Identification of a Single-Nucleotide Polymorphism within CDH2 Gene Associated with Bone Morbidity in Childhood Acute Lymphoblastic Leukemia survivors

Abstract

Aim: To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). Patients & methods: To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. Results: The minor allele of rs1944294 in CDH2 gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). Conclusion: The variant in CDH2 gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.

Keywords::

• acute lymphoblastic leukemia
• bone mineral density
• genetic association study
• genetic variants
• late adverse effects
• skeletal morbidities
• survivorship
• vertebral fractures
• whole exome sequencing

Supplementary data

Acknowledgements

The authors thank all childhood acute lymphoblastic leukemia 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.

Financial & competing interests disclosure

The PETALE study is funded by the Canadian Institutes of Health Research 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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Author contributions

D Sinnett, M Krajinovic, N Alos and C Laverdière conceived the study; S Drouin and L Bertout participated in its design and coordination. P St-Onge and P Beaulieu processed genetic data of study participants. LN Veilleux and F Rauch processed pQCT data of study participants. M Krajinovic and K Petrykey took part in statistical analysis design. M Aaron, G Nadeau, E Ouimet-Grennan, A Shalmiev and M Krajinovic performed computational analyses. M Aaron, G Nadeau, E Ouimet-Grennan, M Krajinovic and N Alos drafted the article. M Krajinovic, N Alos and M Aaron accept responsibility for the integrity of the data analysis. All the authors have contributed to data interpretation and critically revised the manuscript.

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.

Additional information

Funding

The PETALE study is funded by the Canadian Institutes of Health Research 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. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.