Early Detection of Cancer Patients with Germline SDH Deficiency

Division Of Basic Sciences - Nci

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Abstract

Patients with germline succinate dehydrogenase (SDH) subunit mutations have an increased risk of cancer including pheochromocytoma and paraganglioma, gastrointestinal stromal tumor (GIST) and, less commonly, renal cell cancer. Complete resection of localized disease may be curative for both SDH-deficient GIST and PHEO/PGL, but patients with disseminated disease do not have curative options, hence, early detection of these tumors is critical to the care of this patient population. Current recommendations for screening patients with germline SDH subunit mutations include annual or biannual serum or urine catecholamines as well as MRI every 2-3 years starting between the ages of 6 and 15 years. The efficacy of this screening strategy has not been prospectively tested and it is likely to have limited sensitivity for smaller GIST and non-secreting PHEO/PGL. Multiple MRI studies can also be burdensome, particularly for pediatric patients. We hypothesize that cfDNA hypermethylation and metabolic profile can be used to non-invasively identify cancer in patients with germline SDH-deficiency. The Pediatric Oncology Branch cares for over 100 patients with germline SDH-deficiency as part of the Natural History and Biospecimen Acquisition Study for Children and Adults with Rare Solid Tumors (19-C-0016). This cohort of patients, which includes subjects with GIST and PHEO/PGL as we as unaffected carriers will be used to define a cfDNA methylation and serum and urine metabolic signature predictive of GIST and PHEO/PGL. This test will be validated in patients enrolled on the Rare Tumor Natural History Study with germline SDH-deficiency. Global DNA hyper-methylation is a unique feature of these tumors and has has been demonstrated in a all SDH deficient cancer types. Loss of activity of SDH leads to accumulation of succinate. Succinate acts as an inhibitor of a broad array of alpha-ketoglutarate-dependent dioxygenases. The Ten-eleven Translocation (TET) family of aKG-dependent dioxengenase enzymes convert 5-methylcytosine to 5-hydroxymethycytosine leading to DNA demethylation. Inhibition of these enzymes due to SDH deficiency causes DNA hypermethylation. We propose that the DNA hypermethylation present in these tumors will be detectable in cfDNA. Changes in the urine metabolic profile have also been reported in patients with SDH-deficient tumors. Several recent studies have identified an increased succinate:fumarate ratio in patients with SDHx mutant paraganglioma compared to patients with paraganglioma with other molecular drivers. We are using urine and peripheral blood-based methods to develop a non-invasive screening test for SDH-deficient tumors that incorporates methylation analysis of cell-free circulating tumor DNA and urine and serum metabolic profiling.