title: Integrated genomic analysis suggests MLL3 is a novel candidate susceptibility gene for familial nasopharyngeal carcinoma.
abstract: 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 5×, with an average depth of 44×. 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.
  
  
  CONCLUSIONS
  Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC.
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Sasaki
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Skol
authors.affiliation: Center for Research Informatics, The University of Chicago, Chicago, Illinois.
authors.forename: Riyue
authors.initials: R
authors.lastname: Bao
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois.
authors.forename: Lindsay V
authors.initials: LV
authors.lastname: Rhodes
authors.affiliation: Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York.
authors.forename: Rachelle
authors.initials: R
authors.lastname: Chambers
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois.
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.affiliation: Moores Cancer Center, University of California, San Diego, La Jolla, California.
authors.forename: Ezra E W
authors.initials: EE
authors.lastname: Cohen
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois. The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, Illinois. konel@uchicago.edu.
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
mesh_terms: D002277:Carcinoma; D004268:DNA-Binding Proteins / Q000235:genetics*; D023281:Genomics / Q000379:methods*; D018095:Germ-Line Mutation; D006801:Humans; D009154:Mutation; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C452979:KMT2C protein, human