Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

D Matthew Gianferante; Amy Moore; Logan G Spector; William Wheeler; Tianzhong Yang; Aubrey Hubbard; Richard Gorlick; Ana Patiño-Garcia; Fernando Lecanda; Adrienne M Flanagan; Fernanda Amary; Irene L Andrulis; Jay S Wunder; David M Thomas; Mandy L Ballinger; Massimo Serra; Claudia Hattinger; Ellen Demerath; Will Johnson; Brenda M Birmann; Immaculata De Vivo; Graham Giles; Lauren R Teras; Alan Arslan; Roel Vermeulen; Jeannette Sample; Neal D Freedman; Wen-Yi Huang; Stephen J Chanock; Sharon A Savage; Sonja I Berndt; Lisa Mirabello

doi:10.1016/j.canep.2023.102432

Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma

Cancer Epidemiol. 2023 Aug 16:102432. doi: 10.1016/j.canep.2023.102432. Online ahead of print.

Authors

D Matthew Gianferante¹, Amy Moore¹, Logan G Spector², William Wheeler³, Tianzhong Yang⁴, Aubrey Hubbard¹, Richard Gorlick⁵, Ana Patiño-Garcia⁶, Fernando Lecanda⁷, Adrienne M Flanagan⁸, Fernanda Amary⁹, Irene L Andrulis¹⁰, Jay S Wunder¹⁰, David M Thomas¹¹, Mandy L Ballinger¹¹, Massimo Serra¹², Claudia Hattinger¹², Ellen Demerath¹³, Will Johnson¹⁴, Brenda M Birmann¹⁵, Immaculata De Vivo¹⁶, Graham Giles¹⁷, Lauren R Teras¹⁸, Alan Arslan¹⁹, Roel Vermeulen²⁰, Jeannette Sample², Neal D Freedman¹, Wen-Yi Huang¹, Stephen J Chanock¹, Sharon A Savage¹, Sonja I Berndt¹, Lisa Mirabello²¹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, MD, USA.
² Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
³ Information Management Services, Rockville, MD, USA.
⁴ Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
⁵ University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Department of Pediatrics and Solid Tumor Division CIMA, IdiSNA, Clínica Universidad de Navarra, Pamplona, Spain.
⁷ Center for Applied Medical Research (CIMA)-University of Navarra, IdiSNA, and CIBERONC, Pamplona, Spain.
⁸ UCL Cancer Institute, Huntley Street, London WC1E 6BT, UK; Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
⁹ Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex HA7 4LP, UK.
¹⁰ Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
¹¹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
¹² Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; IRCCS Istituto Ortopedico Rizzoli, Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, Pharmacogenomics and Pharmacogenetics Research Unit, Bologna, Italy.
¹³ Division of Epidemiology and Clinical Research, School of Public Health, UMN, USA.
¹⁴ School of Sport, Exercise, and Health Sciences, University of Loughborough, UK.
¹⁵ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹⁶ Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹⁷ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
¹⁸ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
¹⁹ Department of Obstetrics and Gynecology, New York School of Medicine, New York, NY, USA; Department of Population Health, New York University School of Medicine, New York, NY, USA.
²⁰ Institute for Risk Assessment Sciences, Utrecht University, Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
²¹ Division of Cancer Epidemiology and Genetics, NCI, NIH, Rockville, MD, USA. Electronic address: mirabellol@nih.gov.

PMID: 37596165
PMCID: PMC10869637 (available on 2025-02-16)
DOI: 10.1016/j.canep.2023.102432

Abstract

Introduction: Several studies have linked increased risk of osteosarcoma with tall stature, high birthweight, and early puberty, although evidence is inconsistent. We used genetic risk scores (GRS) based on established genetic loci for these traits and evaluated associations between genetically inferred birthweight, height, and puberty timing with osteosarcoma.

Methods: Using genotype data from two genome-wide association studies, totaling 1039 cases and 2923 controls of European ancestry, association analyses were conducted using logistic regression for each study and meta-analyzed to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were conducted by case diagnosis age, metastasis status, tumor location, tumor histology, and presence of a known pathogenic variant in a cancer susceptibility gene.

Results: Genetically inferred higher birthweight was associated with an increased risk of osteosarcoma (OR =1.59, 95% CI 1.07-2.38, P = 0.02). This association was strongest in cases without metastatic disease (OR =2.46, 95% CI 1.44-4.19, P = 9.5 ×10^-04). Although there was no overall association between osteosarcoma and genetically inferred taller stature (OR=1.06, 95% CI 0.96-1.17, P = 0.28), the GRS for taller stature was associated with an increased risk of osteosarcoma in 154 cases with a known pathogenic cancer susceptibility gene variant (OR=1.29, 95% CI 1.03-1.63, P = 0.03). There were no significant associations between the GRS for puberty timing and osteosarcoma.

Conclusion: A genetic propensity to higher birthweight was associated with increased osteosarcoma risk, suggesting that shared genetic factors or biological pathways that affect birthweight may contribute to osteosarcoma pathogenesis.

Keywords: Birthweight; Genetic risk score; Height; Osteosarcoma; Puberty timing.

Abstract

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