Germline pathogenic variants in DNA repair pathways: A key feature in a significant subset of translocation-associated sarcomas Journal Article
| Authors: | Saoud, C.; Dermawan, J. K.; Arora, K.; Tap, W. D.; Reed, D.; Slotkin, E. K.; Wexler, L. H.; Murciano-Goroff, Y. R.; Latham, A.; Mandelker, D. L.; Antonescu, C. R. |
| Article Title: | Germline pathogenic variants in DNA repair pathways: A key feature in a significant subset of translocation-associated sarcomas |
| Abstract: | 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. © The Author(s) 2025. |
| Keywords: | adolescent; adult; cancer chemotherapy; cancer survival; child; controlled study; aged; young adult; major clinical study; overall survival; endometrium cancer; colorectal cancer; gene; dna repair; antineoplastic metal complex; breast cancer; cohort analysis; genetic association; practice guideline; brca1 protein; brca2 protein; retrospective study; protein p53; cancer resistance; ewing sarcoma; prostate cancer; sarcoma; colon cancer; microsatellite instability; telomerase reverse transcriptase; atm protein; genomics; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase inhibitor; checkpoint kinase 2; heterozygosity loss; cyclin dependent kinase inhibitor 2a; synovial sarcoma; microphthalmia associated transcription factor; genetic screening; transcription factor yap1; mismatch repair protein; protein msh6; apc protein; clear cell sarcoma; alveolar soft part sarcoma; desmoplastic small round cell tumor; myxosarcoma; autosomal dominant inheritance; dermatofibrosarcoma protuberans; alveolar rhabdomyosarcoma; bone sarcoma; fanconi anemia group c protein; cyclin dependent kinase inhibitor 2b; transcription factor pax7; germline mutation; fanconi anemia group a protein; stag2 gene; fibroblast growth factor receptor 4; epithelioid hemangioendothelioma; protein msh3; arid1a gene; second-degree relative; dna sequencing; human; male; female; article; mutl protein homolog 1; tumor mutational burden; crfl2 gene; translocation associated sarcoma |
| Journal Title: | npj Precision Oncology |
| Volume: | 9 |
| ISSN: | 2397-768X |
| Publisher: | Springer Nature |
| Date Published: | 2025-05-07 |
| Start Page: | 133 |
| Language: | English |
| DOI: | 10.1038/s41698-025-00925-6 |
| PROVIDER: | scopus |
| PMCID: | PMC12059086 |
| PUBMED: | 40335592 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Cristina Antonescu -- Source: Scopus |
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