Abstract 2262: A case-control analysis of germline pathogenic variants among patients with sarcoma
Authors: Adela Rodriguez Hernandez, Miki Horiguchi, Carolyn Horton, Linda M Polfus, Brittany L. Bychkovsky, Colin Young, Suzanne George George, Priscilla Merriam, Judy E Garber, Huma Q Rana
Journal: Cancer Research (2025)

Abstract Introduction: Sarcomas are heterogeneous malignancies with diverse subtypes and treatments. The utility of multi-gene germline testing in patients (pts) with sarcoma is unclear. This study examines the prevalence and distribution of germline pathogenic variants (PVs) in pts with sarcoma compared to controls to refine genetic testing recommendations. Methods: This retrospective case-control study included pts with sarcoma who underwent germline testing of 37 cancer-related genes from January 2016 to January 2024 at Ambry Genetics (Aliso Viejo, CA). A control group of 1464 cancer-free individuals matched 1:3 by age, sex, and ethnicity, served as the comparator. The prevalence of PVs was compared between cases and matched controls using Fisher’s exact test for each selected gene. The degree of association was summarized with odds ratios (ORs) and corresponding 95% exact confidence intervals (CIs). In the case-only cohort, clinical characteristics were evaluated using logistic regression to assess associations with the presence of PVs in any gene. Results: Among 488 pts with sarcoma, 67.8% (n=331) were female and 32.2% (n=157) male, with a median age at sarcoma diagnosis of 47 years (IQR: 0.5-87.5). PVs were found in 26.2% (n=128) of the pts. The prevalence of PV in pts with sarcoma and no other cancer diagnosis compared to pts with sarcoma and multiple cancer diagnoses was 24.0% (n=61) and 28.6% (n=67) (p=0.141) respectively. PV burden was increased among cases compared to the control group (26.2% vs 12.0%) (OR 2.62, CI: 2.01-3.41; p &amp;lt;0.001). A higher frequency of PV was observed in the cases compared to the control group in the following genes: BRCA2 (4.1% vs 2.1%; p= 0.028), CHEK2 (2.8% vs 1.0%; p=0.012), NF1 (2.7% vs 0.1%; p&amp;lt;0.001), POT1 (0.9% vs 0.1%; p=0.047), SDHA (1.4% vs 0.4%; p= 0.043) and TP53 (5.5% vs 0.1%; p &amp;lt; 0.001). Among CHEK2 PV, 4/13 were not founder mutations, and the low-risk variants (p.I157T, p.S428F, p.T476M) were excluded from the PV count. There was no significant difference in age at sarcoma diagnosis (45.5 vs. 47.0 years; p=0.172) between PV carriers and non-carriers. Multivariable analysis identified male sex (OR 1.63; p=0.039) and younger age at testing (OR 0.99; p=0.037) as significant factors associated with PV presence. Conclusions: This study reveals a prevalence of germline PVs exceeding 25% among pts with sarcoma, reinforcing associations with BRCA2, POT1, and TP53 and uncovering potential new signals in CHEK2. Our findings underscore the importance of comprehensive genetic testing in adult pts with sarcoma, as age at diagnosis alone is insufficient to predict PV status. The lack of family history data in this study introduces potential bias related to referral patterns for germline testing. These results contribute to refining germline testing criteria and advancing personalized prevention strategies. Validation in future, unbiased cohorts is essential to confirm these findings. Citation Format: Adela Rodriguez Hernandez, Miki Horiguchi, Carolyn Horton, Linda M Polfus, Brittany L. Bychkovsky, Colin Young, Suzanne George George, Priscilla Merriam, Judy E Garber, Huma Q Rana. A case-control analysis of germline pathogenic variants among patients with sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2262.