Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients with Osteosarcoma

Lisa Mirabello, Bin Zhu, Roelof Koster, Eric Karlins, Michael Dean, Meredith Yeager, Matthew Gianferante, Logan G. Spector, Lindsay M. Morton, Danielle Karyadi, Leslie L. Robison, Gregory T. Armstrong, Smita Bhatia, Lei Song, Nathan Pankratz, Maisa Pinheiro, Julie M. Gastier-Foster, Richard Gorlick, Silvia Regina Caminada De Toledo, Antonio S. PetrilliAna Patino-Garcia, Fernando Lecanda, Miriam Gutierrez-Jimeno, Massimo Serra, Claudia Hattinger, Piero Picci, Katia Scotlandi, Adrienne M. Flanagan, Roberto Tirabosco, Maria Fernanda Amary, Nilgün Kurucu, Inci Ergurhan Ilhan, Mandy L. Ballinger, David M. Thomas, Donald A. Barkauskas, Gerardo Mejia-Baltodano, Patricia Valverde, Belynda D. Hicks, Mingyi Wang, Amy A. Hutchinson, Margaret Tucker, Joshua Sampson, Maria T. Landi, Neal D. Freedman, Susan Gapstur, Brian Carter, Robert N. Hoover, Stephen J. Chanock, Sharon A. Savage

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Importance: Osteosarcoma, the most common malignant bone tumor in children and adolescents, occurs in a high number of cancer predisposition syndromes that are defined by highly penetrant germline mutations. The germline genetic susceptibility to osteosarcoma outside of familial cancer syndromes remains unclear. Objective: To investigate the germline genetic architecture of 1244 patients with osteosarcoma. Design, Setting, and Participants: Whole-exome sequencing (n = 1104) or targeted sequencing (n = 140) of the DNA of 1244 patients with osteosarcoma from 10 participating international centers or studies was conducted from April 21, 2014, to September 1, 2017. The results were compared with the DNA of 1062 individuals without cancer assembled internally from 4 participating studies who underwent comparable whole-exome sequencing and 27173 individuals of non-Finnish European ancestry who were identified through the Exome Aggregation Consortium (ExAC) database. In the analysis, 238 high-interest cancer-susceptibility genes were assessed followed by testing of the mutational burden across 736 additional candidate genes. Principal component analyses were used to identify 732 European patients with osteosarcoma and 994 European individuals without cancer, with outliers removed for patient-control group comparisons. Patients were subsequently compared with individuals in the ExAC group. All data were analyzed from June 1, 2017, to July 1, 2019. Main Outcomes and Measures: The frequency of rare pathogenic or likely pathogenic genetic variants. Results: Among 1244 patients with osteosarcoma (mean [SD] age at diagnosis, 16 [8.9] years [range, 2-80 years]; 684 patients [55.0%] were male), an analysis restricted to individuals with European ancestry indicated a significantly higher pathogenic or likely pathogenic variant burden in 238 high-interest cancer-susceptibility genes among patients with osteosarcoma compared with the control group (732 vs 994, respectively; P = 1.3 × 10-18). A pathogenic or likely pathogenic cancer-susceptibility gene variant was identified in 281 of 1004 patients with osteosarcoma (28.0%), of which nearly three-quarters had a variant that mapped to an autosomal-dominant gene or a known osteosarcoma-Associated cancer predisposition syndrome gene. The frequency of a pathogenic or likely pathogenic cancer-susceptibility gene variant was 128 of 1062 individuals (12.1%) in the control group and 2527 of 27173 individuals (9.3%) in the ExAC group. A higher than expected frequency of pathogenic or likely pathogenic variants was observed in genes not previously linked to osteosarcoma (eg, CDKN2A, MEN1, VHL, POT1, APC, MSH2, and ATRX) and in the Li-Fraumeni syndrome-Associated gene, TP53. Conclusions and Relevance: In this study, approximately one-fourth of patients with osteosarcoma unselected for family history had a highly penetrant germline mutation requiring additional follow-up analysis and possible genetic counseling with cascade testing.

Original languageEnglish (US)
Pages (from-to)724-734
Number of pages11
JournalJAMA Oncology
Issue number5
StatePublished - May 2020

Bibliographical note

Funding Information:
Funding Support: This study was supported by the intramural research program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health; grant U01CA122371 from the National Institutes of Health (Dr Spector); grant CA21765 from the Cancer Center Support (Dr Robison); grant CA55727 from the National Cancer Institute (Dr Armstrong); grant PI13/01476 from the Fondo de Investigacion Sanitaria, Instituto de Salud Carlos III, La Fundacion La Caixa-Caja Navarra (Dr Patino-Garcia); grant RTICC RD 12/0036/0066 from the Spanish Association Against Cancer, Foundation for Applied Medical Research, Cancer Research Thematic Network of the Instituto de Salud Carlos III (Dr Lecanda); grants CB16/12/00443 and CB16/12/ 00350 from the Centro de Investigacion Biomedica en Red de Cancer (Dr Lecanda); grant RTI2018-094507-B-100 from the Spanish Ministry of Economy and Competitiveness (Dr Lecanda); a grant from the National Institute for Health Research Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and the University College London Experimental Cancer Centre (Dr Flanagan); a grant from the 2013 Hyundai Hope on Wheels (University of Minnesota); grants U10 CA98543 and U24 CA114766 from the National Cancer Institute, National Institutes of Health (Children's Oncology Group); a grant from the QuadW Foundation (Children's Oncology Group); a grant from the Regione Emilia-Romagna; a grant from the Royal National Orthopaedic Hospital Musculoskeletal Research Programme and Biobank; grant APP1004017 from the Australian National Health and Medical Research Council; grant APP1067094 from Cancer Australia; and funding from the Zach Sobiech Osteosarcoma Fund at the Children's Cancer Research Fund (Dr Spector); the American Lebanese-Syrian Associated Charities (Dr Robison); the Departamento De Salud, Gobierno De Navarra, Proyectos de Biomedicina 2018 (Dr Patino-Garcia); the Bone Cancer Research Trust (Dr Flanagan); and the Rainbows for Kate Foundation, the Liddy Shriver Sarcoma Initiative, and the Victorian Cancer Agency (International Sarcoma Kindred study).

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