TY - JOUR
T1 - Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer
AU - Im, Cindy
AU - Neupane, Achal
AU - Baedke, Jessica L.
AU - Lenny, Brian
AU - Delaney, Angela
AU - Dixon, Stephanie B.
AU - Chow, Eric J.
AU - Mostoufi-Moab, Sogol
AU - Yang, Tianzhong
AU - Richard, Melissa A.
AU - Gramatges, M. Monica
AU - Lupo, Philip J.
AU - Sharafeldin, Noha
AU - Bhatia, Smita
AU - Armstrong, Gregory T.
AU - Hudson, Melissa M.
AU - Ness, Kirsten K.
AU - Robison, Leslie L.
AU - Yasui, Yutaka
AU - Wilson, Carmen L.
AU - Sapkota, Yadav
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2024/7/1
Y1 - 2024/7/1
N2 - PURPOSEType 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 METHODSLeveraging 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.RESULTSFour 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: ORAFR, 20.18; P =.023; OREUR, 13.44; P = 1.3 × 10-9).CONCLUSIONOur 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.
AB - PURPOSEType 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 METHODSLeveraging 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.RESULTSFour 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: ORAFR, 20.18; P =.023; OREUR, 13.44; P = 1.3 × 10-9).CONCLUSIONOur 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.
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U2 - 10.1200/jco.23.02281
DO - 10.1200/jco.23.02281
M3 - Article
C2 - 38652878
AN - SCOPUS:85197541211
SN - 0732-183X
VL - 42
SP - 2306
EP - 2316
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 19
ER -