SDH-deficient GIST 2019 Update Michael C. Heinrich, MD Professor - PowerPoint PPT Presentation

SDH-deficient GIST 2019 Update Michael C. Heinrich, MD Professor Department of Medicine Department of Cell, Developmental, and Cancer Biology

Established 2008

The NIH pediatric and wild-type GIST clinic • Bi-annual clinic at NIH established June, 2008 – Collaborative effort between clinicians, researchers, support groups and patients – Objective: further the investigation of the clinical features and oncogenic mechanisms underlying wild-type GIST JAMA Oncology 2016 Surgical Management of Wild-type Gastrointestinal Stromal Tumors: A Report from the NIH Pediatric and Wild-type GIST Clinic; Weldon, CW et al; JCO epub (in press Cancer Discovery 2013

Comparison of Adult and Pediatric/AYA GIST Adult Peds/AYA Primary tumor site Gastric 70% Gastric 90%+ Gender M>F (slight bias) Female predominance SDHB expression Retained Lost KIT mutations More than 70% Minority Multiple primary tumors Rare Common Due to inherited Rare Majority (SDH) mutation Response to imatinib Majority Uncommon Family inheritance Rare Majority

Molecular Classification of GIST 2018 RTK translocation NF1-related RAS mutant 0.1% 0.1% 0.1% Unclassifed BRAF mutant 1.0% 1.5% SDH deficient 10.0% PDGFRA mutant 10.1% KIT mutant 77.1% Note: This data are compiled from series largely composed of adult patients

Succinate dehydrogenase • 4-subunit complex in QH 2 ETC Q IMM mitochondrial matrix • Links TCA to ETC Matrix • Cofactors: • FAD • 3 iron-sulfur clusters • Heme b • Assembly Factors TCA • SDHAF1-4 Cycle Slide courtesy of Jason Kent 6

SDH dysfunction and human disease Slide courtesy of Jason Kent 7

SDH dysfunction and human disease • Inactivation of any subunit results in loss of SDHB and whole-complex activity 8 Slide courtesy of Jason Kent

SDH dysfunction and human disease • Inactivation of any subunit results in loss of SDHB and whole-complex activity 9 Slide courtesy of Jason Kent

SDH dysfunction and human disease • Inactivation of any subunit results in loss of SDHB and whole-complex activity • Loss of SDH activity results in succinate accumulation 10 Slide courtesy of Jason Kent

SDH dysfunction and human disease • Inactivation of any subunit results in loss of SDHB and whole-complex activity • Loss of SDH activity results in succinate accumulation Dioxygenase Example Consequence • Elevated succinate inhibits ⍺ - Hydroxylase HIF prolyl Pseudohypoxia ketoglutarate-dependent hydroxylase dioxygenases resulting in Demethylase TET Hypermethylation pathological phenotypes Image: Wikipedia 11 Slide courtesy of Jason Kent

SDH-deficient GIST tumor are globally hypermethylated

SDH dysfunction and human disease • SDH-deficiency is associated with multiple human diseases – Cancer • Gastrointestinal stromal tumor (GIST) • Paraganglioma and pheochromocytoma (PGL/PCC) • Renal cell carcinoma (RCC) – Leigh syndrome and other neurodegenerative disorders – Neonatal cardiomyopathy 13

SDH-deficiency defined by loss of SDHB SDHB IHC - PGL/PCC tumor samples What causes SDH- SDH-Deficient NEGATIVE deficiency in these tumors? Loss-of-function SDHB mutation SDHC mutation SDHD mutation mutations in SDHx SDH-Proficient POSITIVE VHL mutation RET mutation NF1 mutation Adapted from van Nederveen, 2009 14 Slide courtesy of Jason Kent

SDH-deficiency defined by loss of SDHB SDHB IHC - PGL/PCC tumor samples What causes SDH- SDH-Deficient NEGATIVE deficiency in these tumors? Loss-of-function SDHB mutation SDHC mutation SDHD mutation mutations in SDHx Adapted from Eveneopoel, 2014 15 Slide courtesy of Jason Kent

Out of control automobile as a model of cancer • Car = cell • Car out of control = cancer cell • Jammed accelerator = oncogene (e.g. KIT mutation) – Gain of function – Only need one event (mutation) • Defective brakes = tumor suppressor gene (e.g. SDH) – Loss of function – Need two events (mutations) to inactivate front and rear brakes

SDH-deficient cancers require two SDH mutations for cancer development • Two ‘inactivating’ SDH hits in order to become deficient • First hit – Germline – Somatic – Epimutation 1 2 3 Second hit 1. Somatic 2. Loss of heterozygosity Banno et al 2012 3. Epimutation

Inheriting a loss-of-function SDH mutation results in high life-time risk for tumor development PGL/PCC Neumann et al., 2004; Bausch et al., 2017 18

NIH clinic: Total of 95 WT GIST Pts Analyzed Boikos et al., JAMA Oncology 2016

NIH clinic: Total of 95 WT GIST Pts Analyzed Boikos et al., JAMA Oncology 2016

NIH clinic: Total of 95 GIST Pts Analyzed Boikos et al., JAMA Oncology 2016

NIH clinic: Total of 95 WT GIST Pts Analyzed

NIH clinic: Total of 95 WT GIST Pts Analyzed Boikos et al., JAMA Oncology 2016

NIH clinic: Total of 95 GIST Pts Analyzed

NIH clinic: Total of 95 WTGIST Pts Analyzed Boikos et al., JAMA Oncology 2016

SDH Deficient GIST Janeway K, Inherited and Syndromic GIST. In: Gastrointestinal Stromal Tumors: Bench to Bedside (Scoggins CR, Raut CP, Mullen JT eds.) Based on Boikos S., JAMA Oncology 2016

Frequency of SDHB-negative and SDHB-positive gastric GISTs as a function of age Miettinen et. al Am J Surg Pathol. 2011

SDH mutations and epimutations • Mutations have been found in all 4 SDH genes (A,B,C,D) • most of these are inherited • In addition, some pediatric GIST have silencing of SDHC by “epimutation” • hypermethylation of the SDHC promoter • this abnormality is not inherited • Why does this matter? SDH mutations and epimutations both lead to Carney Triad (GIST, paraganglioma, pulmonary chondroma) and Carney-Stratakis syndrome (GIST, paraganglioma [PGL], pheochromoctyoma [PHEO]) • These distinctions are important for genetic counseling and screening for PGL/PHEO • Carney Triad: not inherited • Carney-Stratakis: usually inherited

Molecular Classification of GIST 2018 “No subgroup left behind” BRAF V600E RAS NF1-related RTK Unclassified KIT ex8 mutation mutation 0.1% translocation 1.0% 0.1% 1.5% 0.1% 0.1% KIT ex17 SDHC 1.0% KIT ex13 epimutation 2.0% 1.0% SDH PDGFRA ex18 mutation D842V KIT ex9 (A/B/C/D) 5.0% 8.0% 9.0% PDGFRA ex18 other 3.0% PDGFRA ex12 2.0% PDGFRA ex14 0.1% KIT ex11 66.0% Note: This data are compiled from series largely composed of adult patients

Patterns of Mutant SDH inheritance Carney-Stratakis Syndrome : -GIST, paragangliomas -germline mutations in succinate dehydrogenase B E Baysal et al. J Med Genet 2002;39:178-183

High risk of cancer for germline pathogenic SDH mutations • Early detection lead to surgical cure • Genetic screening to identify family members • Cancer screening for carriers • Yearly labs • Total body MRI (or CT) every 3-5 years • Upper endoscopy with endoscopic ultrasound every 3-5 years Neumann et al., 2004

Summary • Best pathology diagnostic screen is SDHB IHC • dSDH GISTs overwhelmingly gastric in location and most are multifocal and/or metastatic at presentation • Implications for management • Recently identified: first small bowel dSDH GIST • dSDH GISTs rarely (but sometimes) respond to imatinib • Higher reported response rate to sunitinib and regorafenib • likely due to effects on sunitinib and regorafenib on VEGFR • Most SDH mutations are germline • Significant implications for genetic counseling, prevention and early detection

Future Directions • Continue to study patients with dSDH GIST • Identify genotype/phenotype correlations • Currently no validated cell lines or models! • We are still learning (first case of small intestine dSDH GIST was just reported • Based on increased succinate/aKG ratios global DNA hypermethylation + PHD inhibition “pseudo-hypoxic” state: • Test more potent DNMT inhibitors, e.g., SGI-110 (guadecitabine) study just opened at NCI • Combination therapy (maybe with anti-angiogenic drugs) • PARP inhibitors?? • Understand natural history of disease • Develop prognostic marker (?cfDNA-hypermethylation) • “Metabolic” therapy to exploit the mitochondrial defect in dSDH cells