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

Geffen Kleinstern , Nicola Camp , Lynn R. Goldin (1) , Celine Vachon , Claire Vajdic , Silvia de Sanjosé (2) , J. Brice Weinberg , Yolanda Benavente (3) , Delphine Casabonne , Mark Liebow , Alexandra Nieters (4) , Henrik Hjalgrim , Mads Melbye (5) , Bengt Glimelius (6) , Hans-Olov Adami (7) , Paolo Boffetta (8) , Paul Brennan (9) , Marc Maynadié (10, 11, 12) , James Mckay (13) , Pier Luigi Cocco , Tait Shanafelt (14) , Timothy Call , Aaron Norman (15) , Curtis Hanson , Dennis Robinson , Kari Chaffee , Angela Brooks-Wilson , Alain A. Monnereau (16, 17, 18) , Jacqueline Clavel (17, 18) , Martha Glenn (19) , Karen Curtin (19) , Lucia Conde , Paige Bracci , Lindsay M. Morton (1) , Wendy Cozen (20) , Richard K. Severson (21) , Stephen Chanock (22) , John Spinelli , James Johnston , Nathaniel Rothman (1) , Christine Skibola (23) , Jose Leis , Neil Kay , Karin Smedby (24) , Sonja I Berndt (1) , James Cerhan (14) , Neil Caporaso (1) , Susan L. Slager (25, 14)

1 NCI-NIH - National Cancer Institute [Bethesda]
2 ICO - Catalan Institute of Oncology = Instituto Catalán de Oncología
3 Department of Epidemiology
4 Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany
5 Dept. of Epidemiology Research
6 Uppsala Universitet [Uppsala]
7 MEB - Department of Medical Epidemiology and Biostatistics
8 MSSM - Icahn School of Medicine at Mount Sinai [New York]
9 CIRC - IARC - Centre International de Recherche contre le Cancer - International Agency for Research on Cancer
10 Registre des hémopathies malignes de Côte d'Or
11 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
12 UBFC - Université Bourgogne Franche-Comté [COMUE]
13 IACR - International Agency for Cancer Research
14 Mayo Clinic [Rochester]
15 LISE - Laboratoire Interdisciplinaire de Spectroscopie Electronique
16 Registre des hémopathies malignes de la Gironde
17 EPICENE - Cancer environnement
18 CRESS - U1153 - Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent
19 Huntsman Cancer Institute
20 Norris Comprehensive Cancer Center
21 Wayne State University [Detroit]
22 Division of Cancer Epidemiology and Genetics
23 Emory University [Atlanta, GA]
24 CCK - Cancer Center Karolinska [Karolinska Institutet]
25 Department of Psychiatry

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.

Domaines: Cancer

Geffen Kleinstern, Nicola Camp, Lynn R. Goldin, Celine Vachon, Claire Vajdic, et al.. Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis. Blood, 2018, 131 (23), pp.2541-2551. ⟨10.1182/blood-2017-11-814608⟩. ⟨hal-02066279⟩