Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P 5 4.4310294). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P 5 7.8 3 10230) and observed high discrimination (c-statistic 5 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P 5 9.8 310216). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH.The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL. (Blood. 2018;131(23):2541-2551).
The Utah studies were supported by grants from the National Institutes of Health, National Cancer Institute (grant CA134674); partial support for data collection from the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR); and partial support for all datasets within the UPDB from the Huntsman Cancer Institute (HCI) and the HCI Comprehensive Cancer Center Support grant (grant P30 CA42014); the UCR is supported in part by the National Institutes of Health, National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER) Program (contract HHSN261201000026C), with additional support from the Utah State Department of Health and the University of Utah. The Genetic Epidemiology of CLL Consortium was supported by a grant from the National Institutes of Health, National Cancer Institute (118444). The British Columbia site was supported by grants from the Canadian Institutes for Health Research, Canadian Cancer Society, and Michael Smith Foundation for Health Research. The University of California San Diego Molecular Epidemiology of Non-Hodgkin Lymphoma (UCSF2) studies were supported by grants from the National Institutes of Health, National Cancer Institute (grants CA1046282 and CA154643); the collection of cancer incidence data used in this study was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute’s SEER Program (contract HHSN261201000140C) that was awarded to the Cancer Prevention Institute of California, the University of Southern California (contract HHSN261201000035C), and to the Public Health Institute (contract HHSN261201000034C); and from the Centers for Disease Control and Prevention’s National Program of Cancer Registries awarded to the Public Health Institute (agreement #1U58 DP000807-01). European multi-center case–control study (EpiLymph) was supported by grants from the European Commission (grants QLK4-CT-2000-00422 and FOOD-CT-2006-023103); the Spanish Ministry of Health CIBER de Epidemiología y Salud Pública (grants PI11/01810, PI14/01219, RCESP C03/09, RTICESP C03/10, and RTIC RD06/0020/0095); the Marató de TV3 Foundation (grant 051210); the Agència de Gestiód’AjutsUniversitarisi de Recerca – Generalitat de Catalunya (grant 2014SRG756), which had no role in the data collection, analysis, or interpretation of the results; the National Institutes of Health (contract NO1-CO-12400); the Compagnia di San Paolo—Programma Oncologia; the Federal Office for Radiation Protection (grants StSch4261 and StSch4420); the José Carreras Leukemia Foundation (grant DJCLS-R12/23); the German Federal Ministry for Education and Research (grant BMBF-01-EO-1303); the Health Research Board, Ireland, and Cancer Research Ireland; the Fondation de France; and the Association de Recherche Contre le Cancer. The Czech Republic site was supported by grants from MH CZ–DRO (Masaryk Memorial Cancer Institute grant 00209805) and the Regional Centre for Applied Molecular Oncology (grant CZ.1.05/2.1.00/03.0101). Environmental and Genetic Risks Factors Study in Adult Lymphoma (ENGELA) was supported by grants from the Association pour la Recherche contre le Cancer, Institut National du Cancer, Fondation de France, Fondation contre la Leucémie, Agence nationale de sécurité sanitaire de l’alimentation, and de l’environnement et du travail. Scandinavian Lymphoma Etiology Study (SCALE) was supported by grants from the Swedish Cancer Society (grant 2009/659); Stockholm County Council (grant 20110209); the Strategic Research Program in Epidemiology at Karolinska Institute; Swedish Cancer Society (grant 02 6661); National Institutes of Health, National Cancer Institute (grant 5R01 CA69669-02); and Plan Denmark. The Mayo site was supported by grants from the National Institutes of Health, National Cancer Institute (grant CA97274); Specialized Programs of Research Excellence in Human Cancer (grant P50 CA97274); Molecular Epidemiology of Non-Hodgkin Lymphoma Survival (grant R01 CA129539); Henry J. Predolin Foundation (grant R01 CA92153); National Center for Advancing Translational Science (grant UL1 TR000135); and Mayo Clinic Cancer Center (grant P30 CA15083). The National Cancer Institute SEER study was supported by grants from the Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Public Health Service (grants N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, and N02-PC-71105). The New South Wales, Australia, site was supported by grants from the Australian National Health and Medical Research Council (grant ID990920), the Cancer Council NSW, and the University of Sydney Faculty of Medicine. This study was also supported by grants from the National Institutes of Health, National Cancer Institute (grant R25 CA92049; Mayo Cancer Genetic Epidemiology Training Program). The Mayo Clinic Center for Individualized Medicine provided the Mayo Clinic Biobank materials.
Conflict-of-interest disclosure: M. Maynadie is a consultant to Janssen Pharmaceuticals and receives funding from Novartis and BMS. A.R.B.W.
has stock in Xenon Pharmaceuticals. M.G. is the principal investigator on an Amgen institutional clinical trial. P.M.B. receives research funding from Navidea. J.F.L. receives research funding from ACERTA and Janssen Pharmaceuticals. The remaining authors declare no competing financial interests.
© 2018 by The American Society of Hematology.
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