Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.

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