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Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors

The Pharmacogenomics Journal volume 22, pages 19–24 (2022)Cite this article

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Abstract

Background

A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors.

Methods

Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses.

Results

DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ −2 SD (P = 4.5 × 10−5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ −2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort.

Conclusion

This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

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Availability of data and materials

The datasets used and/or analyzed during the current study are available in the data repositories listed in References, and/or are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all childhood ALL survivors and their parents who consented to take part in the PETALE study, as well as all study collaborators for their precious involvement in the production of this manuscript. The PETALE study is funded by the Institute of Cancer Research (ICR) of the Canadian Institutes of Health Research (CIHR), grant number: 118694, in collaboration with the Cancer Research Society Inc. (CRS), the Garron Family Cancer Center of the Hospital for Sick Children, the Pediatric Oncology Groups of Ontario (POGO), the Canadian Cancer Society Research Institute (CCSRI), the C17 Research Network (C17), the Sainte-Justine Hospital Foundation and the FRQS Applied Medical Genetics Network.

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Author notes

  1. These authors contributed equally: N. Alos, M. Krajinovic.

Authors and Affiliations

  1. University of Montreal, Montreal, QC, Canada

    A. Shalmiev, G. Nadeau, M. Aaron, E. Ouimet-Grennan, A. Rezgui, K. Petrykey, C. Laverdière, D. Sinnett, N. Alos & M. Krajinovic

  2. Sainte-Justine University Hospital Research Centre, Montreal, QC, Canada

    S. Drouin, L. Bertout, P. Beaulieu, P. St-Onge, K. Petrykey, C. Laverdière, D. Sinnett, N. Alos & M. Krajinovic

  3. Montreal Shriners Hospital for Children, Montreal, QC, Canada

    L.-N. Veilleux & F. Rauch

  4. Division of Hematology-Oncology, Sainte-Justine University Hospital Center, Montreal, Canada

    C. Laverdière, D. Sinnett & M. Krajinovic

  5. Division of Endocrinology, Sainte-Justine University Hospital Centre, Montreal, Canada

    N. Alos

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Contributions

MK, NA, DS, and CL conceived the study; SD and LB participated in its coordination. PSO and PB processed genetic data; NA, MA, GN, EOG, LNV, FR, and AR processed clinical data of study participants. AS, MK, and KP took part in statistical analysis design and performed computational analyses. AS, MK, and NA drafted the article and accept responsibility for the integrity of the data analysis. All authors have contributed to data interpretation and revised critically the manuscript.

Corresponding author

Correspondence to M. Krajinovic.

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Competing interests

AS worked at Phinc. Modeling as a pharmacokineticist. GN, MA, EOG, SD, LB, PB, PSO, LNV, FR, AR, KP, CL, SD, NA, and MK have nothing to disclose. All authors declare that they have no competing interests.

Ethical conduct of research

Patients older than 18 years of age and parents of minor patients gave their written informed consent to participate in the study, which was approved by the Institutional Review Board of SJUHC. The study was conducted in accordance with the Declaration of Helsinki.

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Shalmiev, A., Nadeau, G., Aaron, M. et al. Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors. Pharmacogenomics J 22, 19–24 (2022). https://doi.org/10.1038/s41397-021-00252-6

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