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.
Bibliographical noteFunding Information:
The authors have no conflicts of interest to declare. We thank Jen Stein, MS, CGC, then at the Genomic Medicine Institute, Cleveland Clinic, for acting as genetic counselor-coordinator of the PTEN study at an early stage of the study, and Frank Mularo, MS, and Jin-Liang Chen, MS, both of the Eng Laboratory, Genomic Medicine Institute, Cleveland Clinic, for technical assistance. This study was funded, in part, by the Breast Cancer Research Foundation, the William Randolph Hearst Foundation, and the National Cancer Institute, Bethesda, MD (1P01CA124570-01A1) (all to C.E.). K.M.Z. was a Cleveland Clinic Crile Fellow; A.P. was an International Scholar of The Endocrine Society; and Y.N. is a Howard Hughes Medical Institute Predoctoral Fellow in Molecular Medicine at the Cleveland Clinic Lerner College of Medicine. C.E. is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic.