Prognostic implications of a molecular classifier derived from whole-exome sequencing in nasopharyngeal carcinoma.

Abstract

The aim of this study was to use whole-exome sequencing to derive a molecular classifier for nasopharyngeal carcinoma (NPC) and evaluate its clinical performance. We performed whole-exome sequencing on 82 primary NPC tumors from Sun Yat-sen University Cancer Center (Guangzhou cohort) to obtain somatic single-nucleotide variants, indels, and copy number variants. A novel molecular classifier was then developed and validated in another NPC cohort (Hong Kong cohort, n = 99). Survival analysis was estimated by the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards model was adopted for univariate and multivariate analyses. We identified three prominent NPC genetic subtypes: RAS/PI3K/AKT (based on RAS, AKT1, and PIK3CA mutations), cell-cycle (based on CDKN2A/CDKN2B deletions, and CDKN1B and CCND1 amplifications), and unclassified (based on dominant mutations in epigenetic regulators, such as KMT2C/2D, or the Notch signaling pathway, such as NOTCH1/2). These subtypes differed in survival analysis, with good, intermediate, and poor progression-free survival in the unclassified, cell-cycle, and RAS/PI3K/AKT subgroups, respectively, among the Guangzhou, Hong Kong, and combined cohorts (n = 82, P = 0.0342; n = 99, P = 0.0372; and n = 181, P = 0.0023; log-rank test). We have uncovered genetic subtypes of NPC with distinct mutations and/or copy number changes, reflecting discrete paths of NPC tumorigenesis and providing a roadmap for developing new prognostic biomarkers and targeted therapies.

• Authors: Hai-Yun Wang, Fugen Li, Na Liu, Xiao-Yun Liu, Xin-Hua Yang, Yun-Miao Guo, Jin-Xin Bei, Yi-Xin Zeng, Jian-Yong Shao
• Journal: Cancer medicine (Cancer Med) Vol. 8 Issue 6 Pg. 2705-2716 (06 2019) ISSN: 2045-7634 [Electronic] United States
• PMID: 30950204 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Biomarkers, Tumor

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor
• Cell Transformation, Neoplastic (genetics)
• Chromosomal Instability
• Computational Biology
• DNA Copy Number Variations
• Female
• Gene Expression Profiling
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Nasopharyngeal Carcinoma (diagnosis, genetics, metabolism, mortality)
• Neoplasm Staging
• Polymorphism, Single Nucleotide
• Prognosis
• Signal Transduction
• Exome Sequencing
• Young Adult