Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53

Author： Ni Ying He Xin Chen Jinlian Moline Jessica Mester Jessica Orloff Mohammed S. Ringel Matthew D. Eng Charis

Publisher： Oxford University Press

ISSN： 1460-2083

Source： Human Molecular Genetics, Vol.21, Iss.2, 2012-01, pp. : 300-310

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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.