Childhood Cancer Survivors: Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus

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In a study reported in the Journal of Clinical Oncology, Im et al found that genetic variants associated with a risk of treatment-related type 2 diabetes mellitus among childhood cancer survivors of African or European ancestry posed a higher risk of diabetes among those of African ancestry.

As stated by the investigators, “Type 2 diabetes mellitus 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 transancestral genetic risks for treatment-related type 2 diabetes mellitus.”

Study Details

The study used whole-genome sequencing data from the St. Jude Lifetime Cohort to perform ancestry-specific genome-wide association analyses among survivors of African and European genetic ancestry and a transancestry meta-analysis. Analysis of trans-ancestry and within-ancestry variants included data from the Childhood Cancer Survivor Study.

Key Findings

A total of four novel type 2 diabetes mellitus risk loci showing evidence of trans-/within-ancestry replication were identified, with three of these showing genome-wide significance (P < 5 × 10−8).

For the three loci, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent–related type 2 diabetes mellitus risk in both ancestral groups, and disproportionately greater risk in survivors with African ancestry; across the three loci, odds ratios for type 2 diabetes mellitus ranged from 3.95 to 17.81 for survivors with African ancestry vs 2.37 to 3.32 for survivors with European ancestry.

RNA sequencing data from 207 survivors showed that the 19p12 locus variant was associated with greater dysregulation of ZNF492 expression after exposure to alkylating agents.

Increased type 2 diabetes mellitus risks across ancestries groups were associated with increasing values for multi-ancestry type 2 diabetes mellitus polygenic risk scores, with notable increases in risk being observed in survivors treated with alkylating agents. Among those receiving alkylating agents, odds ratios for type 2 diabetes mellitus for the highest vs lowest quintile of cumulative doses were 20.18 (P = .023) among African-ancestry survivors and 13.44 (P = 1.3 × 10−9) among European-ancestry survivors. By comparison, among European-ancestry survivors not treated with alkylating agents who had the same level of polygenic risk, the odds ratio for type 2 diabetes mellitus was 6.5.

The investigators concluded, “Our findings suggest therapy-related genetic risks contribute to the increased type 2 diabetes mellitus burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.”

Yadav Sapkota, PhD, of the Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute, American Lebanese Syrian Associated Charities, and others. For full disclosures of the study authors, visit

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