title: 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.
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Ni
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Zbuk
authors.forename: Tammy
authors.initials: T
authors.lastname: Sadler
authors.forename: Attila
authors.initials: A
authors.lastname: Patocs
authors.forename: Glenn
authors.initials: G
authors.lastname: Lobo
authors.forename: Emily
authors.initials: E
authors.lastname: Edelman
authors.forename: Petra
authors.initials: P
authors.lastname: Platzer
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Orloff
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Waite
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010641:Phenotype; D013385:Succinate Dehydrogenase / Q000235:genetics* / Q000502:physiology
chemical_list: C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051059:PTEN Phosphohydrolase