natl Acad. Sci. 2018;115:E5115. doi: 10.1073/pnas.1804184115.
- Jahr S, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61:1659–1665.
- Stroun M, Lyautey J, Lederrey C, Olson-Sand A, Anker P. About the possible origin and mechanism of circulating DNA: Apoptosis and active DNA release. Clin. Chim. acta. 2001;313:139–142. doi: 10.1016/S0009-8981(01)00665-9.
- Lam WKJ, et al. Sequencing analysis of plasma Epstein-Barr Virus DNA Reveals nasopharyngeal carcinoma-associated single nucleotide variant profiles. Clin. Chem. 2020;66:598–605. doi: 10.1093/clinchem/hvaa027.
- Xiong, G. et al. Epstein-Barr virus (EBV) infection in Chinese children: a retrospective study of age-specific prevalence. PLoS ONE9, e99857 (2014).
- Zhang L-F, et al. Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis. Chin. J. Cancer. 2015;34:350–357.
- Correia S, et al. Sequence variation of Epstein-Barr virus: viral types, geography, codon usage, and diseases. J. Virol. 2018;92:e01132–01118. doi: 10.1128/JVI.01132-18.
- Ye W, et al. Development of a population-based cancer case-control study in southern China. Oncotarget. 2017;8:87073–87085. doi: 10.18632/oncotarget.19692.
- Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA. The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog. 2009;5:e1000496. doi: 10.1371/journal.ppat.1000496.
- Liu Z, et al. Oral hygiene and risk of nasopharyngeal carcinoma—a population-based case–control study in China. Cancer Epidemiol. Prev. Biomark. 2016;25:1201–1207. doi: 10.1158/1055-9965.EPI-16-0149.
- Kieff E.D., et al. Fields virology. Lippincott Williams & Wilkins; 2007. Epstein-Barr virus and its replication.
- Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat. Med. 2002;8:594–599. doi: 10.1038/nm0602-594.
- Frangou P, Buettner M, Niedobitek G. Epstein-Barr virus (EBV) infection in epithelial cells in vivo: rare detection of EBV replication in tongue mucosa but not in salivary glands. J. Infect. Dis. 2005;191:238–242. doi: 10.1086/426823.
- Kundu S, Aulchenko YS, van Duijn CM, Janssens ACJ. PredictABEL: an R package for the assessment of risk prediction models. Eur. J. Epidemiol. 2011;26:261. doi: 10.1007/s10654-011-9567-4.
- Hosmer DW, Hosmer T, Le Cessie S, Lemeshow S. A comparison of goodness‐of‐fit tests for the logistic regression model. Stat. Med. 1997;16:965–980. doi: 10.1002/(SICI)1097-0258(19970515)16:9<965::AID-SIM509>;2-O.
- Ferlay, J., Ervik, M., Lam, F., Colombet, M., Mery, L., Piñeros, M., Znaor, A., Soerjomataram, I., Bray, F. (2020). Global Cancer Observatory: Cancer Today. Lyon, France: International Agency for Research on Cancer. Available from: , accessed [25 October 2019].
Source: PubMed