Common genetic polymorphisms contribute to the association between chronic lymphocytic leukaemia and non-melanoma skin cancer

the InterLymph Consortium

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Abstract

Background: Epidemiological studies have demonstrated a positive association between chronic lymphocytic leukaemia (CLL) and non-melanoma skin cancer (NMSC). We hypothesized that shared genetic risk factors between CLL and NMSC could contribute to the association observed between these diseases. Methods: We examined the association between (i) established NMSC susceptibility loci and CLL risk in a meta-analysis including 3100 CLL cases and 7667 controls and (ii) established CLL loci and NMSC risk in a study of 4242 basal cell carcinoma (BCC) cases, 825 squamous cell carcinoma (SCC) cases and 12802 controls. Polygenic risk scores (PRS) for CLL, BCC and SCC were constructed using established loci. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Higher CLL-PRS was associated with increased BCC risk (OR4th-quartile-vs-1stquartile ¼ 1.13, 95% CI: 1.02-1.24, Ptrend ¼ 0.009), even after removing the shared 6p25.3 locus. No association was observed with BCC-PRS and CLL risk (Ptrend ¼ 0.68). These findings support a contributory role for CLL in BCC risk, but not for BCC in CLL risk. Increased CLL risk was observed with higher SCC-PRS (OR4th-quartile-vs-1st-quartile ¼ 1.22, 95% CI: 1.08-1.38, Ptrend ¼ 1.36 × 10-5), which was driven by shared genetic susceptibility at the 6p25.3 locus. Conclusion: These findings highlight the role of pleiotropy regarding the pathogenesis of CLL and NMSC and shows that a single pleiotropic locus, 6p25.3, drives the observed association between genetic susceptibility to SCC and increased CLL risk. The study also provides evidence that genetic susceptibility for CLL increases BCC risk.

Original languageEnglish
Pages (from-to)1325-1334
Number of pages10
JournalInternational Journal of Epidemiology
Volume50
Issue number4
DOIs
StatePublished - 2021

Bibliographical note

Funding Information:
This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Caroline Besson thanks the Monahan Foundation for providing her a research travel grant. A complete list of study-specific acknowledgements can be found in the Supplementary Material. CLL GWAS data used in this manuscript have been deposited in the dbGaP repository with accession code phs000801.v2.p1. All other relevant data generated for this study are available upon request from the authors. All studies were approved by the respective institutional review boards as listed. These are ATBC: (NCI Special Studies Institutional Review Board); BCCA: UBC BC Cancer Agency Research Ethics Board; CPS-II: American Cancer Society; ELCCS: Northern and Yorkshire Research Ethics Committee; ENGELA: IRB00003888-Comite d' Evaluation Ethique de l'Inserm IRB # 1; EPIC: Imperial College London; EpiLymph: International Agency for Research on Cancer, HPFS: Harvard School of Public Health (HSPH) Institutional Review Board; Iowa-Mayo SPORE: University of Iowa Institutional Review Board; Italian GxE: Comitato Etico Azienda Ospedaliero Universitaria di Cagliari; Mayo Clinic Case-Control: Mayo Clinic Institutional Review Board; Mayo GEC: Mayo Clinic Institutional Review Board, #07-005788-03; MCCS: Cancer Council Victoria's Human Research Ethics Committee; MD Anderson: University of Texas MD Anderson Cancer Center Institutional Review Board; MSKCC: Memorial Sloan-Kettering Cancer Center Institutional Review Board; NCI-SEER (NCI Special Studies Institutional Review Board); NHS: Partners Human Research Committee, Brigham and Women's Hospital, NSW: NSW Cancer Council Ethics Committee; NYU-WHS: New York University School of Medicine Institutional Review Board; PLCO: (NCI Special Studies Institutional Review Board); SCALE: Scientific Ethics Committee for the Capital Region of Denmark; SCALE: Regional Ethical Review Board in Stockholm (Section 4) IRB#5; UCSF2: University of California San Francisco Committee on Human Research; Utah: University of Utah; WHI: Fred Hutchinson Cancer Research Center; Yale: Human Investigation Committee, Yale University School of Medicine. Informed consent was obtained from all participants. 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:
This work was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. Caroline Besson thanks the Monahan Foundation for providing her a research travel grant. A complete list of study-specific acknowledgements can be found in the Supplementary Material.

Publisher Copyright:
© 2021 Oxford University Press. All rights reserved.

Keywords

  • CLL
  • NMSC
  • Pleiotropy
  • Polygenic risk score

ASJC Scopus subject areas

  • Epidemiology

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