[Skip to Content]
[Skip to Content Landing]
Original Investigation
March 19, 2020

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

Author Affiliations
  • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
  • 2Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland
  • 3Department of Pediatrics, University of Minnesota, Minneapolis
  • 4Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, Tennessee
  • 5Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham
  • 6Department of Pathology and Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus
  • 7Department of Pediatrics, University of Texas MD Anderson Cancer Center, Houston
  • 8Laboratorio de Genetica, Instituto de Oncologia Pediatrica, Grupo de Apoio ao Adolescente e a Crianca com Cancer/Universidade Federal de Sao Paulo, Sao Paulo, Brazil
  • 9Solid Tumor Division, Department of Pediatrics, University Clinic of Navarra and Center for Applied Medical Research, Navarra Institute for Health Research, Pamplona, Spain
  • 10Center for Applied Medical Research, University of Navarra, Instituto de Investigacion Sanitaria de Navarra, and Centro de Investigacion Biomedica en Red Cancer, Pamplona, Spain
  • 11Laboratory of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Ortopedico Rizzoli, Bologna, Italy
  • 12Research Department of Pathology, UCL Cancer Institute, London, United Kingdom
  • 13Royal National Orthopaedic Hospital NHS Trust, Stanmore, Middlesex, United Kingdom
  • 14Department of Pediatric Oncology, A.Y. Ankara Oncology Training and Research Hospital, Yenimahalle, Ankara, Turkey
  • 15Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
  • 16St. Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia
  • 17Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles
  • 18Hospital Infantil Manuel De Jesus Rivera, Managua, Nicaragua
  • 19Unidad Nacional de Oncología Pediatrica, Guatemala City, Guatemala
  • 20Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
JAMA Oncol. 2020;6(5):724-734. doi:10.1001/jamaoncol.2020.0197
Key Points

Question  What is the frequency of pathogenic or likely pathogenic germline genetic variants in known cancer-susceptibility genes in a large population of patients with osteosarcoma who were unselected for family history?

Findings  In this next-generation exome sequencing study of 1244 patients with osteosarcoma, 28.0% of patients in the discovery set carried a rare pathogenic or likely pathogenic germline variant in a cancer-susceptibility gene compared with 12.1% of individuals without cancer who were comparably sequenced and 9.3% of individuals of non-Finnish European ancestry identified through the Exome Aggregation Consortium database.

Meaning  A higher than expected frequency of patients with osteosarcoma carrying a pathogenic or likely pathogenic germline variant suggests germline genetic testing may be warranted for individuals with osteosarcoma.


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 27 173 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 27 173 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.

Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words