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

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SDH-deficient GIST 2019 Update

Michael C. Heinrich, MD Professor

Department of Medicine Department of Cell, Developmental, and Cancer Biology

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Established 2008

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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

ncogenic mechanisms underlying wild-type GIST

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

JAMA Oncology 2016

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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 mutation Rare Majority (SDH) Response to imatinib Majority Uncommon Family inheritance Rare Majority

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KIT mutant 77.1% PDGFRA mutant 10.1% SDH deficient 10.0% BRAF mutant 1.5% RAS mutant 0.1% NF1-related 0.1% RTK translocation 0.1% Unclassifed 1.0%

Molecular Classification of GIST 2018

Note: This data are compiled from series largely composed of adult patients

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Matrix IMM

Succinate dehydrogenase

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TCA Cycle Q QH2 ETC

4-subunit complex in

mitochondrial matrix

Links TCA to ETC
Cofactors:
FAD
3 iron-sulfur clusters
Heme b
Assembly Factors
SDHAF1-4

Slide courtesy of Jason Kent

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SDH dysfunction and human disease

Slide courtesy of Jason Kent

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SDH dysfunction and human disease

Inactivation of any subunit

results in loss of SDHB and whole-complex activity

Slide courtesy of Jason Kent

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SDH dysfunction and human disease

Inactivation of any subunit

results in loss of SDHB and whole-complex activity

Slide courtesy of Jason Kent

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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

Slide courtesy of Jason Kent

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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

Elevated succinate inhibits ⍺-

ketoglutarate-dependent dioxygenases resulting in pathological phenotypes

Dioxygenase Example Consequence Hydroxylase HIF prolyl hydroxylase Pseudohypoxia Demethylase TET Hypermethylation

Image: Wikipedia

Slide courtesy of Jason Kent

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SDH-deficient GIST tumor are globally hypermethylated

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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

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SDH dysfunction and human disease

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SDH-deficiency defined by loss of SDHB

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SDHB IHC - PGL/PCC tumor samples

SDH-Deficient SDH-Proficient

Adapted from van Nederveen, 2009

SDHB mutation SDHC mutation SDHD mutation VHL mutation RET mutation NF1 mutation

NEGATIVE POSITIVE

What causes SDH- deficiency in these tumors? Loss-of-function mutations in SDHx

Slide courtesy of Jason Kent

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SDH-deficiency defined by loss of SDHB

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SDHB IHC - PGL/PCC tumor samples

SDH-Deficient

SDHB mutation SDHC mutation SDHD mutation

What causes SDH- deficiency in these tumors? Loss-of-function mutations in SDHx

Adapted from Eveneopoel, 2014

NEGATIVE

Slide courtesy of Jason Kent

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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

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SDH-deficient cancers require two SDH mutations for cancer development

Two ‘inactivating’ SDH hits in order to become deficient
First hit

– Germline – Somatic – Epimutation

Banno et al 2012

Second hit

1. Somatic
2. Loss of heterozygosity
3. Epimutation

1 2 3

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Inheriting a loss-of-function SDH mutation results in high life-time risk for tumor development

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Neumann et al., 2004; Bausch et al., 2017

PGL/PCC

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