SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor.

Maria A Pantaleo,Maristella Saponara,Daniela Turchetti,Annalisa Astolfi,Dario De Biase,Antonella Brunello,Valentina Indio,Andrea Ardizzoni,Marco Seri,Margherita Nannini,Elena Fumagalli,Angela Schipani,Giovanni Grignani,Gloria Ravegnini,Milena Urbini,Elena Conca,Giovanni Tallini,Elisa Gruppioni,Paola Secchiero,Annalisa Altimari,Mariaelena Casagrande,Bruno Vincenzi,Antonio De Leo

doi:10.3389/fonc.2021.778461

Abstract

BackgroundSDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent. Here we sought to evaluate the presence and prevalence of SDHA variants in the germline lineage in a population of SDHA-deficient GIST.MethodsGermline SDHA status was assessed by Sanger sequencing on a series of 14 patients with gastric SDHA-deficient GIST.ResultsAll patients carried a germline SDHA pathogenic variant, ranging from truncating, missense, or splicing variants. The second hit was the loss of the wild-type allele or an additional somatic mutation. One-third of the patients were over 50 years old. GIST was the only disease presentation in all cases except one, with no personal or familial cancer history. Seven metastatic cases received a multimodal treatment integrating surgery, loco-regional and medical therapy. The mean follow-up time was of 10 years, confirming the indolent clinical course of the disease.Conclusion SDHA germline variants are highly frequent in SDHA-deficient GIST, and the disease may occur also in older adulthood. Genetic testing and surveillance of SDHA-mutation carriers and relatives should be performed.

Highlights

SDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST [1]
This syndrome was firstly described in 2002 as a hereditary condition characterized by the occurrence of GIST and paraganglioma
The prediction with the tool Alternative Splice Site Predictor (ASSP) revealed that the c.457-2_457del is likely to generate an alternative acceptor splice site of exon 5, while the c.1663+3 G>C probably leads to the loss of donor splice site at exon 12 with consequent intron retention

Summary

Introduction

SDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST [1]. Most of SDH mutations in GIST are germline, in particular germline mutations in SDHB, SDHC, and SDHD occur in about 20–30% of SDH-deficient disease and may be referred to as a Carney-Stratakis syndrome (CSS) [4]. This syndrome was firstly described in 2002 as a hereditary condition characterized by the occurrence of GIST and paraganglioma. SDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDHcomplex subunits, with SDHA mutations as the most frequent.

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