Bancos, Irina

Abstract Context SDHB mutations are found in an increasing number of neoplasms, most notably in paragangliomas and pheochromocytomas (PPGLs). SDHB-PPGLs are slow-growing tumors, but ∼50% of them may develop metastasis. The molecular basis of metastasis in these tumors is a long-standing and unresolved problem. Thus, a better understanding of the biology of metastasis is needed. Objective This study aimed to identify gene methylation changes relevant for metastatic SDHB-PPGLs. Design We performed genome-wide profiling of DNA methylation in diverse clinical and genetic PPGL subtypes, and validated protocadherin γ-C3 (PCDHGC3) gene promoter methylation in metastatic SDHB-PPGLs. Results We define an epigenetic landscape specific for metastatic SDHB-PPGLs. DNA methylation levels were found significantly higher in metastatic SDHB-PPGLs than in SDHB-PPGLs without metastases. One such change included long-range de novo methylation of the PCDHA, PCDHB, and PCDHG gene clusters. High levels of PCDHGC3 promoter methylation were validated in primary metastatic SDHB-PPGLs, it was found amplified in the corresponding metastases, and it was significantly correlated with PCDHGC3 reduced expression. Interestingly, this epigenetic alteration could be detected in primary tumors that developed metastasis several years later. We also show that PCDHGC3 down regulation engages metastasis-initiating capabilities by promoting cell proliferation, migration, and invasion. Conclusions Our data provide a map of the DNA methylome episignature specific to an SDHB-mutated cancer and establish PCDHGC3 as a putative suppressor gene and a potential biomarker to identify patients with SDHB-mutated cancer at high risk of metastasis who might benefit from future targeted therapies.

AbstractIntroductionPatients undergoing unilateral adrenalectomy for primary aldosteronism (PA) may have a solitary adenoma, unilateral hyperplasia, or multiple adenomas on final pathology. This study investigated whether the underlying pathological diagnosis was associated with differences in clinical presentation and postoperative outcomes.MethodsA retrospective cohort study of patients undergoing unilateral adrenalectomy for PA from 2004 to 2015 at our institution was performed. Baseline clinical and laboratory parameters, as well as postoperative biochemical and hypertension cure rates, were compared across the three aforementioned pathological groups.ResultsOf 206 patients who met criteria for inclusion, 152 (73.8%) had a single adenoma, 33 (16%) had unilateral hyperplasia, and 21 (10.2%) had multiple unilateral adenomas. Patients with unilateral hyperplasia were more likely to be male (81.2% vs 57.9%, P = .03), undergo left‐sided adrenalectomy (78.8% vs 47.4%, P < .01), and had a lower median adrenal venous sampling lateralization index (9.8 vs 19.8, P = .04) compared to those with solitary, but not multiple unilateral adenomas. No differences were seen in age, duration of hypertension, preoperative plasma aldosterone levels, plasma renin activities, 24‐h urinary aldosterone excretion, serum potassium concentrations, and the number of preoperative antihypertensive medications across all three pathological groups. All patients achieved biochemical cure following adrenalectomy, and no significant differences in the rates of hypertension cure or improvement were observed in comparisons across pathological subtype.ConclusionsClinical presentation and postoperative outcomes are similar regardless of underlying pathology in patients with PA. Because one in four patients may harbor unilateral hyperplasia or multiple adenomas, total unilateral adrenalectomy should be performed as the operation of choice over adrenal‐sparing approaches.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross‐sectional imaging. Mild autonomous cortisol secretion ( MACS ) from the adrenal mass is demonstrated in 5–48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS , and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS ‐associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS , discuss data on emerging biomarkers, and suggest future directions in the field of MACS .