PMID- 35939300 OWN - NLM STAT- MEDLINE DCOM- 20221028 LR - 20221028 IS - 2574-3805 (Electronic) IS - 2574-3805 (Linking) VI - 5 IP - 8 DP - 2022 Aug 1 TI - Association of Single-Nucleotide Variants in the Human Leukocyte Antigen and Other Loci With Childhood Hodgkin Lymphoma. PG - e2225647 LID - 10.1001/jamanetworkopen.2022.25647 [doi] LID - e2225647 AB - IMPORTANCE: Studies focusing on genetic susceptibility of childhood Hodgkin lymphoma (HL) are limited. OBJECTIVES: To identify genetic variants associated with childhood-onset HL vs adult-onset HL. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study was performed with 3 cohorts: the St Jude Lifetime Cohort Study (SJLIFE), initiated in 2007 with ongoing follow-up, and the original and expansion cohorts of the Childhood Cancer Survivor Study (CCSS), initiated in the 1990s with ongoing follow-up. Results of these genome-wide association studies (GWASs) were combined via meta-analysis. Data were analyzed from June 2021 to June 2022. MAIN OUTCOMES AND MEASURES: Childhood HL was the focused outcome. Single-nucleotide variant (SNV, formerly single-nucleotide polymorphism) array genotyping and imputation were conducted for the CCSS original cohort, and whole-genome sequencing was performed for the SJLIFE and CCSS expansion cohort. RESULTS: A total of 1286 HL cases (mean diagnosis [SD] age, 14.6 [3.9] years), 6193 non-HL childhood cancer cases, and 369 noncancer controls, all of European ancestry, were included in the analysis. Using step-wise conditional logistic regression, the odds ratios (ORs) for each of the 3 independent SNVs identified in the human leukocyte antigen (HLA) locus were 1.80 (95% CI, 1.59-2.03; P = 2.14 x 10-21) for rs28383311, 1.53 (95% CI, 1.37-1.70; P = 2.05 x 10-14) for rs3129198, and 1.51 (95% CI, 1.35-1.69; P = 6.21 x 10-13) for rs3129890. Further HLA imputation revealed 9 alleles and 55 amino acid changes that potentially conferred HL susceptibility. In addition, 5 non-HLA loci were identified: (1) rs1432297 (OR, 1.29; 95% CI, 1.18-1.41; P = 2.5 x 10-8; r2 = 0.55; D' = 0.75 with previously reported rs1432295, REL); (2) rs2757647 (OR, 1.30; 95% CI, 1.18-1.42; P = 3.5 x 10-8; r2 = 0.59; D' = 0.83 with previously reported rs6928977, AHI1); (3) rs13279159 (OR, 1.33; 95% CI, 1.20-1.47; P = 1.7 x 10-8; r2 = 0.75; D' = 1.00 with previously reported rs2019960, PVT1); (4) rs3824662 (OR, 1.52; 95% CI, 1.33-1.73; P = 3.9 x 10-10; r2 = 0.91; D' = 1.00 with previously reported rs3781093, GATA3); and (5) rs117953624 (OR, 1.98; 95% CI, 1.56-2.51; P = 1.5 x 10-8; minor allele frequency, 0.02), a novel uncommon SNV mapped to PDGFD. Twelve of 18 previously reported genome-wide significant non-HLA SNVs (67%) were replicated with statistically significant results. CONCLUSIONS AND RELEVANCE: In this genetic association study, a predominantly common and potentially unique genetic etiology was found between childhood-onset and adulthood-onset HL. FAU - Chen, Cheng AU - Chen C AD - School of Public Health, Shanghai Jiaotong University, Shanghai, China. AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Song, Nan AU - Song N AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. AD - College of Pharmacy, Chungbuk National University, Cheongju, Korea. FAU - Dong, Qian AU - Dong Q AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Sun, Xiaojun AU - Sun X AD - Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Mulder, Heather L AU - Mulder HL AD - Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Easton, John AU - Easton J AD - Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Zhang, Jinghui AU - Zhang J AD - Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Yasui, Yutaka AU - Yasui Y AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Bhatia, Smita AU - Bhatia S AD - University of Alabama at Birmingham. FAU - Armstrong, Gregory T AU - Armstrong GT AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Wang, Hui AU - Wang H AD - School of Public Health, Shanghai Jiaotong University, Shanghai, China. FAU - Ness, Kirsten K AU - Ness KK AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Hudson, Melissa M AU - Hudson MM AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. AD - Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Robison, Leslie L AU - Robison LL AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. FAU - Wang, Zhaoming AU - Wang Z AD - Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee. AD - Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. LA - eng GR - P30 CA021765/CA/NCI NIH HHS/United States GR - U01 CA195547/CA/NCI NIH HHS/United States GR - U24 CA055727/CA/NCI NIH HHS/United States PT - Journal Article PT - Meta-Analysis PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220801 PL - United States TA - JAMA Netw Open JT - JAMA network open JID - 101729235 RN - 0 (HLA Antigens) SB - IM MH - Adolescent MH - Adult MH - Humans MH - Cohort Studies MH - *Genome-Wide Association Study MH - HLA Antigens/genetics MH - *Hodgkin Disease/genetics PMC - PMC9361085 COIS- Conflict of Interest Disclosures: None reported. EDAT- 2022/08/09 06:00 MHDA- 2022/08/11 06:00 PMCR- 2022/08/08 CRDT- 2022/08/08 11:33 PHST- 2022/08/08 11:33 [entrez] PHST- 2022/08/09 06:00 [pubmed] PHST- 2022/08/11 06:00 [medline] PHST- 2022/08/08 00:00 [pmc-release] AID - 2794974 [pii] AID - zoi220724 [pii] AID - 10.1001/jamanetworkopen.2022.25647 [doi] PST - epublish SO - JAMA Netw Open. 2022 Aug 1;5(8):e2225647. doi: 10.1001/jamanetworkopen.2022.25647.