Overexpression of miR-210 is associated with SDH-related pheochromocytomas, paragangliomas, and gastrointestinal stromal tumours

miR-210 is a key regulator of response to hypoxia. Pheochromocytomas (PCs) and paragangliomas (PGLs) with germline SDHx or VHLmutations have pseudohypoxic gene expression signatures. We hypothesised that PC/PGLs containing SDHx or VHLmutations, and succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs),wouldoverexpressmiR210 relative to non-SDH or -VHL-mutated counterparts. miR-210 was analysed by quantitative PCR in i) 39 PC/PGLs, according to genotype (one SDHA, five SDHB, seven VHL, three NF1, seven RET, 15 sporadic, one unknown) and pathology (18 benign, eight atypical, 11 malignant, two unknown); ii) 18 GISTs, according to SDHB immunoreactivity (nine SDH-deficient and nine SDHproficient) and iii) twonovel SDHB-mutant neurosphere cell lines.miR-210was higher in SDHxor VHL-mutated PC/PGLs (7.6-fold) compared with tumours without SDHx or VHLmutations (PZ0.0016).miR-210washigher inmalignant than inunequivocally benignPC/PGLs (PZ0.05), but significancewas lostwhen benign and atypical tumourswere combined (PZ0.08). Inmultivariate analysis, elevated miR-210 was significantly associated with SDHx or VHLmutation, but not with malignancy. In GISTs, miR-210 was higher in SDH-deficient (median 2.58) compared with SDHproficient tumours (median 0.60; PZ0.0078). miR-210was higher in patient-derived neurosphere cell lines containing SDHBmutations (6.5-fold increase) compared with normal controls, in normoxic conditions (P!0.01). Furthermore, siRNA-knockdownof SDHB inHEK293 cells increased miR-210 by 2.7-fold (PZ0.001) under normoxia. Overall, our results suggest that SDHdeficiency in Key Words