Projects per year
Abstract
Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
Original language | English |
---|---|
Pages (from-to) | 200-217 |
Number of pages | 18 |
Journal | Journal of Translational Genetics and Genomics |
Volume | 5 |
Issue number | 2 |
DOIs | |
Publication status | Published - 2021 |
Keywords
- chronic lymphocytic leukemia
- diffuse large B-cell lymphoma
- follicular lymphoma
- homozygosity
- marginal zone lymphoma
- Non-Hodgkin lymphoma
Projects
-
Precision Public Health for major cancers - novel approaches to building the genetic, epigenetic and lifestyle knowledge base for assessing risk and prognosis
Giles, G. G., Southey, M., Jenkins, M. A. & Hopper, J. L.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/15 → 31/12/19
Project: Research
-
The Epidemiology of Chronic Disease, Health Interventions and DNA studies (ECHIDNAs)
Tonkin, A.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/02 → 31/12/06
Project: Research
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In: Journal of Translational Genetics and Genomics, Vol. 5, No. 2, 2021, p. 200-217.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes
AU - Moore, Amy
AU - Machiela, Mitchell J.
AU - Machado, Moara
AU - Wang, Sophia S.
AU - Kane, Eleanor
AU - Slager, Susan L.
AU - Zhou, Weiyin
AU - Carrington, Mary
AU - Lan, Qing
AU - Milne, Roger L.
AU - Birmann, Brenda M.
AU - Adami, Hans Olov
AU - Albanes, Demetrius
AU - Arslan, Alan A.
AU - Becker, Nikolaus
AU - Benavente, Yolanda
AU - Bisanzi, Simonetta
AU - Boffetta, Paolo
AU - Bracci, Paige M.
AU - Brennan, Paul
AU - Brooks-Wilson, Angela R.
AU - Canzian, Federico
AU - Caporaso, Neil
AU - Clavel, Jacqueline
AU - Cocco, Pierluigi
AU - Conde, Lucia
AU - Cox, David G.
AU - Cozen, Wendy
AU - Curtin, Karen
AU - De Vivo, Immaculata
AU - de Sanjose, Silvia
AU - Foretova, Lenka
AU - Gapstur, Susan M.
AU - Ghesquières, Hervé
AU - Giles, Graham G.
AU - Glenn, Martha
AU - Glimelius, Bengt
AU - Gao, Chi
AU - Habermann, Thomas M.
AU - Hjalgrim, Henrik
AU - Jackson, Rebecca D.
AU - Liebow, Mark
AU - Link, Brian K.
AU - Maynadie, Marc
AU - McKay, James
AU - Melbye, Mads
AU - Miligi, Lucia
AU - Molina, Thierry J.
AU - Monnereau, Alain
AU - Nieters, Alexandra
AU - North, Kari E.
AU - Offit, Kenneth
AU - Patel, Alpa V.
AU - Piro, Sara
AU - Ravichandran, Vignesh
AU - Riboli, Elio
AU - Salles, Gilles
AU - Severson, Richard K.
AU - Skibola, Christine F.
AU - Smedby, Karin E.
AU - Southey, Melissa C.
AU - Spinelli, John J.
AU - Staines, Anthony
AU - Stewart, Carolyn
AU - Teras, Lauren R.
AU - Tinker, Lesley F.
AU - Travis, Ruth C.
AU - Vajdic, Claire M.
AU - Vermeulen, Roel C.H.
AU - Vijai, Joseph
AU - Weiderpass, Elisabete
AU - Weinstein, Stephanie
AU - Doo, Nicole Wong
AU - Zhang, Yawei
AU - Zheng, Tongzhang
AU - Chanock, Stephen J.
AU - Rothman, Nathaniel
AU - Cerhan, James R.
AU - Dean, Michael
AU - Camp, Nicola J.
AU - Yeager, Meredith
AU - Berndt, Sonja I.
N1 - Funding Information: SCALE - Swedish Cancer Society (2009/659). Stockholm County Council (20110209) and the Strategic Research Program in Epidemiology at Karolinska Institutet. National Institutes of Health (5R01 CA69669-02); Plan Denmark. UCSF2 - The UCSF studies were supported by the NCI, National Institutes of Health, 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 Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention’s National Program of Cancer Registries, under agreement #1U58 DP000807-01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the authors, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute, or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred. UTAH/Sheffield - National Institutes of Health CA134674. Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB is provided by the Huntsman Cancer Institute (HCI) and the HCI Cancer Center Support grant, P30 CA42014. The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. Partial support for data collection in Sheffield, UK was made possible by funds from Yorkshire Cancer Research and the Sheffield Experimental Cancer Medicine Centre. We thank the NCRI Haemato-oncology Clinical Studies Group, colleagues in the North Trent Cancer Network the North Trent Haemato-oncology Database. UTAH-MM - National Institutes of Health CA134674, the Leukemia Lymphoma Society 6067-09, and pilot funds from the Huntsman Cancer Institute (HCI). Partial support for data collection at the Utah site was made possible by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). Partial support for all datasets within the UPDB is provided by the HCI Comprehensive Cancer Center Support grant, P30 CA42014 (M Beckerle). The UCR is supported in part by NIH contract HHSN261201000026C from the National Cancer Institute SEER Program with additional support from the Utah State Department of Health and the University of Utah. WHI - WHI investigators are: Program Office - (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center - (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers - (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; Women’s Health Initiative Memory Study - (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, United States Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C. Funding Information: This project was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH and in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. It has also been funded in whole or in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. Funding Information: All authors declare that there are no conflicts of interest. Disclaimer: This project was funded by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH and in part with federal funds from the Frederick National Laboratory for Cancer Research, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. This Research was supported in part by the Intramural Research Program of the NIH, Frederick National Lab, Center for Cancer Research. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. Funding Information: ATBC - The ATBC Study is supported by the Intramural Research Program of the United States National Cancer Institute, National Institutes of Health, Department of Health and Human Services. BCCA - Canadian Institutes for Health Research (CIHR); Canadian Cancer Society; Michael Smith Foundation for Health Research. CPS-II - The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples were supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. The authors would also like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. ELCCS - Blood Cancer UK, United Kingdom. ENGELA - Association pour la Recherche contre le Cancer (ARC), Institut National du Cancer (INCa), Fondation de France, Fondation contre la Leucémie, Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES). EPIC - Coordinated Action (Contract #006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK. The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Angency for Research on Cancer. The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l'Education National, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Centre (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); ERC-2009-AdG 232997 and Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway); Health Research Fund (FIS), PI131/00061 to Granada, PI13/01162 to EPIC-Murcia, Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, ISCIII RETIC ((RD06/0020) (Spain); Swedish Cancer Society, Swedish Research Council and Country Councils of Skåne and Västerbotten (Sweden); Cancer Research UK [14136 to K.T. Khaw, N.J. Wareham; C570/A16491 to RCT and C8221/A19170 to T. Key (EPIC-Oxford)], Medical Research Council [10001433 to K.T. Khaw, N.J. Wareham, MR/M012190/1 to T. Key (EPIC-Oxford)] (United Kingdom). EpiLymph - European Commission (grant references QLK4-CT-2000-00422 and FOOD-CT-2006-023103); We thank CERCA programme/Generalitat de Catalunya for institutional support. This work was supported by Spanish Ministry of Economy and Competitiveness - Carlos III Institute of Health cofunded by FEDER funds/European Regional Develpment Fund (ERDF) - a way to build Europe (grant references CIBERESP, PI17/01280, PI20/00288) with the support of the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1085) who had no role in the data collection, analysis or interpretation of the results; the NIH (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 (BMBF-01-EO-1303); the Health Research Board, Ireland and Cancer Research Ireland; Czech Republic supported by MH CZ - DRO (MMCI, 00209805) and MEYS - NPSI - LO1413; Fondation de France and Association de Recherche Contre le Cancer. GEC/Mayo GWAS - National Institutes of Health (CA118444, CA148690, CA92153). Intramural Research Program of the NIH, National Cancer Institute. Veterans Affairs Research Service. Data collection for Duke University was supported by a Leukemia & Lymphoma Society Career Development Award, the Bernstein Family Fund for Leukemia and Lymphoma Research, and the National Institutes of Health (K08CA134919), National Center for Advancing Translational Science (UL1 TR000135). HPFS (Walter C. Willet) - The HPFS was supported in part by National Institutes of Health grants U01 CA167552, R01 CA149445, and R01 CA098122. We would like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. Iowa-Mayo SPORE - NCI Specialized Programs of Research Excellence (SPORE) in Human Cancer (P50 CA97274); National Cancer Institute (P30 CA086862, P30 CA15083); Henry J. Predolin Foundation. Italian GxE - Italian Association for Cancer Research (AIRC, Investigator Grant 11855) (PC); Fondazione Banco di Sardegna 2010-2012, and Regione Autonoma della Sardegna (LR7 CRP-59812/2012) (MGE). Mayo Clinic Case-Control - National Institutes of Health (R01 CA92153 and CA200703); National Cancer Institute (P30 CA015083). MCCS - The Melbourne Collaborative Cohort Study recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. MSKCC - Geoffrey Beene Cancer Research Grant, Lymphoma Foundation (LF5541); Barbara K. Lipman Lymphoma Research Fund (74419); Robert and Kate Niehaus Clinical Cancer Genetics Research Initiative (57470); U01 HG007033; ENCODE; U01 HG007033. NCI-SEER - Intramural Research Program of the National Cancer Institute, National Institutes of Health, and Public Health Service (N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105). NHS (Meir J. Stampfer) - The NHS was supported in part by National Institutes of Health grants CA186107, CA87969, CA49449, CA149445, CA098122 and CA134958. We would like to thank the participants and staff of the Nurses' Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data. NSW - NSW was supported by grants from the Australian National Health and Medical Research Council (ID990920), the Cancer Council NSW, and the University of Sydney Faculty of Medicine. NYU-WHS - National Cancer Institute (R01 CA098661, P30 CA016087); National Institute of Environmental Health Sciences (ES000260). PLCO - This research was supported by the Intramural Research Program of the National Cancer Institute and by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Publisher Copyright: © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
PY - 2021
Y1 - 2021
N2 - Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
AB - Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk. Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis. Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity. Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.
KW - chronic lymphocytic leukemia
KW - diffuse large B-cell lymphoma
KW - follicular lymphoma
KW - homozygosity
KW - marginal zone lymphoma
KW - Non-Hodgkin lymphoma
UR - http://www.scopus.com/inward/record.url?scp=85153859752&partnerID=8YFLogxK
U2 - 10.20517/jtgg.2021.08
DO - 10.20517/jtgg.2021.08
M3 - Article
C2 - 34622145
AN - SCOPUS:85153859752
SN - 2578-5281
VL - 5
SP - 200
EP - 217
JO - Journal of Translational Genetics and Genomics
JF - Journal of Translational Genetics and Genomics
IS - 2
ER -