Related Experiment Video
Updated: Jun 9, 2026
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Genomic Profiling of Cardiac Angiosarcoma Reveals Novel Targetable KDR Variants, Recurrent MED12 Mutations, and a
Igor Odintsov1, David J Papke1, Suzanne George2
1Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Purpose:
Cardiac angiosarcoma is a rare, aggressive malignancy with limited treatment options. Both sporadic and familial cases occur, with recent links to germline POT1 mutations. The genomic landscape of this disease is poorly understood.
Experimental Design:
We conducted comprehensive genomic profiling of cardiac angiosarcoma to assess the burden of germline predisposition and identify other recurrent genomic alterations of clinical significance.
Results:
Six patients were female, and four were male. The median age at presentation was 40 years (range, 21-69 years). All cases with available follow-up exhibited an aggressive clinical course (6/8 patients died of disease). KDR alterations, including novel structural variants, were found in 9/11 cases at a rate significantly higher than that in noncardiac angiosarcomas. POT1 mutations were present in 45.5% of cardiac angiosarcoma cases. In three of five POT1-mutant cases, the germline status was confirmed through testing of normal tissue, and in one additional case, the germline status was inferred with high probability through allele frequency analysis. Additionally, we identified novel recurrent MED12 exon 2 mutations in POT1 wild-type cardiac angiosarcoma, suggesting an alternative path to cardiac angiosarcoma oncogenesis.
Conclusions:
Cardiac angiosarcoma demonstrates a unique genetic profile, distinct from noncardiac angiosarcoma. This study highlights the role of germline POT1 burden on cardiac angiosarcoma development and demonstrates recurrent MED12 alterations for the first time. The reported KDR variants provide a potential avenue for the treatment of this aggressive disease. Given the prevalence of germline POT1 mutations reported in this study, germline genetic testing should be considered in patients diagnosed with cardiac angiosarcoma.
Insights
Cardiac angiosarcoma has a unique genetic profile, with frequent POT1 mutations and novel KDR and MED12 alterations. Germline genetic testing is recommended for patients with this rare cancer.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Cardiac angiosarcoma is a rare and aggressive cancer with limited treatment options.
- The genetic underpinnings of cardiac angiosarcoma are not well understood.
- Previous research suggests a link between germline POT1 mutations and familial cases.
Purpose of the Study:
- To perform comprehensive genomic profiling of cardiac angiosarcoma.
- To determine the frequency of germline predisposition in cardiac angiosarcoma.
- To identify recurrent genomic alterations with potential clinical significance.
Main Methods:
- Comprehensive genomic profiling of 11 cardiac angiosarcoma cases.
- Analysis of germline predisposition through POT1 mutation assessment.
- Identification and characterization of novel genomic alterations, including KDR and MED12 variants.
Main Results:
- KDR alterations were identified in 9/11 cases, significantly more than in noncardiac angiosarcomas.
- POT1 mutations were found in 45.5% of cases, with germline status confirmed in most.
- Novel recurrent MED12 exon 2 mutations were identified in POT1 wild-type tumors.
Conclusions:
- Cardiac angiosarcoma possesses a distinct genomic profile compared to noncardiac angiosarcoma.
- Germline POT1 mutations play a significant role in cardiac angiosarcoma development.
- Recurrent KDR and MED12 alterations present potential therapeutic targets and warrant consideration for germline genetic testing.
