Open AccessSDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing
Author(s) -
Maria Abbondanza Pantaleo,
Annalisa Astolfi,
Valentina Indio,
Richard A. Moore,
Nina Thiessen,
Michael C. Heinrich,
Chiara Gnocchi,
Donatella Santini,
Federico Coccolini,
Serena Formica,
Pier Luigi Martelli,
Rita Casadio,
Andrea Pession,
Guido Biasco
Publication year - 2011
Publication title -
journal of the national cancer institute
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.797
H-Index - 356
eISSN - 1460-2105
pISSN - 0027-8874
DOI - 10.1093/jnci/djr130
Subject(s) - sdha , pdgfra , sdhb , sdhd , biology , nonsense mutation , missense mutation , cancer research , mutation , genetics , germline mutation , gene , stromal cell , gist , gene expression
Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA.