Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.
| Autor: | Im C; Department of Pediatrics, University of Minnesota, Minneapolis, MN., Neupane A; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Baedke JL; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Lenny B; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Delaney A; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.; Division of Endocrinology, Department of Pediatric Medicine, St Jude Children's Research Hospital, Memphis, TN., Dixon SB; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN., Chow EJ; Public Health Sciences and Clinical Research Divisions, Fred Hutchinson Research Center, Seattle, WA., Mostoufi-Moab S; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA., Yang T; Department of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN., Richard MA; Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX., Gramatges MM; Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX., Lupo PJ; Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX., Sharafeldin N; Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL., Bhatia S; Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL., Armstrong GT; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN., Hudson MM; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.; Department of Oncology, St Jude Children's Research Hospital, Memphis, TN., Ness KK; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Robison LL; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Yasui Y; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Wilson CL; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN., Sapkota Y; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN. |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Journal of clinical oncology : official journal of the American Society of Clinical Oncology [J Clin Oncol] 2024 Jul 01; Vol. 42 (19), pp. 2306-2316. Date of Electronic Publication: 2024 Apr 23. |
| DOI: | 10.1200/JCO.23.02281 |
| Abstrakt: | Purpose: Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D. Patients and Methods: Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci. Results: Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance ( P < 5 × 10 -8 ). Among these, common variants at 5p15.2 ( LINC02112 ), 2p25.3 ( MYT1L ), and 19p12 ( ZNF492 ) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: OR Conclusion: Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|