Disclosures 3/27/2017. Case 5. Clinical History. Disclosure of Relevant Financial Relationships

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1 Hereditary Cancer Predisposition in Children Case 5 Cristina R. Antonescu, MD Disclosure of Relevant Financial Relationships USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY Disclosures No relevant financial relationship or conflict of interest to disclose. Clinical History 17 year old male presented to the ER with an acute abdomen thought to represent an acute appendicitis. Upon intra abdominal laparoscopic exploration a 4.5 cm gastric mass was identified and a distal gastric resection was performed. Morphology Solid Areas of Undifferentiated Round Cell Component Morphology Myxoid and Spindle cell areas 30 MF/10 HPFs 1

2 IHC: CD117 staining Diagnosis High Risk Gastric GIST IHC: SDHB loss Diagnosis High Risk SDH Deficient Pediatric GIST Additional Family History Next Generation Sequencing Father and uncle had hx of H&N paraganglioma resected Mitochondrial tumor suppressor gene SDHB mutation diagnosed in other male family members SDHB germline mutation in exon 4 downstream splice site mutation NM_0300:c.423+1G>A KRAS G12V somatic 2

3 30,000 25,000 20,000 15,000 10,000 5,000 0 KIT PDGFRA 3/27/2017 Clinical Follow up Fulminant Course Diagnosis SDH deficient pediatric GIST with an inherited SDHB germline mutation 10/13 partial gastrectomy 4.5 cm high risk GIST 1/14 omentectomy for metastatic disease multiple nodules (up to 15 cm largest size) s/p multiple TKI (imatinib, sunitinib, sorafenib, pazopanib+ trametinib) clinical trial regimens (Glutaminase inhibitor trial) 5/15 i abdominal debulking for metastatic disease multiple nodules (largest 13 cm) 11/15 DOD Points of discussion Pediatric GIST (differences from adult GIST) GIST in the setting of inherited or other syndromic conditions Pediatric GIST SDH deficient GIST (clinical spectrum) 2 nd Genetic hits in GIST (KRAS mutation) 1 st paradigm in GIST: KIT mutation KIT activation Response to TKI Wild Type GISTs lacking KIT/PDGFRA/BRAF mutations KIT Before After Adult GIST (10%) KIT mrna Pediatric GIST (85%) Clinical Subsets Sporadic Incidental Pediatric Syndromic KIT Imatinib Syndromic GIST Neurofibromatosis type I Carney s Triad (GIST, paraganglioma, pulmonary chondroma) Stratakis Carney Dyad CTRS42_re CTRS6 CTRS8 gist 14 gist 194 1A gist gist gist 218 gist 223 gist 237_11 gist 237_2 gist 289 gist 293 gist 363_1 gist 363_2 gist 411 gist 416_1 gist 416_2 gist 416_3 gist 84 gist385 gist 23 gist 320 gist 325 gist 66 KIT protein 3

4 Pediatric GIST Clinical Aspects Pediatric GIST Pathology Sex: female Site: stomach (multifocal) Pathologic criteria to predict risk of malignancy (size, mitotic activity) in adult GIST do not apply in pediatric GIST Clinical behavior: indolent, despite of high risk of recurrence (peritoneum, LNs, distant to liver) KIT (CD117) Multiple nodules Gastric location Epithelioid LN mets CD117 positivity Path criteria do NOT apply for risk of malignancy Comparison Pediatric vs. Adult GIST Pediatric Adult Location Stomach multinodular Stomach>SB solitary Sex Female Equal Histology Epithelioid Spindle LN mets Common Rare Clinical Course Indolent Aggressive KIT/PDGFRA WT 80-90% Imatinib Response No Yes, depends on mutation type Inherited or other syndromic GIST Familial GIST Syndromic GIST Neurofibromatosis type I Carney s Triad (GIST, paraganglioma, pulmonary chondroma) Carney Stratakis Dyad (GIST, paraganglioma) Syndromic GIST lacking KIT/PDGFRA mutations Neurofibromatosis type I somatic inactivation of NF1 Carney s Triad (GIST, paraganglioma, pulmonary chondroma) similar to pediatric GIST SDHCme Carney Stratakis Dyad (GIST, paraganglioma) inactivating germline mutations in SDH genes, similar with other inherited paragangliomas 4

5 GIST and NF1 NF1 associated multiple GISTs Increased risk of GIST development in NF1 (7%) Shares clinical and pathologic charateristics with familial GIST (small size, multifocal, ICC hyperplasia) Somatic inactivation of NF1 (WT for KIT/PDGFRA) Response to TKI not well defined NF1 associated multiple GISTs and ICC Hyperplasia Carney s Triad Non familial multitumor syndrome (Carney, 1977) Gastric GIST +/ paraganglioma +/ pulm chondroma Mainly females / significant overlap to pediatric GIST SDHx WT SDHC epimutation (CpG island promoter methylation) Incidence of Carney s Triad among Pediatric GIST may be underestimated Carney Stratakis dyad Gastric GIST+ Paraganglioma Germline SDHx mutation (B,C,D) Autosomal dominant, incomplete penetrance No gender predilection Epithelioid & Spindle GIST Bilateral Pulmonary Chondromas After 30 months of diagnosis Pasini, et al. Eur J Hum Genet

6 SDH Deficient GIST = WT Gastric GIST SDH deficient GIST Wild type pediatric GIST Carney s triad GIST Carney Stratakis dyad GIST/PGL A subset of wild type gastric adult GIST Succinate Dehydrogenase Complex (SDH A D) Conserved Effector of Cellular Metabolism and Energy Production Loss of SDHB expression by IHC evidence of any subunit disruption / impaired SDH function, 4 protein subunit in the mitochondria matrix 2 catalytic domains: SDHA oxidation of succinate to fumarate (Krebs cycle) SDHB electron transfer in the respiratory chain SDHC,D: membrane anchoring subunits SDHB KIT KIT mutant SDHA Pediatric wildtype SDHB Disruption of any subunit impaired SDH function, loss of SDHB expression by IHC PKCθ Actin Role of Oncometabolites in Epigenetic Reprogramming Global HyperMethylation in SDHB deficient GIST dsdhb GIST GIST STS succinate/αkg ratio pseudo hypoxic state Disruption of oxidative demethylation (inhibit dioxygenases) Global DNA and Histone Hypermethylation 450k Illumina Methylation Array 6

7 SDH Abnormalities in GIST Biallelic Inactivation Tumor Suppressor Gene 2 hit Model 2/3 SDHx mutations 1/3 SDHx WT epigenetic mode of gene inactivation SDHC promoter CpG island homozygous methylation (recurrent gene silencing epimutation) 6/15 patients occurred in Carney triad SDHx mutant GIST SDHA mutation is the most frequent 30 40% in older patients (median 34 years) lower F/M ratio SDHB,C,D 20% Killian et al, Science Translational Medicine 2014 SDHA mutations are associated with loss of both SDHA and SDHB protein expression SDH and Paragangliomas (PGL) SDHA Germline SDHA Somatic SDHA No SDHA Mutation No SDHA Mutation Familial Paragangliomas (35%) Germline mutations SDHB,C,D Rare: VHL, MEN, NF1 SDHx germline PGL + GIST= Carney Stratakis dyad SDHB Young Adult WT GIST Young Adult WT GIST Pediatric WT GIST Young Adult KIT exon 11DEL SDHB mutant PGL: predisposition Extra adrenal, solitary, high risk PGL Other neoplasms: papillary thyroid carcinoma, RCC, GIST Italiano A et al, BMC Cancer 2012 Primary GIST and 2 nd Genetic Hits (co existing mutations with KIT/PDGFRA) Tumor suppressor genes: TP53 mutations & P16 inactivation: tumor progression/high risk KRAS mutations rare (0.2 5%) What is the Role of Tyrosine Kinase Inhibitors in WT GIST? CR PR SD PD side effects N/A adju vant recen t TOT Imatinib HD Imatinib Sunitinib Nilotinib Sorafenib Dasatinib TOTALS (1%) (1%) (16%) (60%) (21%) Hechtman et al. (2015) *DOD 24 mo after dg * The response rate to TKI therapy is much lower than for adults with KIT/PDGFRAmutated GIST 7

8 Summary SDH deficient GIST Encompasses a wide spectrum of gastric WT GIST, including pediatric, Carney s triad, Carney Stratakis dyad, and a subset of adult WT GIST SDH abnormalities, either SDHx mutations (2/3 of cases) or SDHCme (1/3), are detected in most if not all SDH deficient GIST Most Carney s triad GIST show homozygous CpG island SDHC promoter methylation (SDHC epimutation) Mitochondrial toxic metabolite (succinate) results in decreased DNA demethylation and subsequently an altered epigenome driving tumorigenesis Summary SDH deficient GIST 2 nd genetic hits in GIST are rare but appear to drive a highly aggressive clinical behavior, including in the setting of SDHB deficient GIST New therapeutic strategies are needed to target the vulnerabilities of abnormal metabolic and epigenetic pathways in SDH deficient GIST, which are notoriously resistant to TKI regimens 8