title: Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53.
abstract: Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been recently reported in 23% of a large series of classic CS. Here, we validated our small (n = 10) pilot study in a large patient series that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% (49/608) of PTEN mutation-negative CS and CS-like (CSL) individuals (SDH(var+)). None of these SDHx variants was found in 700 population controls (P < 0.0001). We then found that SDHx variants also occur in 6% (26/444) of PTEN mutation-positive (PTEN(mut+)) CS/CSL individuals (PTEN(mut+)/SDH(var+)). Of 22 PTEN(mut+)/SDH(var+) females, 17 had breast cancers compared with 34/105 PTEN(mut+) (P < 0.001) or 27/47 SDH(var+) patients (P = 0.06). Notably, individuals with SDH(var+) alone had the highest thyroid cancer prevalence (24/47) compared with PTEN(mut+) patients (27/105, P = 0.002) or PTEN(mut+)/SDH(var+) carriers (6/22, P = 0.038). Patient-derived SDH(var+) lymphoblastoid cells had elevated cellular reactive oxygen species, highest in PTEN(mut+)/SDH(var+) cells, correlating with apoptosis resistance. SDH(var+) cells showed stabilized and hyperactivated hypoxia inducible factor (HIF)1α signaling. Most interestingly, we also observed the loss of steady-state p53 in the majority of SDH(var+) cells. This loss of p53 was regulated by MDM2-independent NADH quinone oxidoreductase 1-mediated protein degradation, likely due to the imbalance of flavin adenine dinucleotide/nicotinamide adenine dinucleotide in SDH(var+) cells. Our data suggest the potential regulation of HIF1α, p53 and PTEN signaling by mitochondrial metabolism in CS/CSL tumorigenesis. Together, our findings suggest the importance of considering SDHx as candidate predisposing and modifier genes for CS/CSL-related malignancy risks, and a mechanism which suggests ways of therapeutic reversal or prevention.
authors: Genomic Medicine Institute, Lerner Research Institute, Howard Hughes Medical Institute Doctoral Program in Molecular Medicine, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA.
authors: Ying
authors: Y
authors: Ni
authors: Xin
authors: X
authors: He
authors: Jinlian
authors: J
authors: Chen
authors: Jessica
authors: J
authors: Moline
authors: Jessica
authors: J
authors: Mester
authors: Mohammed S
authors: MS
authors: Orloff
authors: Matthew D
authors: MD
authors: Ringel
authors: Charis
authors: C
authors: Eng
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D016158:Genes, p53; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics*; D006801:Humans; D009243:NAD / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: D009243:NAD; D005182:Flavin-Adenine Dinucleotide; D013385:Succinate Dehydrogenase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human