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

Abstract

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 MEASURESThe 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.

Analysis in the Prospective Lynch Syndrome Database identifies sarcoma as part of the Lynch syndrome tumor spectrum

“…7 Most recently, MSH2 was reported as one of a small number of genes that showed a significantly higher burden of pathogenic or likely pathogenic variants in European OS patients compared to controls (0.4%, 3 of 732 patients). 8 We conclude that the incidence of OS in LS patients is significantly increased compared to the general population. We suggest that osteosarcoma is part of the LS spectrum in adults and seems to be associated particularly with the path_MSH2 genotype.…”

“…Regarding the type of path_MMR variants identified in these patients, predicted missense changes were most common (7/16), followed by splicing (5/16) and deletion variants (4/16). Regarding gender, equal numbers of females (8) and males 8were affected.…”

Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants

“…Compared to regular population incidences (0.34/100,000 for osteosarcomas [39] and 3.4/100,000 for soft-tissue sarcomas [40]), this indicates that osteosarcoma and soft-tissue sarcoma incidences are >50 timers and >1.8 times higher, respectively, in LS patients. Reinforcing this increased risk of osteosarcomas, recently Mirabello et al [41] investigated germline causes of 1244 patients with osteosarcoma and identified more germline MSH2 pathogenic variants in cases than in the control cohorts (p < 0.05).…”

Role of POT1 in Human Cancer

“…Four POT1 mutations were identified significantly more frequently in breast cancer patients ( n = 1067) than in healthy controls ( n = 1110) [ 101 ]. Moreover, in a recent study focusing on pathogenic osteosarcoma germline mutations, five POT1 germline variants (p.Asp42Tyr, p.Gln376Arg, p.Leu69Phe, p.Asp617fs; p. and c.670G > A) were detected ( n = 5/1004) [ 102 ]. In those with European ancestry, POT1 germline mutation frequency was statistically significantly enriched in those with disease (0.5%, n = 4/732), indicating a potential association between POT1 germline variants and risk of developing osteosarcoma [ 102 ].…”

“…Moreover, in a recent study focusing on pathogenic osteosarcoma germline mutations, five POT1 germline variants (p.Asp42Tyr, p.Gln376Arg, p.Leu69Phe, p.Asp617fs; p. and c.670G > A) were detected ( n = 5/1004) [ 102 ]. In those with European ancestry, POT1 germline mutation frequency was statistically significantly enriched in those with disease (0.5%, n = 4/732), indicating a potential association between POT1 germline variants and risk of developing osteosarcoma [ 102 ]. Furthermore, one case–control study has shown that the presence of the rs10244817 variant in POT1 is significantly associated with lung cancer [ 103 ], and a single nucleotide polymorphism (SNP) near POT1 (rs116895242) is associated with a reduced likelihood of acquiring colorectal, ovarian, and lung cancer [ 104 ].…”