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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

ABSTRACT: Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10^-8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10^-9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10^-8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.

SUBMITTER: Berndt SI

PROVIDER: S-EPMC10337695 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

Berndt Sonja I SI Vijai Joseph J Benavente Yolanda Y Camp Nicola J NJ Nieters Alexandra A Wang Zhaoming Z Smedby Karin E KE Kleinstern Geffen G Hjalgrim Henrik H Besson Caroline C Skibola Christine F CF Morton Lindsay M LM Brooks-Wilson Angela R AR Teras Lauren R LR Breeze Charles C Arias Joshua J Adami Hans-Olov HO Albanes Demetrius D Anderson Kenneth C KC Ansell Stephen M SM Bassig Bryan B Becker Nikolaus N Bhatti Parveen P Birmann Brenda M BM Boffetta Paolo P Bracci Paige M PM Brennan Paul P Brown Elizabeth E EE Burdett Laurie L Cannon-Albright Lisa A LA Chang Ellen T ET Chiu Brian C H BCH Chung Charles C CC Clavel Jacqueline J Cocco Pierluigi P Colditz Graham G Conde Lucia L Conti David V DV Cox David G DG Curtin Karen K Casabonne Delphine D De Vivo Immaculata I Diepstra Arjan A Diver W Ryan WR Dogan Ahmet A Edlund Christopher K CK Foretova Lenka L Fraumeni Joseph F JF Gabbas Attilio A Ghesquières Hervé H Giles Graham G GG Glaser Sally S Glenn Martha M Glimelius Bengt B Gu Jian J Habermann Thomas M TM Haiman Christopher A CA Haioun Corinne C Hofmann Jonathan N JN Holford Theodore R TR Holly Elizabeth A EA Hutchinson Amy A Izhar Aalin A Jackson Rebecca D RD Jarrett Ruth F RF Kaaks Rudolph R Kane Eleanor E Kolonel Laurence N LN Kong Yinfei Y Kraft Peter P Kricker Anne A Lake Annette A Lan Qing Q Lawrence Charles C Li Dalin D Liebow Mark M Link Brian K BK Magnani Corrado C Maynadie Marc M McKay James J Melbye Mads M Miligi Lucia L Milne Roger L RL Molina Thierry J TJ Monnereau Alain A Montalvan Rebecca R North Kari E KE Novak Anne J AJ Onel Kenan K Purdue Mark P MP Rand Kristin A KA Riboli Elio E Riby Jacques J Roman Eve E Salles Gilles G Sborov Douglas W DW Severson Richard K RK Shanafelt Tait D TD Smith Martyn T MT Smith Alexandra A Song Kevin W KW Song Lei L Southey Melissa C MC Spinelli John J JJ Staines Anthony A Stephens Deborah D Sutherland Heather J HJ Tkachuk Kaitlyn K Thompson Carrie A CA Tilly Hervé H Tinker Lesley F LF Travis Ruth C RC Turner Jenny J Vachon Celine M CM Vajdic Claire M CM Van Den Berg Anke A Van Den Berg David J DJ Vermeulen Roel C H RCH Vineis Paolo P Wang Sophia S SS Weiderpass Elisabete E Weiner George J GJ Weinstein Stephanie S Doo Nicole Wong NW Ye Yuanqing Y Yeager Meredith M Yu Kai K Zeleniuch-Jacquotte Anne A Zhang Yawei Y Zheng Tongzhang T Ziv Elad E Sampson Joshua J Chatterjee Nilanjan N Offit Kenneth K Cozen Wendy W Wu Xifeng X Cerhan James R JR Chanock Stephen J SJ Slager Susan L SL Rothman Nathaniel N

Leukemia 20221022 12

Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes an ...[more]

PMID: 36273105

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Project description:BackgroundNon-Hodgkin lymphoma (NHL) comprises biologically and clinically heterogeneous subtypes. Previously, study size has limited the ability to compare and contrast the risk factor profiles among these heterogeneous subtypes.MethodsWe pooled individual-level data from 17 471 NHL cases and 23 096 controls in 20 case-control studies from the International Lymphoma Epidemiology Consortium (InterLymph). We estimated the associations, measured as odds ratios, between each of 11 NHL subtypes and self-reported medical history, family history of hematologic malignancy, lifestyle factors, and occupation. We then assessed the heterogeneity of associations by evaluating the variability (Q value) of the estimated odds ratios for a given exposure among subtypes. Finally, we organized the subtypes into a hierarchical tree to identify groups that had similar risk factor profiles. Statistical significance of tree partitions was estimated by permutation-based P values (P NODE).ResultsRisks differed statistically significantly among NHL subtypes for medical history factors (autoimmune diseases, hepatitis C virus seropositivity, eczema, and blood transfusion), family history of leukemia and multiple myeloma, alcohol consumption, cigarette smoking, and certain occupations, whereas generally homogeneous risks among subtypes were observed for family history of NHL, recreational sun exposure, hay fever, allergy, and socioeconomic status. Overall, the greatest difference in risk factors occurred between T-cell and B-cell lymphomas (P NODE < 1.0×10(-4)), with increased risks generally restricted to T-cell lymphomas for eczema, T-cell-activating autoimmune diseases, family history of multiple myeloma, and occupation as a painter. We further observed substantial heterogeneity among B-cell lymphomas (P NODE < 1.0×10(-4)). Increased risks for B-cell-activating autoimmune disease and hepatitis C virus seropositivity and decreased risks for alcohol consumption and occupation as a teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia.ConclusionsUsing a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility.

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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes.

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