The profile of platelet-derived growth factor receptor alpha (PDGFRA) gene alterations in GIST patients (pts) from Brazil

Abstract

10561 Background: Oncogenic activation mutations of the PDGFRA gene have been identified in a small subset of GIST that lack KIT mutations (WT-KIT). Most of the PDGFRA mutations occur in exon 18 and the site of mutation may influence response to tyrosine kinase inhibitors (TKIs). Further, Brazilian population is characterized by a very heterogeneous genetic background. Our goal was to evaluate PDGFRA gene alterations in WT- KIT GIST pts from Brazil. Methods: Eight-one pts with completely resected GISTs CD117+ from Jan 1990 to Apr 2003 were included. WT-KIT (exons 9, 11, 13 and 17) GISTs were examined for mutation in PDGFRA gene (exons 12, 14 and 18) by direct sequencing. Clinical and pathologic data were retrieved from medical records. Tumors were classified according to the risk into very low-, low-, intermediate-, and high-risk based on tumor size and mitotic index (Fletcher et al, Hum Pathol 2002). Results: Out of 81 GIST pts included, mutation analysis was feasible in 55 pts. Median age was 55 (9–77); Male/female 40/60 %. Eleven (20.0%) pts had very low-risk tumors, 12 (21.8%) had low-risk, 12 (21.8%) had intermediate risk and 14 (25.5%) had high-risk tumors. Six (10.9%) pts had metastasis at the time of surgery and were classified as overtly malignant. Primary tumor sites were stomach (47.3%) and others (52.7%). Overall, KIT mutations were found in 40/55 (72.7%) tumors examined (exon 11, 38/55 (69.1%); exon 9, 2/55 (3.6%)). We found PDGFRA mutations in 4/55 (7.3%) cases including 3 missense mutations and 1 deletion. There was a predominance of exon 12 mutations, 3/55 (5.5%) compared to mutations in exon 18, 1/55 (1.8%). All GISTs carrying PDGFRA mutations were gastric tumors of very low- or low-risk and 3 were histologically epithelioid. Three genomic sequence alterations without changing amino acid of the PDGFRA protein were seen in 6/15 (40.0%) WT-KIT GISTs (2472 C>T; 1701 G>A; IVS17–50insT). Conclusions: Of note, in contrast to published data the region encoding juxtamembrane domain (exon 12) of PDGFRA gene was the most common site of mutation in our population. Once data is confirmed in a larger pts population this may have implications for pts selection to TKIs. Further, we found three polymorphisms in our WT-KIT tumors with still unknown biologic significance. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Brazil S.A.