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.

Impact: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC.

Figure 1. Nasopharyngeal Carcinoma family pedigree

Shown is a four-generation pedigree of the family. Germline and tumor DNA of individuals with NPC (Individuals I-1, I-2, and II-1) were analyzed by WES.

Figure 2. MLL3 mutations in NPC

Diagram of MLL3 with functional domains. Black lollipops indicate germline mutations identified in this study. White lollipops indicate previously identified somatic mutations.