{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:12:39Z","timestamp":1789841559342,"version":"4.0.1"},"reference-count":52,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,3,4]],"date-time":"2023-03-04T00:00:00Z","timestamp":1677888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Maria Abbondanza Pantaleo","award":["AIRC IG 26010"],"award-info":[{"award-number":["AIRC IG 26010"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Loss of function of the succinate dehydrogenase complex characterizes 20\u201340% of all KIT\/PDGFRA-negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB, SDHC, and SDHD mutations in GIST occur in only 20\u201330% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives.<\/jats:p>","DOI":"10.3390\/genes14030646","type":"journal-article","created":{"date-parts":[[2023,3,6]],"date-time":"2023-03-06T05:18:43Z","timestamp":1678079923000},"page":"646","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update"],"prefix":"10.3390","volume":"14","author":[{"given":"Angela","family":"Schipani","sequence":"first","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy"},{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2103-1960","authenticated-orcid":false,"given":"Margherita","family":"Nannini","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy"},{"name":"Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2732-0747","authenticated-orcid":false,"given":"Annalisa","family":"Astolfi","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Pantaleo","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy"},{"name":"Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,4]]},"reference":[{"key":"ref_1","first-page":"1259","article-title":"Gastrointestinal Pacemaker Cell Tumor (GIPACT): Gastrointestinal Stromal Tumors Show Phenotypic Characteristics of the Interstitial Cells of Cajal","volume":"152","author":"Kindblom","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"469","DOI":"10.2174\/138920206779315755","article-title":"Gain-of-Function Mutations of Receptor Tyrosine Kinases in Gastrointestinal Stromal Tumors","volume":"7","author":"Isozaki","year":"2006","journal-title":"Curr. Genomics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1158\/1078-0432.CCR-16-0152","article-title":"Quadruple-Negative GIST Is a Sentinel for Unrecognized Neurofibromatosis Type 1 Syndrome","volume":"23","author":"Gasparotto","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Nannini, M., Astolfi, A., Urbini, M., Indio, V., Santini, D., Heinrich, M.C., Corless, C.L., Ceccarelli, C., Saponara, M., and Mandrioli, A. (2014). Integrated Genomic Study of Quadruple-WT GIST (KIT\/PDGFRA\/SDH\/RAS Pathway Wild-Type GIST). BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-685"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/s12967-017-1212-x","article-title":"The Progressive Fragmentation of the KIT\/PDGFRA Wild-Type (WT) Gastrointestinal Stromal Tumors (GIST)","volume":"15","author":"Nannini","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1002\/ajmg.10235","article-title":"Familial Paraganglioma and Gastric Stromal Sarcoma: A New Syndrome Distinct from the Carney Triad","volume":"108","author":"Carney","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1016\/j.radcr.2020.08.002","article-title":"Carney-Stratakis Syndrome: A Dyad of Familial Paraganglioma and Gastrointestinal Stromal Tumor","volume":"15","author":"Recht","year":"2020","journal-title":"Radiol. Case Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1016\/j.biocel.2014.05.033","article-title":"Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumors (GISTs)\u2014A Review","volume":"53","author":"Miettinen","year":"2014","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/gim.2014.115","article-title":"Good Survival Outcome of Metastatic SDH-Deficient Gastrointestinal Stromal Tumors Harboring SDHA Mutations","volume":"17","author":"Pantaleo","year":"2015","journal-title":"Genet. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1097\/00000478-200604000-00008","article-title":"Gastrointestinal Stromal Tumors of the Jejunum and Ileum: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 906 Cases before Imatinib with Long-Term Follow-Up","volume":"30","author":"Miettinen","year":"2006","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1097\/PAS.0b013e3182671178","article-title":"Immunohistochemical Loss of Succinate Dehydrogenase Subunit a (SDHA) in Gastrointestinal Stromal Tumors (GISTs) Signals SDHA Germline Mutation","volume":"37","author":"Miettinen","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1002\/pbc.21312","article-title":"Treatment of Wild-Type Gastrointestinal Stromal Tumor (WT-GIST) with Imatinib and Sunitinib","volume":"50","author":"Murray","year":"2008","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Indio, V., Schipani, A., Nannini, M., Urbini, M., Rizzo, A., De Leo, A., Altimari, A., Di Scioscio, V., Messelodi, D., and Tarantino, G. (2021). Gene Expression Landscape of Sdh-Deficient Gastrointestinal Stromal Tumors. J. Clin. Med., 10.","DOI":"10.3390\/jcm10051057"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6733","DOI":"10.1158\/1078-0432.CCR-17-1397","article-title":"Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance","volume":"23","author":"Bannon","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1158\/2159-8290.CD-13-0092","article-title":"Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor","volume":"3","author":"Killian","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Urbini, M., Astolfi, A., Indio, V., Heinrich, M.C., Corless, C.L., Nannini, M., Ravegnini, G., Biasco, G., and Pantaleo, M.A. (2015). SDHC Methylation in Gastrointestinal Stromal Tumors (GIST): A Case Report. BMC Med. Genet., 16.","DOI":"10.1186\/s12881-015-0233-7"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.tibs.2017.01.003","article-title":"Mitochondrial Complex II: At the Crossroads","volume":"42","author":"Rohlena","year":"2017","journal-title":"Trends Biochem. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1097\/PAP.0b013e31825c6bc6","article-title":"Succinate Dehydrogenase-Deficient Tumors: Diagnostic Advances and Clinical Implications","volume":"19","author":"Barletta","year":"2012","journal-title":"Adv. Anat. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1073\/pnas.1009199108","article-title":"Defects in Succinate Dehydrogenase in Gastrointestinal Stromal Tumors Lacking KIT and PDGFRA Mutations","volume":"108","author":"Janeway","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Baysal, B.E. (2007). A Recurrent Stop-Codon Mutation in Succinate Dehydrogenase Subunit B Gene in Normal Peripheral Blood and Childhood T-Cell Acute Leukemia. PLoS ONE, 2.","DOI":"10.1371\/journal.pone.0000436"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1188\/14.ONF.555-557","article-title":"Cowden Syndrome: What Oncology Nurses Need to Know about Increased Risk of Developing Certain Cancers","volume":"41","author":"Beamer","year":"2014","journal-title":"Oncol. Nurs. Forum"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E1386","DOI":"10.1210\/jc.2015-2689","article-title":"Succinate Dehydrogenase (SDH)-Deficient Pancreatic Neuroendocrine Tumor Expands the SDH-Related Tumor Spectrum","volume":"19","author":"Niemeijer","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1002\/ijc.24595","article-title":"Insulin-like Growth Factor 1 Receptor Expression in Wild-Type GISTs: A Potential Novel Therapeutic Target","volume":"125","author":"Pantaleo","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1016\/j.celrep.2020.03.022","article-title":"TET-Mediated Hypermethylation Primes SDH-Deficient Cells for HIF2\u03b1-Driven Mesenchymal Transition","volume":"30","author":"Morin","year":"2020","journal-title":"Cell Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/s41586-019-1668-3","article-title":"Altered Chromosomal Topology Drives Oncogenic Programs in SDH-Deficient GISTs","volume":"575","author":"Flavahan","year":"2019","journal-title":"Nature"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/jnci\/djr130","article-title":"SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing","volume":"103","author":"Pantaleo","year":"2011","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2938","DOI":"10.1210\/jc.2007-0797","article-title":"Genetics of Carney Triad: Recurrent Losses at Chromosome 1 but Lack of Germline Mutations in Genes Associated with Paragangliomas and Gastrointestinal Stromal Tumors","volume":"92","author":"Matyakhina","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1097\/PAS.0b013e3182671155","article-title":"Loss of SDHA Expression Identifies SDHA Mutations in Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors","volume":"37","author":"Dwight","year":"2013","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/modpathol.2012.186","article-title":"SDHA Mutations in Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors","volume":"26","author":"Oudijk","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fonc.2013.00117","article-title":"Succinate Dehydrogenase Deficiency in Pediatric and Adult Gastrointestinal Stromal Tumors","volume":"3","author":"Belinsky","year":"2013","journal-title":"Front. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1038\/modpathol.2012.153","article-title":"Loss of Expression of SDHA Predicts SDHA Mutations in Gastrointestinal Stromal Tumors","volume":"26","author":"Wagner","year":"2013","journal-title":"Mod. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1001\/jamaoncol.2016.0256","article-title":"Molecular Subtypes of KIT\/PDGFRA Wild-Type Gastrointestinal Stromal Tumors","volume":"2","author":"Boikos","year":"2016","journal-title":"JAMA Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s13053-019-0124-6","article-title":"Germline c.1A>C Heterozygous Pathogenic Variant in SDHA Reported for the First Time in a Young Adult with a Gastric Gastrointestinal Stromal Tumour (GIST): A Case Report","volume":"17","author":"Carrera","year":"2019","journal-title":"Hered. Cancer Clin. Pract."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/ejhg.2013.80","article-title":"Analysis of All Subunits, SDHA, SDHB, SDHC, SDHD, of the Succinate Dehydrogenase Complex in KIT\/PDGFRA Wild-Type GIST","volume":"22","author":"Pantaleo","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1097\/PAS.0b013e318230a523","article-title":"A Distinct Pediatric-Type Gastrointestinal Stromal Tumor in Adults: Potential Role of Succinate Dehydrogenase Subunit a Mutations","volume":"35","author":"Pantaleo","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5400","DOI":"10.3389\/fonc.2021.778461","article-title":"SDHA Germline Variants in Adult Patients With SDHA-Mutant Gastrointestinal Stromal Tumor","volume":"11","author":"Pantaleo","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Italiano, A., Chen, C.L., Sung, Y.S., Singer, S., DeMatteo, R.P., LaQuaglia, M.P., Besmer, P., Socci, N., and Antonescu, C.R. (2012). SDHA Loss of Function Mutations in a Subset of Young Adult Wild-Type Gastrointestinal Stromal Tumors. BMC Cancer, 12.","DOI":"10.1186\/1471-2407-12-408"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"a002584","DOI":"10.1101\/mcs.a002584","article-title":"Germline SDHA Mutations in Children and Adults with Cancer","volume":"4","author":"Gault","year":"2018","journal-title":"Cold Spring Harb. Mol. Case Stud."},{"key":"ref_39","first-page":"12188","article-title":"A Novel Germline Mutation in SDHA Identified in a Rare Case of Gastrointestinal Stromal Tumor Complicated with Renal Cell Carcinoma","volume":"8","author":"Jiang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/sj.ejhg.5201904","article-title":"Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD","volume":"16","author":"Pasini","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1365-2796.2009.02110.x","article-title":"The Triad of Paragangliomas, Gastric Stromal Tumours and Pulmonary Chondromas (Carney Triad), and the Dyad of Paragangliomas and Gastric Stromal Sarcomas (Carney-Stratakis Syndrome): Molecular Genetics and Clinical Implications","volume":"266","author":"Stratakis","year":"2009","journal-title":"Proc. J. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1712","DOI":"10.1097\/PAS.0b013e3182260752","article-title":"Succinate Dehydrogenase-Deficient GISTs: A Clinicopathologic, Immunohistochemical, and Molecular Genetic Study of 66 Gastric GISTs with Predilection to Young Age","volume":"35","author":"Miettinen","year":"2011","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1056\/NEJMc071191","article-title":"Familial Gastrointestinal Stromal Tumors and Germ-Line Mutations","volume":"357","author":"McWhinney","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"17588359211023278","DOI":"10.1177\/17588359211023278","article-title":"Targeted Therapy in SDH-Deficient GIST","volume":"13","author":"Nannini","year":"2021","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.annonc.2021.09.005","article-title":"Gastrointestinal Stromal Tumours: ESMO\u2013EURACAN\u2013GENTURIS Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up","volume":"33","author":"Casali","year":"2022","journal-title":"Ann. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e7668","DOI":"10.1097\/MD.0000000000007668","article-title":"Clinicopathologic Study of Succinate-Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: A Single-Institutional Experience in China","volume":"96","author":"Liu","year":"2017","journal-title":"Medicine"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1093\/annonc\/mdw228","article-title":"Long-Term Follow-up Results of the Multicenter Phase II Trial of Regorafenib in Patients with Metastatic and\/or Unresectable GI Stromal Tumor after Failure of Standard Tyrosine Kinase Inhibitor Therapy","volume":"27","author":"Barysauskas","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1093\/annonc\/mdt484","article-title":"A Multicenter Phase II Study of Pazopanib in Patients with Advanced Gastrointestinal Stromal Tumors (GIST) Following Failure of at Least Imatinib and Sunitinib","volume":"25","author":"Ganjoo","year":"2014","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1158\/1078-0432.CCR-19-1069","article-title":"Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study","volume":"26","author":"George","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9941","DOI":"10.2147\/CMAR.S269388","article-title":"Abnormal Mgmt Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome","volume":"12","author":"Lou","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3588","DOI":"10.21037\/tcr-21-131","article-title":"Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor: From Diagnostic Dilemma to Novel Personalised Therapy in 2 Case Reports","volume":"10","author":"Rastogi","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"10507","DOI":"10.1200\/jco.2015.33.15_suppl.10507","article-title":"A Phase Ib\/II Study of MEK162 (Binimetinib [BINI]) in Combination with Imatinib in Patients with Advanced Gastrointestinal Stromal Tumor (GIST)","volume":"33","author":"Chi","year":"2015","journal-title":"J. Clin. Oncol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/646\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:47:39Z","timestamp":1760122059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/14\/3\/646"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,4]]},"references-count":52,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["genes14030646"],"URL":"https:\/\/doi.org\/10.3390\/genes14030646","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,4]]}}}