[34] Novel Kinase Mutations in KDR/VEGFR2, TIE1, and SNRK in Angiosarcoma (AS) Patients

CR Antonescu, A Yoshida, NP Agaram, NE Chang, RG Maki. Memorial Sloan-Kettering Cancer Ctr, New York, NY

Background: The pathogenesis of AS is not well understood and anecdotal evidence suggests that at least a subset of patients respond to VEGFR targeted therapy. However no potential molecular candidates have been identified so far to guide a more specific therapeutic intervention.
Design: Forty-two samples from 39 AS patients were included in the analysis. A HG U133A Affymetrix platform (22,000 transcripts) was used to mine the gene expression of 22 AS, compared to a control group of a well-characterized set of 45 soft tissue sarcomas. Candidate kinase genes overexpressed in AS compared to other sarcoma types were selected for full-length sequencing using a high throughput mutational profiling. Identified mutations were then validated by direct sequencing in matched tumor/normal samples. Selected genes were also validated at the protein level by IHC in an AS tissue microarray.
Results: Unsupervised clustering showed that AS formed a tight genomic group distinct from all other sarcoma types. Its distinctive expression profile included overexpression of a number of kinase genes, such as TIE1, KDR/VEGFR2, SNRK, TEK, and FLT1/ VEGFR1. Full-sequencing of these 5 genes identified mutations in 10 (25%) patients, including KDR (6/10), TIE1 (2/10) and SNRK (2/10). KDR mutations were identified only in AS located in the breast/chest wall, with or without radiation exposure. However, overall kinase mutations were seen more often in radiation-associated tumors (40% vs 18%). The 2 patients with lymphedema-associated tumors lacked mutations. The presence of KDR mutations correlated with the protein expression by IHC in the AS TMA, being 3+ positive in all 6 KDR-mutated tumors, while negative in the TIE1 or SNRK-mutated AS.
Conclusions: We identified novel mutations in KDR, TIE1 and SNRK in 25% of AS patients. These findings open new ground for understanding the AS pathogenesis and will be instrumental in identifying the subset of patients responding to VEGFR specific targeting. Furthermore, KDR immunoreactivity, which was seen in 60% of AS, may be useful as a screening method for potential kinase mutations.
Category: Bone & Soft Tissue

Tuesday, March 10, 2009 9:30 AM

Poster Session III # 1, Tuesday Morning