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 BirmannImmaculata 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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Article number102432
JournalCancer Epidemiology
Volume92
Early online date16 Aug 2023
DOIs
Publication statusPublished - Oct 2024

Bibliographical note

Publisher Copyright:
© 2023

Funding

We are indebted to the participating families, whose generosity and cooperation have made this study possible. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. For the Melbourne Collaborative Cohort Study (MCCS) cohort, recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further augmented by Australian National Health and Medical Research Council grants 209057, 396414 and 1074383 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the Australian Cancer Database. For the American Cancer Society (ACS)/Cancer Prevention Study-II (CPS-II), the authors express sincere appreciation to all Cancer Prevention Study-II participants, and to each member of the study and biospecimen management group. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries and cancer registries supported by the National Cancer Institute’s Surveillance Epidemiology and End Results Program. ACS intramural funding: The American Cancer Society funds the creation, maintenance, and updating of the Cancer Prevention Study-II cohort. For the European Prospective Investigation into Cancer (EPIC), funding includes Coordinated Action (Contract #006438, SP23-CT-2005–006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK. For Health Professionals Follow-up Study (HPFS), HPFS (Walter C. Willet) – The HPFS was supported in part by National Institutes of Health grants UO1 CA167552, R01 CA149445, and R01 CA098122. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. We would also like to thank the participants and staff of the Health Professionals Follow-up Study for their valuable contributions. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. For Nurses' Health Study (NHS), NHS (Meir J. Stampfer) – The NHS was supported in part by National Institutes of Health grants UM1 CA186107, P01 CA87969, R01 CA49449, R01 CA149445, R01 CA098122 and R01 CA134958. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. We also thank the participants and staff of the Nurses' Health Study for their valuable contributions. The study protocol was approved by the institutional review boards of the Brigham and Women’s Hospital and Harvard T.H. Chan School of Public Health, and those of participating registries as required. This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute . This work was also supported by grants to ILA and JSW from the Ontario Cancer Research Network , the Ontario Research Fund, and Canadian Foundation for Innovation . JSW holds the Rubinoff-Gross Chair in Orthopaedic Oncology. Please see acknowledgement section for additional funding information.

FundersFunder number
Coordinated Action006438, SP23-CT-2005–006438
HPFS
Human Genetics Foundation
NHSR01 CA49449, P01 CA87969, R01 CA134958, UM1 CA186107
National Cancer Institute’s Surveillance Epidemiology and End Results Program
Ontario Cancer Research Network
National Institutes of HealthR01 CA098122, R01 CA149445, UO1 CA167552
National Institutes of Health
National Cancer Institute
Division of Cancer Epidemiology and Genetics, National Cancer Institute
Ontario Research Foundation
Canada Foundation for Innovation
Cancer Research UK
National Health and Medical Research Council396414, 209057, 1074383
National Health and Medical Research Council
Cancer Council Victoria
VicHealth

    Keywords

    • Birthweight
    • Genetic risk score
    • Height
    • Osteosarcoma
    • Puberty timing

    Fingerprint

    Dive into the research topics of 'Genetically inferred birthweight, height, and puberty timing and risk of osteosarcoma'. Together they form a unique fingerprint.

    Cite this