# Germline Genetic Testing in Patients with Bone and Soft Tissue Sarcoma: A Prospective Multicenter Study to Evaluate Cancer Susceptibility

## TL;DR

This study finds that 8.7% of sarcoma patients have harmful genetic variants, suggesting germline testing could help assess cancer risk and treatment options.

## Contribution

The study identifies novel germline variants in sarcoma patients, many of which are not detected by current guidelines.

## Key findings

- 8.7% of sarcoma patients had pathogenic germline variants in genes like TP53, BRCA1, and ATM.
- 70% of identified variants would not have been detected using current clinical guidelines.
- Germline testing could improve therapeutic and familial risk assessments for sarcoma patients.

## Abstract

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–III). 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.