Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes

Abstract

Individuals with PTEN mutations have Cowden syndrome (CS), associated with breast, thyroid, and endometrial neoplasias. Many more patients with features of CS, not meeting diagnostic criteria (termed CS-like), are evaluated by clinicians for CS-related cancer risk. Germline mutations in succinate dehydrogenase subunits SDHB-D cause pheochromocytoma-paraganglioma syndrome. One to five percent of SDHB/SDHD mutation carriers have renal cell or papillary thyroid carcinomas, which are also CS-related features. SDHB-D may be candidate susceptibility genes for some PTEN mutation-negative individuals with CS-like cancers. To address this hypothesis, germline SDHB-D mutation analysis in 375 PTEN mutation-negative CS/CS-like individuals was performed, followed by functional analysis of identified SDH mutations/variants. Of 375 PTEN mutation-negative CS/CS-like individuals, 74 (20%) had increased manganese superoxide dismutase (MnSOD) expression, a manifestation of mitochondrial dysfunction. Among these, 10 (13.5%) had germline mutations/variants in SDHB (n = 3) or SDHD (7), not found in 700 controls (p < 0.001). Compared to PTEN mutation-positive CS/CS-like individuals, those with SDH mutations/variants were enriched for carcinomas of the female breast (6/9 SDH versus 30/107 PTEN, p < 0.001), thyroid (5/10 versus 15/106, p < 0.001), and kidney (2/10 versus 4/230, p = 0.026). In the absence of PTEN alteration, CS/CS-like-related SDH mutations/variants show increased phosphorylation of AKT and/or MAPK, downstream manifestations of PTEN dysfunction. Germline SDH mutations/variants occur in a subset of PTEN mutation-negative CS/CS-like individuals and are associated with increased frequencies of breast, thyroid, and renal cancers beyond those conferred by germline PTEN mutations. SDH testing should be considered for germline PTEN mutation-negative CS/CS-like individuals, especially in the setting of breast, thyroid, and/or renal cancers.

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

“…Two patients (6%) had an SDHD germline sequence change with questionable pathogenicity (c. 34 G > A) that has previously been reported to be present in patients with pheochromocytoma (24), hereditary paraganglioma (25), and Cowden syndrome (26). In Cowden syndrome, the resulting amino acid change, G12S, was associated with a twofold increase in AKT and MAPK activity and an increase in reactive oxygen species.…”

“…In Cowden syndrome, the resulting amino acid change, G12S, was associated with a twofold increase in AKT and MAPK activity and an increase in reactive oxygen species. However, this SDHD sequence alteration has also been seen in control populations, with an incidence ranging from 0% to 2.5% (24,26).…”

Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis

“…Given the high PTC incidence rates (incidence of PTC estimated at 7.3/100 000) (49,50), it is no surprise that thyroid tumors are relatively frequently encountered as incidental findings in patients who are under active surveillance. Taken together, the occurrence of PTCs in the SDHdeficient state may be either coincidental, reflecting the highly prevalent nature of this particular malignancy, or may be less likely attributable to cross talk of SDH-and PTEN-related signaling pathways leading to tissue-specific Cowden syndrome (CS)/CS-like tumorigenesis (51,52). With regard to SDHB-related renal neoplasia, all RCC cases (case nos 4-6) confirm previous histopathological and SDHB immunohistochemical observations (11,23), highlighting the fact that distinct morphological traits along with SDHB immunonegativity could aid in screening for SDHB mutations.…”

An Overview of Autosomal Dominant Tumour Syndromes with Prominent Features in the Oral and Maxillofacial Region

“…This is exemplified by the identification of mutations in succinate dehydrogenase subunits B and D that are associated with a Cowden-like syndrome in patients who lack PTEN mutations. These succinate dehydrogenase mutations influence the same biochemical pathway as PTEN emphasising that these syndromes should be considered a continuous rather than discrete variable [105].…”