Prevalence of hereditary GIST susceptibility in adults with GIST.

Abstract

10043 Background: GIST is the most common mesenchymal tumor of the GI tract, associated with somatic gain-of-function mutations in KIT and less often, PDGFRA. Families with inherited mutations in KIT/PDGFRA have autosomal dominant transmission of GIST predisposition. Germline mutations of the succinate dehydrogenase complex (SDH) may underlie kindreds with GIST and paraganglioma, particularly in GISTS of the pediatric/wild-type histology. We are conducting a multicenter study to ascertain the prevalence of hereditary GIST. Methods: Individuals ≥ age 18 years with confirmed GIST are recruited through sarcoma specialty clinics at the Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute, or a web recruitment tool. Participants are stratified to high- and low-hereditary risk groups based on questionnaire and family history review. Germline analysis of KIT and PDGFRA is ongoing at Oregon Health & Science University on specimens from all high-risk subjects; SDHX analysis is in process for a subset. Results: Thus far we have enrolled 512 participants. Specimens from 92 high-risk and 41 low-risk subjects have been analyzed to date. Eight mutations were found in KIT, zero in PDGFRA. In-frame deletion of KIT D579 was found in 5 families, two of which report a common ancestor, and W557R, K642E, and K509I were identified each in one family. Two of these families, one segregating D579del and the second W557R, were reported previously by other groups, and one, K642E, was reported in the course of this study. Germline analysis of KIT exons 8, 9, 11, 13, 17 and PDGFRA 12, 14, 18 is negative in four families. KIT mutations were identified only in individuals with family history of GIST in relatives. Two individuals with SDHB mutations, identified by other investigators in the course of this study, are included. Germline analysis of the SDH family of genes in five individuals with pediatric/wild-type GIST and/or family history of pheochromocytoma or paraganglioma is in progress. Conclusions: The hereditary form of GIST constitutes a small fraction of all GISTs. Individuals with GIST and without a family history of GIST in other relatives are unlikely to carry inherited susceptibility linked to the KIT or PDGFRA protooncogenes.