Germline pathogenic variants in DNA repair pathways: a key feature in a significant subset of translocation-associated sarcomas

Translocation-associated sarcomas (TAS) are rare, phenotypically heterogeneous, with predisposition for young adults. We aimed to investigate the clinical impact of germline pathogenic/likely pathogenic (P/LP) variants in a diverse group of TAS and to conduct a comprehensive comparative analysis of clinicopathologic features, genomic alterations, and survival outcomes. A retrospective cohort of 426 TAS patients with both tumor and germline DNA sequencing was investigated for clinical actionability of P/LP variants, and potential impact on current screening guidelines and clinical interventions. Twenty-eight patients (6.6%) carried Tier 1 germline P/LP variants (moderate to high penetrance autosomal dominant (AD) variants), while 27 (6.3%) patients carried Tier 2 variants (monoallelic autosomal recessive or low penetrance AD variants). Compared to Tier 2, Tier 1 patients were more commonly of European ancestry and had a higher frequency of first- and second-degree relatives with cancer history. Notably, the frequency of both tiers variants was lower among pediatric patients compared to older patients and differed across TAS histologies, with the highest observed in solitary fibrous tumors. All germline P/LP variants were monoallelic, dispersed across multiple genes, and enriched in DNA damage repair pathways. There was no association between the germline P/LP variants and somatic genomic profile, nor any survival impact when stratified by histotype. Our findings highlight the incidence of clinically significant germline P/LP variants in TAS is lower in pediatric patients, questioning current sarcoma genetic screening guidelines and supporting germline testing for all TAS patients. Significant interventions were triggered in 46% of Tier 1 (n = 13), including platinum-based chemotherapy and PARP inhibitors in two BRCA1/2 patients.