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

Abstract

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.

Figure 1.. Overview of Study Samples and Design

CSG indicates cancer-susceptibility gene; ExAC, Exome Aggregation Consortium database; NCI, National Cancer Institute; P/LP, pathogenic/likely pathogenic; and UMN, University of Minnesota. ^aGenetic ancestry was determined using the available microarray from single-nucleotide polymorphism genome-wide association studies or whole-exome sequencing data from structure and principal component analyses. Individuals with more than 80% European ancestry were considered European. ^bSequencing of 238 cancer-susceptibility genes.

Figure 2.. Frequency of Rare Pathogenic or Likely Pathogenic Germline Variants in Cancer-Susceptibility Genes

A, Includes 1004 patients in the discovery set, 1062 individuals in the control group, and 27 173 individuals in the ExAC group. Genes with both AD and AR inheritance patterns and variants in genes with unknown inheritance are grouped with AD genes. B, Includes genes with a significantly higher frequency of pathogenic/likely pathogenic, damaging, or rare variants in 732 European patients compared with 27 173 individuals in the ExAC group. P values represent European patient-control group burden tests, with P < .0002 significant at the Bonferroni threshold. AD indicates autosomal-dominant genes; AR, autosomal-recessive genes; ExAC, Exome Aggregation Consortium database; P/LP, pathogenic/likely pathogenic; and XLR, X-linked or Y-linked recessive inheritance pattern genes.

Figure 3.. Frequency of Pathogenic or Likely Pathogenic Variants

Frequency of pathogenic or likely pathogenic variants in the 1004 patients and 1062 individuals in the control group. P values represent European patient-control group burden tests, with P < .0002 significant at the Bonferroni threshold.

Figure 4.. Frequency of Rare Pathogenic or Likely Pathogenic Variants

All ADGs include genes TP53 and CDKN2A. A total of 151 patients were aged 0 to 10 years, 698 patients were aged 11 to 20 years, and 125 patients were aged 21 years and older. ADG indicates autosomal-dominant gene and CSG, cancer-susceptibility gene.