TY - JOUR
T1 - Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in Patients with Osteosarcoma
AU - Mirabello, Lisa
AU - Zhu, Bin
AU - Koster, Roelof
AU - Karlins, Eric
AU - Dean, Michael
AU - Yeager, Meredith
AU - Gianferante, Matthew
AU - Spector, Logan G.
AU - Morton, Lindsay M.
AU - Karyadi, Danielle
AU - Robison, Leslie L.
AU - Armstrong, Gregory T.
AU - Bhatia, Smita
AU - Song, Lei
AU - Pankratz, Nathan
AU - Pinheiro, Maisa
AU - Gastier-Foster, Julie M.
AU - Gorlick, Richard
AU - De Toledo, Silvia Regina Caminada
AU - Petrilli, Antonio S.
AU - Patino-Garcia, Ana
AU - Lecanda, Fernando
AU - Gutierrez-Jimeno, Miriam
AU - Serra, Massimo
AU - Hattinger, Claudia
AU - Picci, Piero
AU - Scotlandi, Katia
AU - Flanagan, Adrienne M.
AU - Tirabosco, Roberto
AU - Amary, Maria Fernanda
AU - Kurucu, Nilgün
AU - Ilhan, Inci Ergurhan
AU - Ballinger, Mandy L.
AU - Thomas, David M.
AU - Barkauskas, Donald A.
AU - Mejia-Baltodano, Gerardo
AU - Valverde, Patricia
AU - Hicks, Belynda D.
AU - Wang, Mingyi
AU - Hutchinson, Amy A.
AU - Tucker, Margaret
AU - Sampson, Joshua
AU - Landi, Maria T.
AU - Freedman, Neal D.
AU - Gapstur, Susan
AU - Carter, Brian
AU - Hoover, Robert N.
AU - Chanock, Stephen J.
AU - Savage, Sharon A.
N1 - Publisher Copyright:
© 2020 American Medical Association. All rights reserved.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
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U2 - 10.1001/jamaoncol.2020.0197
DO - 10.1001/jamaoncol.2020.0197
M3 - Article
C2 - 32191290
AN - SCOPUS:85082339224
SN - 2374-2437
VL - 6
SP - 724
EP - 734
JO - JAMA Oncology
JF - JAMA Oncology
IS - 5
ER -