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

128 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

Publisher Copyright:
© 2020 American Medical Association. All rights reserved.


Dive into the research topics of 'Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients with Osteosarcoma'. Together they form a unique fingerprint.

Cite this