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

Geffen Kleinstern, Nicola J. Camp, Lynn R. Goldin, Celine M. Vachon, Claire M. Vajdic, Silvia de Sanjose, J. Brice Weinberg, Yolanda Benavente, Delphine Casabonne, Mark Liebow, Alexandra Nieters, Henrik Hjalgrim, Mads Melbye, Bengt Glimelius, Hans-Olov Adami, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Pier Luigi Cocco, Tait D. Shanafelt, Timothy G. Call, Aaron D. Norman, Curtis Hanson, Dennis Robinson, Kari G. Chaffee, Angela R. Brooks-Wilson, Alain Monnereau, Jacqueline Clavel, Martha Glenn, Karen Curtin, Lucia Conde, Paige M. Bracci, Lindsay M. Morton, Wendy Cozen, Richard K. Severson, Stephen J. Chanock, John J. Spinelli, James B. Johnston, Nathaniel Rothman, Christine F. Skibola, Jose F. Leis, Neil E. Kay, Karin E. Smedby, Sonja I. Berndt, James R. Cerhan, Neil Caporaso and Susan L. Slager

Key Points

  • PRS, based on the known CLL loci, predicts CLL risk with high discrimination.

  • This PRS predicts risk of monoclonal B-cell lymphocytosis, a precursor to CLL and a condition that has clinical impact beyond risk for CLL.

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.

  • Submitted November 3, 2017.
  • Accepted March 23, 2018.
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