| Title: |
Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients With Osteosarcoma |
| Authors: |
Mirabello, L; Zhu, B; Koster, R; Karlins, E; Dean, M; Yeager, M; Gianferante, M; Spector, LG; Morton, LM; Karyadi, D; Robison, LL; Armstrong, GT; Bhatia, S; Song, L; Pankratz, N; Pinheiro, M; Gastier-Foster, JM; Gorlick, R; de Toledo, SRC; Petrilli, AS; Patino-Garcia, A; Lecanda, F; Gutierrez-Jimeno, M; Serra, M; Hattinger, C; Picci, P; Scotlandi, K; Flanagan, AM; Tirabosco, R; Amary, MF; Kurucu, N; Ilhan, IE; Ballinger, ML; Thomas, DM; Barkauskas, DA; Mejia-Baltodano, G; Valverde, P; Hicks, BD; Wang, M; Hutchinson, AA; Tucker, M; Sampson, J; Landi, MT; Freedman, ND; Gapstur, S; Carter, B; Hoover, RN; Chanock, SJ; Savage, SA |
| Source: |
JAMA Oncology (2020) (In press). |
| Publication Year: |
2020 |
| Collection: |
University College London: UCL Discovery |
| Description: |
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 ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10096599/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10096599/ |
| Accession Number: |
edsbas.D8734B00 |
| Database: |
BASE |