Abstract 4178: Germline mutations in BRCA2 and pediatric/adolescent non-Hodgkin's lymphoma: A report from the St. Jude Lifetime (SJLIFE) and Childhood Cancer Survivor Study (CCSS) cohorts
Authors: Wang Zhaoming , Chang Ti-Cheng , Wilson Carmen L. , Kesserwan Chimene A. , Gibson Todd M. , Li Nan , Easton John , Mulder Heather L. , Wu Gang , Edmonson Michael N. , Rusch Michael C. , Downing James R. , Nichols Kim E. , Bhatia Smita , Armstrong Gregory T. , Hudson Melissa M. , Zhang Jinghui , Yasui Yutaka , Robison Leslie L. 
Published: August 2019

Abstract
Pathogenic or likely pathogenic (P/LP) monoallelic germline mutations in BRCA2 increase risk of developing breast, ovarian, prostate, and pancreatic cancers. In a prior report from the SJLIFE study, BRCA2 was the third most frequently mutated gene (14 occurrences) among 3006 survivors of childhood cancer with the highest number observed among lymphoma survivors (7/586). To further investigate BRCA2 as a potential predisposition gene for pediatric/adolescent lymphoma, we analyzed 781 additional lymphoma survivors in the SJLIFE and CCSS cohorts with whole-genome sequencing (30X coverage). In the combined set of 1367 survivors (808 Hodgkin’s lymphoma [HL], 559 non-Hodgkin’s lymphoma [NHL]; 54% male; median age at diagnosis 12.6 [range 1.1-22.7] years), 13 P/LP mutations in BRCA2 were identified, with 7 mapped to the breast or ovarian cancer cluster regions defined by the Consortium of Investigators of Modifiers of BRCA1/2. Compared to reference controls in the Genome Aggregation Database (gnomAD) (Table 1), a significant association was observed between lymphoma and mutations in BRCA2 (odds ratio [OR], 3.1; 95% CI, 1.7-5.5) but not BRCA1. When stratified by diagnosis, the association was significant for NHL (OR, 4.8; 95% CI, 2.0-9.6) but not for HL. BRCA2 mutation carriers included a broad spectrum of NHL histological subtypes. Our findings support inclusion of pediatric/adolescent NHL in the spectrum of cancers associated with germline BRCA2 mutations. Approximately 1.4% of survivors of pediatric/adolescent NHL are carriers of a P/LP mutation in BRCA2, which may be the underlying etiology of their primary diagnosis. Clinically, counselling regarding BRCA2 mutation status should be considered for pediatric/adolescent NHL patients. Large scale genetic studies of newly diagnosed pediatric/adolescent lymphoma patients are warranted to replicate and refine diagnosis-specific risk estimates.
Table 1.Comparisons of Mutation Carriers for BRCA1/2 Genes Between Lymphoma Survivors and gnomAD ControlsLymphoma SurvivorsgnomAD Controls (Hu et al. JAMA 2018)Cancer Risk (Fisher''s Exact Test)GeneCancer DiagnosisCarriersNon-CarriersCarriersNon-CarriersOdds Ratio (95% CI)P ValueBRCA2HL+NHL1313543131024263.1 (1.7-5.5)0.00045HL58033131024262.0 (0.7-4.8)0.11NHL85513131024264.8 (2.0-9.6)0.00041BRCA1HL+NHL313642081039141.1 (0.2-3.3)0.76HL18072081039140.6 (0.02-3.5)1.0NHL25572081039141.8 (0.2-6.6)0.31
Citation Format: Zhaoming Wang, Ti-Cheng Chang, Carmen L. Wilson, Chimene A. Kesserwan, Todd M. Gibson, Nan Li, John Easton, Heather L. Mulder, Gang Wu, Michael N. Edmonson, Michael C. Rusch, James R. Downing, Kim E. Nichols, Smita Bhatia, Gregory T. Armstrong, Melissa M. Hudson, Jinghui Zhang, Yutaka Yasui, Leslie L. Robison. Germline mutations in BRCA2 and pediatric/adolescent non-Hodgkin's lymphoma: A report from the St. Jude Lifetime (SJLIFE) and Childhood Cancer Survivor Study (CCSS) cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4178.