Genetic predisposition in adult sarcoma patients: Beyond TP53

Background TP53 is the primary gene associated with sarcoma predisposition. Most studies have focused on the pediatric population, leaving a gap in fully understanding the genetic determinants in the adult sarcoma population.MethodsAmong adult sarcoma patients who underwent genetic counseling between January 2020 and December 2023 at Cochin Hospital (Paris, France), a NETSARC + reference center for sarcoma patients, we collected characteristics of those who had germline analysis. This included the presence of a germline variant in a panel of 27 genes, and patients characteristics (age, sex, histology, and stage of sarcoma, personal and familial cancer history).ResultsAmong 205 sarcoma patients who had a genetic consultation, 122 had germline analysis based on their personal and familial history. 57/122 (47%) were male, 80 (66%) had soft tissue sarcoma (STS), 42 (34%) had bone sarcoma (BS). The median age at sarcoma diagnosis was 44 years old (yo) (IQR 29-60). The main STS histology was undifferentiated pleomorphic sarcoma (n= 15), the main BS was chondrosarcoma (n= 15). 51 (42%) patients met Chompret criteria, 50 (41%) had a personal history of another cancer, 81 (68%) had first-degree family cancer history. 17/122 (14%) patients had a germline pathogenic or likely pathogenic variant (GPV) : 8/17 (47%) in a homologous recombination (HR) gene (3 BRCA2, 1 BRCA1, 1 BRIP1, 1 ATM, 1 RAD51C, 1 had both BRCA1 and CHEK2), 3/17 (18%) in a mismatch repair (MMR) gene (2 MSH6, 1 MLH1), 3/17 (18%) in TP53 and 3/17 (18%) in another gene (1 RB1, 1 CDKN2A, 1 DICER1). 13/122 (11%) patients had a variant of unknown significance in BRCA2, TP53, CHEK2, MSH6, PALB2, MSH2, POT1, ATM genes. The median age at cancer diagnosis was younger in patients with a GPV than in patients without (30 vs 53 yo, p= 0.025). Chompret criteria and the sarcoma subtype were not predictive of the presence of a GPV.ConclusionsThe profile of cancer predisposition genes seems to differ among adult sarcoma patients. TP53 is not the most frequently mutated gene in our cohort. The prevalence of GPV in HR and MMR genes is more than 3-fold higher than in TP53. Larger studies are needed to redefine the spectrum of GPV involved in adult sarcoma predisposition, especially since these genes may have a theranostic impact.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureAll authors have declared no conflicts of interest.