Identification of 4 autophagy-related genetic variants as risk factors for chronic lymphocytic leukemia

Abstract

Health services and outcomes; Lymphoid neoplasia

Servicios de salud y resultados; Neoplasia linfoide

Serveis de salut i resultats; Neoplàsia limfoide

We investigated the influence of 55 583 autophagy-related single-nucleotide polymorphisms (SNPs) on chronic lymphocytic leukemia (CLL) risk across 4 independent populations comprising 5472 CLL cases and 726 465 controls. We also examined their impact on overall survival (OS), time to first treatment (TTFT), autophagy flux, and immune responses. A meta-analysis of the 4 populations identified, to our knowledge, for the first time, significant associations between CDKN2A (rs3731204) and BCL2 (rs4940571, rs12457371, and rs1026825) SNPs and CLL risk, with CDKN2A showing the strongest association (P = 1.57 × 10−12). We also validated previously reported associations for FAS, BCL2, and BAK1 SNPs with CLL risk (P = 4.73 × 10−21 to 3.39 × 10−9). The CDKN2Ars3731204 and FASrs1926194 SNPs associated with increased CDKN2A and ACTA2 messenger RNA expression levels in the whole blood and/or lymphocytes (P = 5.1 × 10−7, P = 1.58 × 10−21, and P = 7.8 × 10−41), although no significant effect on autophagy flux was observed. However, associations were found between CDKN2A, BCL2, and FAS SNPs and various T-cell subsets, cytokine production, and circulating concentrations of interferon gamma, tumor necrosis factor–related apoptosis-inducing ligand, CD40, chemokine ligand 20, and interleukin-2 receptor subunit β proteins (P ≤ .005). No significant association was detected between autophagy variants and OS or TTFT, suggesting that these variants drive disease initiation rather than progression. In conclusion, this study identified 4 novel associations for CLL and provided insights into the biological pathways that influence CLL development.

This work has been funded by The Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (FEDER; Madrid, Spain; PI17/02256 and PI20/01845 [J.S.]; PI11/02213 and PI15/00966 [R.M.-G.]), Consejería de Transformación Económica, Industria, Conocimiento y Universidades and FEDER (PY20/01282 [J.S.]), Josep Carreras Leukaemia Research Institute (grant no. FIJC1100 [R.M.-G.]), and the voluntary economical contribution of patients. This research was also supported by the EU fund, PNRR CN3 Terapia Genica-Spoke 2 (project no. CN00000041) and Associazione Italiana contro le Leucemie Modena Organizzazione di Volontariato (M.L.). The University of Utah was supported by funding from the National Cancer Institute (NCI) grants R01 CA134674 and P30 CA042014-29S9 (N.J.C.). Data collection in Utah was supported by the Utah Population Database (UPDB) and the Utah Cancer Registry (UCR). The UPDB is supported by the Huntsman Cancer Institute (HCI) (including Huntsman Cancer Foundation), The University of Utah, and NCI grant P30 CA2014. The UCR was additionally funded by the NCI’s Surveillance, Epidemiology, and End Results Program, HHSN261201800016I, and the US Center for Disease Control and Prevention’s National Program of Cancer Registries (NU58DP007131). The University of Utah thanks all study participants and the ascertainment, laboratory, biobanking, and research informatics teams at the HCI. The Interlymph Data Coordinating Center was supported by the NCI grant U01CA257679.