{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T10:20:03Z","timestamp":1780482003643,"version":"3.54.1"},"reference-count":22,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Mayo Transform the Practice Grant, Mayo Clinic Center for Individualized Medicine, Desert Mountain Members\u2019 CARE Foundation, David and Twila Woods Foundation and a Faculty Career Development Award from the Gerstner Foundation (NJS)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Sarcomas are rare heterogenous mesenchymal tumors with over seventy-five different subtypes, with varying biology and outcomes, with no clear inciting factor in the vast majority. To determine the prevalence of pathogenic germline variants (PGV) in patients with sarcomas, we undertook a prospective multi-site study of germline sequencing using an 84-gene next-generation sequencing panel among patients receiving care at the four Mayo Clinic Cancer Centers. Of 115 patients with bone and soft tissue sarcoma, the median age was 60 years, 49.6% were female, 82.6% were White. The anatomical location of the primary tumor included extremities (34.8%), retroperitoneum (19.1%), trunk (13.0%), and head and neck (7.8%). Family history of cancer was present in 62.6% of the study population. Ten patients (8.7%) had a pathogenic\/likely pathogenic variant (PGV). Of these, three had stage IV sarcoma, and seven had earlier-stage sarcoma (stages I\u2013III). Among the 55 (48.7%) patients who had variant of uncertain significance (VUS), 41.1% (22\/55) had stage IV sarcoma and 58.9% (33\/55) had earlier-stage disease. Of the ten patients with PGV, high-to-moderate penetrance gene abnormalities were identified in eight patients (80%) involving TP53 (3), BRCA1 (1), SDHA (1), ATM (2), and NBN (1) genes. The vast majority of the PGVs (70%) would not have been detected using the current guidelines. Because of the paucity of sarcomas and lack of effective treatment options for advanced disease, germline testing in sarcomas represents a potentially impactful strategy to assess therapeutic options and for assessment of familial risk.<\/jats:p>","DOI":"10.3390\/ijms26072839","type":"journal-article","created":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T07:25:00Z","timestamp":1742541900000},"page":"2839","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Germline Genetic Testing in Patients with Bone and Soft Tissue Sarcoma: A Prospective Multicenter Study to Evaluate Cancer Susceptibility"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6998-2274","authenticated-orcid":false,"given":"Isaak","family":"Ailts","sequence":"first","affiliation":[{"name":"Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA"},{"name":"Division of Hematology\/Oncology, University of North Dakota, Fargo, ND 58122, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7666-7782","authenticated-orcid":false,"given":"Michael A.","family":"Golafshar","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Phoenix, AZ 85043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6850-6823","authenticated-orcid":false,"given":"Katie L.","family":"Kunze","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic, Phoenix, AZ 85043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Klint","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Phoenix, AZ 85043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Barrus","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Phoenix, AZ 85043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Nussbaum","sequence":"additional","affiliation":[{"name":"Labcorp Genetics (formerly Invitae), San Francisco, CA 94103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9205-3756","authenticated-orcid":false,"given":"Edward D.","family":"Esplin","sequence":"additional","affiliation":[{"name":"Labcorp Genetics (formerly Invitae), San Francisco, CA 94103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandie","family":"Leach","sequence":"additional","affiliation":[{"name":"Labcorp Genetics (formerly Invitae), San Francisco, CA 94103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5916-6393","authenticated-orcid":false,"given":"Sarah","family":"Young","sequence":"additional","affiliation":[{"name":"Labcorp Genetics (formerly Invitae), San Francisco, CA 94103, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N. Jewel","family":"Samadder","sequence":"additional","affiliation":[{"name":"Department of Clinical Genomics, Mayo Clinic, Phoenix, AZ 85043, USA"},{"name":"Division of Gastroenterology & Hepatology, Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA"},{"name":"Center for Individualized Medicine, Mayo Clinic, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh","family":"Seetharam","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ 85054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1634\/theoncologist.2016-0079","article-title":"Sarcomas Associated with Genetic Cancer Predisposition Syndromes: A Review","volume":"21","author":"Farid","year":"2016","journal-title":"Oncologist"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.18632\/oncotarget.26809","article-title":"Sarcomas in the United States: Recent trends and a call for improved staging","volume":"10","author":"Gage","year":"2019","journal-title":"Oncotarget"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.6004\/jnccn.2020.0058","article-title":"NCCN Guidelines Insights: Soft Tissue Sarcoma, Version 1.2021","volume":"18","author":"Kane","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1002\/cncr.26390","article-title":"Sarcomas in TP53 germline mutation carriers: A review of the IARC TP53 database","volume":"118","author":"Ognjanovic","year":"2012","journal-title":"Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.mce.2017.07.018","article-title":"Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome","volume":"469","author":"Settas","year":"2018","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1200\/JCO.2017.74.9374","article-title":"Contemporary Sarcoma Diagnosis, Genetics, and Genomics","volume":"36","author":"Schaefer","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cell.2018.03.039","article-title":"Pathogenic Germline Variants in 10,389 Adult Cancers","volume":"173","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/S1470-2045(16)30147-4","article-title":"Monogenic and polygenic determinants of sarcoma risk: An international genetic study","volume":"17","author":"Ballinger","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"77","DOI":"10.6004\/jnccn.2021.0001","article-title":"Genetic\/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology","volume":"19","author":"Daly","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e11131","DOI":"10.15252\/emmm.201911131","article-title":"Sarcoma treatment in the era of molecular medicine","volume":"12","author":"Grunewald","year":"2020","journal-title":"EMBO Mol. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1001\/jamaoncol.2018.0723","article-title":"Targetable Alterations in Adult Patients with Soft-Tissue Sarcomas: Insights for Personalized Therapy","volume":"4","author":"Lucchesi","year":"2018","journal-title":"JAMA Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1038\/bjc.2014.624","article-title":"BRCA1 haplotype and clinical benefit of trabectedin in soft-tissue sarcoma patients","volume":"112","author":"Chaire","year":"2015","journal-title":"Br. J. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.pharmthera.2019.06.010","article-title":"TP53 in bone and soft tissue sarcomas","volume":"202","author":"Thoenen","year":"2019","journal-title":"Pharmacol. Ther."},{"key":"ref_14","first-page":"742","article-title":"Li-Fraumeni Syndrome","volume":"8","author":"Vogel","year":"2017","journal-title":"J. Adv. Pract. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e2200517","DOI":"10.1200\/PO.22.00517","article-title":"Multigene panel testing yields high rates of clinically actionable variants among patients with colorectal cancer","volume":"6","author":"Coughlin","year":"2022","journal-title":"JCO Precis. Oncol."},{"key":"ref_16","first-page":"61","article-title":"Prevalence and clinical implications of germline pathogenic variants in cancer predisposing genes in young patients across sarcoma subtypes","volume":"61","author":"Santiago","year":"2023","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Abu-Hijih, R., Sharaf, B., Salah, S., Bani Hani, H., Alqaisieh, M., Alzibdeh, A., Ababneh, L., Mahafdah, S., and Abdel-Razeq, H. (2024). Germline genetic mutations in adult patients with sarcoma: Insight into the middle east genetic landscape. Cancers, 16.","DOI":"10.3390\/cancers16091668"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.33696\/Signaling.4.104","article-title":"DIS3L2: Unveiling a New Player in Tumorigenesis, with a Key Role in Colorectal Cancer","volume":"4","author":"Matos","year":"2023","journal-title":"J Cell Signal."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1158\/1078-0432.CCR-22-1703","article-title":"NBN pathogenic germline variants are associated with pan-cancer susceptibility and in vitro DNA damage response defect","volume":"29","author":"Belhadj","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1001\/jamaoncol.2020.6252","article-title":"Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome","volume":"7","author":"Samadder","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_21","unstructured":"R Core Team (2022) (2024, December 21). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria. Available online: https:\/\/www.R-project.org."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"P05","DOI":"10.1158\/1940-6215.PrecPrev22-P056","article-title":"Abstract P056: Germline cancer susceptibility gene testing in unselected patients with soft tissue sarcoma: A multi-center prospective study","volume":"16","author":"Ailts","year":"2023","journal-title":"Cancer Prev. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/2839\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:57:45Z","timestamp":1760029065000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/7\/2839"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,21]]},"references-count":22,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["ijms26072839"],"URL":"https:\/\/doi.org\/10.3390\/ijms26072839","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,21]]}}}