Familial Gastrointestinal Stromal Tumors (GISTs) via the PDGFRA Gene

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors found in the gastrointestinal tract. In most cases, GISTs spontaneously arise due to somatic mutations in the KIT gene, and less frequently in the PDGFRA gene. Families with GISTs and germline mutations in the KIT and PDGFRA genes have been described. Familial GISTs are often distinct from sporadic GISTs in that they are multiple in number, smaller in size, and present hyperplasia of interstitial cells of Cajal (ICC). Individuals with PDGFRA mutations show clinical manifestations similar to patients with KIT germline mutations, including dysphagia, hyperpigmentation and urticaria pigmentosa; however patients with germline PDGFRA mutations have distinct clinical features, such as large hands, lipomas, intestinal neurofibromatosis, and small intestine fibrous tumors. (Postow and Robson. Clinical Sarcoma Research 2:16, 2012) . In addition, patients with a germline PDGFRA mutation appear to have better outcomes compared to individuals with KIT germline mutations (Maleddu et al. Journal of Translational Medicine 9:75, 2011; Antonescu. Seminars in Diagnostic Pathology 23:63-69, 2006). Interestingly, individuals who are positive for either KIT and PDGFRA tumor mutations are treated with Imatinib, a KIT and PDGFRA inhibitor, which has been successfully used in the treatment of metastatic GISTs (Lasota and Miettinen. Histopathology 53, 245–266, 2008). Other diseases in which germline PDGFRA mutations are present include Hypereosinophilic syndrome, Vitiligo vulgaris, and isolated cleft palate.

Familial GISTs are inherited as an autosomal dominant disease caused by mutations in KIT and PDGFRA. While the majority of mutations are found in the KIT gene, several families have been found to have causative mutations in the PDGFRA gene. PDGFRA encodes a trans-membrane receptor that belongs to the type III tyrosine kinase family whose natural ligands are stem cell factor (SCF) and platelet derived growth factor (Maleddu et al., 2011). Ligand binding promotes autophosphorylation of the PDGRA receptor and activation of downstream targets, such as the Ras/MAP kinase, Rac/Rho-JNK, PI3K/AKT, and SFK/STAT signaling networks (Antonescu, 2006). These pathways are involved in cellular differentiation and growth. Deregulation leads to tumorigenesis. The majority of causative germline mutations in the PDFRA gene are missense mutations, and are mostly similar to those found in sporadic GISTs (Lasota and Miettinen, 2008). No consistent genotype-phenotypes correlations exist for Familial GISTs.

Approximately 90% of individuals with Familial GISTS will have a mutation in the KIT and PDGFRA genes. PDGFRA causative mutations are found in approximately 1/3 of patients who test negative for KIT mutations (Antonescu. Seminars in Diagnostic Pathology 23:63-69, 2006).

This test provides full coverage of all coding exons of the PDGFRA gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.