Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Geffen Kleinstern¹, Nicola J Camp², Lynn R Goldin³, Celine M Vachon¹, Claire M Vajdic⁴, Silvia de Sanjose^{5

6}, J Brice Weinberg^{7

8

9}, Yolanda Benavente^{5

6}, Delphine Casabonne^{5

6}, Mark Liebow¹⁰, Alexandra Nieters¹¹, Henrik Hjalgrim^{12

13}, Mads Melbye^{12

14}, Bengt Glimelius¹⁵, Hans-Olov Adami¹⁶, Paolo Boffetta¹⁷, Paul Brennan¹⁸, Marc Maynadie¹⁹, James McKay¹⁸, Pier Luigi Cocco²⁰, Tait D Shanafelt²¹, Timothy G Call²¹, Aaron D Norman¹, Curtis Hanson²², Dennis Robinson¹, Kari G Chaffee¹, Angela R Brooks-Wilson^{23

24}, Alain Monnereau^{25

26

27}, Jacqueline Clavel^{26

27}, Martha Glenn², Karen Curtin², Lucia Conde²⁸, Paige M Bracci²⁹, Lindsay M Morton³, Wendy Cozen^{30

31}, Richard K Severson³², Stephen J Chanock³, John J Spinelli^{33

34}, James B Johnston³⁵, Nathaniel Rothman³, Christine F Skibola³⁶, Jose F Leis³⁷, Neil E Kay²⁰, Karin E Smedby³⁸, Sonja I Berndt³, James R Cerhan¹, Neil Caporaso³, Susan L Slager¹

Affiliations

¹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
² Huntsman Cancer Institute and Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
⁴ Centre for Big Data Research in Health, University of New South Wales, Sydney, NSW, Australia.
⁵ CIBER de Epidemiología y Salud Pública, Barcelona, Spain.
⁶ Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Institute d'Investigacio Biomedica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Department of Medicine and.
⁸ Department of Immunology, Duke University Medical Center, Durham, NC.
⁹ Durham Veterans Affairs Medical Center, Durham, NC.
¹⁰ Division of General Internal Medicine, Mayo Clinic, Rochester, MN.
¹¹ Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg, Germany.
¹² Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
¹³ Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA.
¹⁵ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁸ International Agency for Research on Cancer, Lyon, France.
¹⁹ Registre des Hémopathies Malignes de Côte d'Or, INSERM UMR1231, Université de Bourgogne-Franche-Comté, Dijon, France.
²⁰ Department of Medical Sciences and Public Health, Occupational Health Section, University of Cagliari, Monserrato, Italy.
²¹ Division of Hematology and.
²² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
²³ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
²⁴ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
²⁵ Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, University of Bordeaux, INSERM, Team EPICENE, UMR 1219, Bordeaux, France.
²⁶ Epidemiology of Childhood and Adolescent Cancers Group, INSERM, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, Paris, France.
²⁷ Université Paris Descartes, Paris, France.
²⁸ UCL Cancer Institute, London, United Kingdom.
²⁹ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
³⁰ Department of Preventive Medicine and.
³¹ Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA.
³² Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI.
³³ Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
³⁴ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
³⁵ Department of Medical Oncology, Cancer Care Manitoba, Winnipeg, MB, Canada.
³⁶ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.
³⁷ Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ; and.
³⁸ Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

PMID: 29674426
PMCID: PMC5992865
DOI: 10.1182/blood-2017-11-814608

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Geffen Kleinstern et al. Blood. 2018.

. 2018 Jun 7;131(23):2541-2551.

doi: 10.1182/blood-2017-11-814608. Epub 2018 Apr 19.

Authors

Affiliations

¹ Department of Health Sciences Research, Mayo Clinic, Rochester, MN.
² Huntsman Cancer Institute and Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
⁴ Centre for Big Data Research in Health, University of New South Wales, Sydney, NSW, Australia.
⁵ CIBER de Epidemiología y Salud Pública, Barcelona, Spain.
⁶ Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Institute d'Investigacio Biomedica de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Department of Medicine and.
⁸ Department of Immunology, Duke University Medical Center, Durham, NC.
⁹ Durham Veterans Affairs Medical Center, Durham, NC.
¹⁰ Division of General Internal Medicine, Mayo Clinic, Rochester, MN.
¹¹ Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg, Germany.
¹² Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen, Denmark.
¹³ Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
¹⁴ Department of Medicine, Stanford University School of Medicine, Stanford, CA.
¹⁵ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
¹⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
¹⁷ The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
¹⁸ International Agency for Research on Cancer, Lyon, France.
¹⁹ Registre des Hémopathies Malignes de Côte d'Or, INSERM UMR1231, Université de Bourgogne-Franche-Comté, Dijon, France.
²⁰ Department of Medical Sciences and Public Health, Occupational Health Section, University of Cagliari, Monserrato, Italy.
²¹ Division of Hematology and.
²² Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
²³ Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
²⁴ Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
²⁵ Registre des Hémopathies Malignes de la Gironde, Institut Bergonié, University of Bordeaux, INSERM, Team EPICENE, UMR 1219, Bordeaux, France.
²⁶ Epidemiology of Childhood and Adolescent Cancers Group, INSERM, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, Paris, France.
²⁷ Université Paris Descartes, Paris, France.
²⁸ UCL Cancer Institute, London, United Kingdom.
²⁹ Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA.
³⁰ Department of Preventive Medicine and.
³¹ Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA.
³² Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI.
³³ Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
³⁴ School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada.
³⁵ Department of Medical Oncology, Cancer Care Manitoba, Winnipeg, MB, Canada.
³⁶ Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA.
³⁷ Department of Hematology and Oncology, Mayo Clinic, Phoenix, AZ; and.
³⁸ Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.

PMID: 29674426
PMCID: PMC5992865
DOI: 10.1182/blood-2017-11-814608

Abstract

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 = 4.4 × 10^-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10^-30) and observed high discrimination (c-statistic = 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 = 9.8 × 10^-16). 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.

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Conflict of interest statement

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.

Figures

**Figure 1.**
**Polygenic risk score distribution by InterLymph CLL and controls and GEC CLL, MBL, controls, and Mayo Clinic controls.** Histograms of polygenic risk scores (x-axis) and density (y-axis). (A) InterLymph CLL (dashed red line) and controls (solid purple line). (B) Mayo controls (purple), GEC controls (green), GEC MBL (blue), and GEC CLL (red). Vertical lines indicate the median for the corresponding polygenic risk score distribution.

See this image and copyright information in PMC

References

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Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Affiliations

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases

Miscellaneous