期刊
CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION
卷 24, 期 8, 页码 1222-1228出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1055-9965.EPI-15-0275
关键词
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资金
- National Institutes of Health [HD0433871, CA129045, CA40046]
- American Cancer Society - Illinois Division
- Cancer Research Foundation
- University of Chicago GREAT KIDS (Genomics for Risk Evaluation and Anticancer Therapy in Kids) Program
- Biological Science Division
- Institute for Translational Medicine/CTSA at The University of Chicago [NIH UL1 RR024999]
Background: Little is known about genetic factors associated with nasopharyngeal carcinoma (NPC). To gain insight into NPC etiology, we performed whole exome sequencing on germline and tumor DNA from three closely related family members with NPC. Methods: The family was ascertained through the Pediatric Familial Cancer Clinic at The University of Chicago (Chicago, IL). The diagnosis of NPC was confirmed pathologically for each individual. For each sample sequenced, 97.3% of the exome was covered at 5x, with an average depth of 44x. Candidate germline and somatic variants associated with NPC were identified and prioritized using a custom pipeline. Results: We discovered 72 rare deleterious germline variants in 56 genes shared by all three individuals. Of these, only three are in previously identified NPC-associated genes, all of which are located within MLL3, a gene known to be somatically altered in NPC. One variant introduces an early stop codon in MLL3, which predicts complete loss-of-function. Tumor DNA analysis revealed somatic mutations and Epstein-Barr virus (EBV) integration events; none, however, were shared among all three individuals. Conclusions: These data suggest that inherited mutations in MLL3 may have predisposed these three individuals from a single family to develop NPC, and may cooperate with individually acquired somatic mutations or EBV integration events in NPC etiology. Impact: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC. (C)2015 AACR.
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