# Genomic and Demographic Characteristics of Angiosarcoma as Described in the AACR Project GENIE Registry

## TL;DR

This study uses a large cancer registry to analyze the genomic and demographic features of angiosarcoma, identifying key mutations and differences between patient groups.

## Contribution

This is the first study to analyze angiosarcoma genomics in the AACR GENIE database, revealing new patterns of mutations and sex-based differences.

## Key findings

- Recurrent mutations in TP53, KDR, and PIK3CA were identified, along with co-occurring and mutually exclusive gene pairs.
- Sex differences were observed, with females showing MYC and HRAS enrichment and males showing POT1, NTRK2, and FAT1 enrichment.
- Metastatic tumors showed distinct mutation patterns compared to primary tumors, including ZFHX4 and FGFR1 mutations.

## Abstract

In this study, we analyzed the AACR GENIE registry to characterize genomic and demographic characteristics of angiosarcoma. Angiosarcoma carries high mortality but has low prevalence, and consequently, there are limited large-scale genomic studies. Though prior studies have identified mutations associated with angiosarcoma, this is the first study to specifically analyze angiosarcoma genomics in the AACR GENIE database. We aimed to characterize the landscape of angiosarcoma and, therefore, highlight potential therapeutic targets that may aid future management strategies. Our analysis revealed recurrent mutations in TP53, KDR, and PIK3CA, with several genes demonstrating co-occurrence or mutual exclusivity. There was also variation in the predominant mutations between sexes and between primary and metastatic tumors.

Background: Despite the high mortality associated with angiosarcoma, its low prevalence has limited sample sizes in prior studies. To address these gaps, we analyzed the AACR Project GENIE registry, a large, multi-institutional database. Methods: 359 tumor samples from 346 patients with angiosarcoma were identified from the AACR Project GENIE v18.0-public database using cBioPortal. Somatic mutations and copy number alterations were assessed. Statistical significance was assessed by t-test for continuous variables and a chi-squared test for categorical data, with significance set at p < 0.05. Results: Recurrent mutations included TP53 (20.6%), KDR (13.6%), and PIK3CA (10.6%). Copy number alterations occurred in MYC (27.3%), CRKL (10.4%), FLT4 (5.5%), and KDR (4.8%). Homozygous deletions occurred in CDKN2A (6.6%), CDKN2B (6.56%), and MTAP (3.81%). Significant co-occurrence included FAT1-NOTCH2, TP53-ATRX, and NOTCH1-ARID1A. Mutual exclusivity was seen with KDR-FLT4 and KDR-ATRX. Females exhibited enrichment in MYC and HRAS, while males exhibited enrichment in POT1, NTRK2, and FAT1. Compared with primary tumors, metastatic tumors more often displayed ZFHX4, FGFR1, MSI2, HIST1H1C, and TOP1 mutations, while MAPK7 mutations occurred only in primary tumors. Conclusions: In one of the largest genomic analyses of angiosarcoma to date, we identified recurrent alterations, suggesting potential future therapeutic targets.