Preferential hypermethylation in SDH-deficient wild-type GIST.

Aims: Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation.

BRAF V600E Mutant Lung Adenocarcinoma Presenting With a Skull Base Metastasis and Pituitary Adenoma Collision Tumour.

We report an unusual initial presentation for metastatic lung adenocarcinoma (LAC) with progressive loss of vision, a rare molecular phenotype and rapid visual response to surgical resection. A 60-year-old female presented with rapid and progressive visual loss over four weeks. Contrast-enhanced CT and MRI scans showed an enhancing lobulated mass in the base of skull infiltrating into the sella turcica.

The role of [ Ga]Ga-DOTATATE PET/CT in wild-type KIT/PDGFRA gastrointestinal stromal tumours (GIST).

Background: [ Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [ Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called 'wild-type' GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST.

Lorlatinib for the treatment of inflammatory myofibroblastic tumour with TPM4-ALK fusion following failure of entrectinib.

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases.

SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice.

The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma. SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene. However, clinical diagnostic testing for an SDHC epimutation is not widely available.

Translating metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility.

Purpose: Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL) 1, 2, gastrointestinal stromal tumours (GIST) 3, renal cell carcinoma (RCC) 4 and pituitary adenomas5. SDH-related tumorigenesis is believed to be secondary to accumulation of the oncometabolite succinate. Our aim was to investigate the potential clinical applications of MRI spectroscopy (H-MRS) in a range of suspected SDH-related tumours.

SDHA related tumorigenesis: a new case series and literature review for variant interpretation and pathogenicity.

Purpose: To evaluate the role of germline mutation analysis by (1) comprehensive literature review, (2) description of novel germline mutations and (3) in silico structural prediction analysis of missense substitutions in SDHA.

Patients And Methods: A systematic literature review and a retrospective review of the molecular and clinical features of patients identified with putative germline variants in UK molecular genetic laboratories was performed. To evaluate the molecular consequences of missense variants, a novel model of the SDHA/B/C/D complex was generated and the structural effects of missense substitutions identified in the literature, our UK novel cohort and a further 32 "control missense variants" were predicted by the mCSM computational platform.