Germline Genetic and Treatment-Related Risk Factors for Diabetes Mellitus in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study and St Jude Lifetime Cohorts

Authors

Melissa A Richard
Sogol Mostoufi-Moab
Nisha Rathore
Jessica Baedke
Austin L Brown
Stephen J Chanock
Danielle N Friedman
M Monica Gramatges
Rebecca M Howell
Kala Y Kamdar
Wendy M Leisenring
Lillian R Meacham
Lindsay M Morton
Kevin Oeffinger
Leslie L Robison
Yadav Sapkota
Charles A Sklar
Gregory T Armstrong
Smita Bhatia
Philip J Lupo

Publication Date

12-1-2022

Journal

JCO Precision Oncology

DOI

10.1200/PO.22.00239

PMID

36480781

PMCID

PMC10166479

PubMedCentral® Posted Date

12-8-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Child, Humans, Cancer Survivors, Neoplasms, Genome-Wide Association Study, Diabetes Mellitus, Risk Factors, DNA Helicases

Abstract

Purpose: To characterize germline genetic risk factors of diabetes mellitus among long-term survivors of childhood cancer.

Methods: Adult survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS) Original Cohort (n = 5,083; 383 with diabetes) were used to conduct a discovery genome-wide association study. Replication was performed using the CCSS Expansion (n = 2,588; 40 with diabetes) and the St Jude Lifetime (SJLIFE; n = 3,351; 208 with diabetes) cohorts. Risk prediction models, stratified on exposure to abdominal radiation, were calculated using logistic regression including attained age, sex and body mass index, diagnosis, alkylating chemotherapy, age at cancer diagnosis, and a polygenic risk score (PRS) on the basis of 395 diabetes variants from the general population. Area under the receiver operating characteristic curve (AUC) was calculated for models on the basis of traditional risk factors, clinical risk factors, and PRS.

Results: There was a genome-wide significant association of rs55849673-A with diabetes among survivors (odds ratio, 2.9; 95% CI, 2.0 to 4.2; P = 3.7 × 10-8), which is related to expression of ERCC6L2 in the Genotype-Tissue Expression project. The association of rs55849673-A was observed largely among survivors not exposed to abdominal radiation (odds ratio = 3.5, P = 1.1 × 10-7) and the frequency of rs55849673-A was consistently higher among diabetic survivors in the CCSS Expansion and SJLIFE cohorts. Risk prediction models including traditional diabetes risk factors, clinical risk factors and PRS had an optimism-corrected AUC of 0.801, with an AUC of 0.751 in survivors treated with abdominal radiation versus 0.813 in survivors who did not receive abdominal radiation.

Conclusion: There is evidence for a novel locus of diabetes among survivors not exposed to abdominal radiation. Further refinement and validation of clinic-based risk prediction models for diabetes among long-term survivors of childhood cancer is warranted.