Jamie E. Flerlage1, Lynn Goldin2, Mary L. McMaster2, Charles Mullighan3, Kim Nichols1, Chimene Kesserwan1, Kayla Hamilton1, Jamie Maciaszek1, Evadnie Rampersaud4, Gang Wu4, Max Qian5, Mariesha Williams1, Monika L. Metzger1, Jun J.Yang5
1 Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA, 2 National Cancer Institute, Bethesda, MD, USA, 3 Department of Pathology, St. Jude Children‘s Research Hospital, Memphis, TN, USA, 4 Department of Computational Biology, St. Jude Children‘s Research Hospital, Memphis, TN, USA, 5 Department of Pharmaceutical Sciences, St. Jude Children‘s Research Hospital, Memphis, TN, USA
Background: Classical pediatric Hodgkin lymphoma (cHL) is rare with documented familial aggregation and thus a plausible genetic basis for disease susceptibility. Large population studies have shown that first-degree relatives of individuals with cHL have 2- to 6-fold increased risk of developing cHL. Responsible pathogenetic mechanisms are largely unknown and few genomic aberrations have been described to date. Genome-wide association studies identified genetic variations at the HLA locus at 6p21.32 and analysis of whole-exome sequencing of affected individuals from 17 families with a high frequency of cHL found a potential germline predisposing mutation in the KDR gene. Recent advances in genomic profiling techniques enables comprehensive examination of risk variants at single base-pair resolution throughout the genome. Taking such a systematic approach, we sought to perform whole genome sequencing (WGS) on kindreds with a high frequency of cHL (affected and unaffected family members) to comprehensively describe the genomic basis of predisposing variants in familial HL.
Methods: Families were identified from St. Jude Children's Research Hospital (SJCRH), outside referrals and via collaboration with the National Cancer Institute (NCI) and were eligible if one person was diagnosed with cHL ≤ 21 years of age and has another affected first-degree relative. Affected and unaffected family members are eligible. Germline DNA was subjected to WGS. Data were analyzed using Genome Analysis ToolKit, Bambino, CONSERTING and CREST for mapping, variant calling, and identification of structural variations. Potential cHL risk alleles were identified on the basis of co-segregation with the disease phenotype, frequency in controls, and predicted functional consequences.
Results: To date, whole genome sequencing has been performed on 229 individuals comprised of 12 families (50 individuals) from SJCRH and 23 families (179 individuals) through collaboration with the NCI. 77 individuals were affected with cHL (38 female, 39 male, average age at diagnosis 21.8 years (range 11–75) and 152 were unaffected (86 female, 66 male, average age = 44.7 years in those collected from SJCRH). Results from WGS of these families will be presented.