Abstract 1538P
Background
Sarcomas are rare mesenchymal tumors whose etiology remains largely unclear. The germline genetic susceptibility to sarcoma is poorly characterized.
Methods
We conducted targeted sequencing of a 148-gene panel (OncoPanscan, Genetronhealth) of the genomic DNA from 779 patients with sarcoma and quantified the prevalence of pathogenic or likely pathogenic germline variants.
Results
The median age of this cohort was 48 (0-88) years, and 72% were soft tissue sarcoma (STS), 13% were osteosarcoma. 19 (2.4%) patients had a variant that mapped to a known sarcoma-associated cancer predisposition syndrome gene (CHEK2, DICER1, NF1, RECQL4, SMARCA4, TP53, WRN). 39 (5.0%) patients harbored deleterious mutations in DNA damage repair (DDR) genes including BRCA2 (n =1), BARD1 (n =1), PALB2 (n =1), RAD50 (n =1), RAD51D (n =1) of the homologous recombination repair (HRR) pathway, MSH6 (n =2), PMS2 (n =2), PMS1 (n =1) of the mismatch repair (MMR) pathway, ERCC2 (n =1), ERCC5 (n =1), XPA (n =1) of the nucleotide excision repair (NER) pathway, BRIP1 (n =1), FANCM (n =1), FANCL (n =2), FANCD2 (n =2) of the Fanconi anemia (FA) pathway, and RECQL (n =3), RECQL4 (n =1), WRN (n =2) of the DNA helicase family. SMARCA4 and SMARCE1 encode key components of the BAF chromatin-remodeling complex and mutations of these two genes are known to drive rhabdoid tumor predisposition syndrome 2 and inherited spinal meningioma, respectively. Interestingly, we observed three sarcoma patients harboring truncating variants in SMARCA4 (n =1) or SMARCE1 (n =2). DICER1 encodes a component of the microRNA biogenesis machinery and its deficiency was recently linked to sarcoma. Deletion of Dicer1 in osteoprogenitor cells reduced expression of Sbds, which encodes a ribosome maturation factor and is mutated in 90% of Schwachman-Bodian-Diamond syndrome cases. In addition to two patients with DICER1 truncating variants, we observed 11 sarcoma patients harboring the same pathogenic SBDS c.258+2T>C mutation.
Conclusions
Our study provides novel insights regarding the contribution of germline mutations to the pathogenesis of sarcomas. These findings have the potential to identify sarcoma patients who may benefit from precision therapy and genetic counseling.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
S. Liu, X. Li, T. Ma: Financial Interests, Personal, Full or part-time Employment: Genetron Health (Beijing) Technology, Co. Ltd. All other authors have declared no conflicts of interest.