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  1. Sosipatros A. Boikos, Suzanne George, Katherine A. Janeway, Keith J. Killian, Su Young Kim, Michael P. LaQuaglia, Lauren Long, Paul S. Meltzer, Markku M. Miettinen, Karel Pacak, Alberto Pappo, Margarita Raygada, Joshua Schiffman, Constantine Stratakis, Jonathan Trent, Margaret Von Mehren, Christopher B. Weldon, Jennifer Wright, Lee J. Helman On behalf of the Consortium for Pediatric & wildtype GIST Research October 31, 2013 Connective Tissue Oncology Society An integrated analysis of genetic and epigenetic alterations in gastrointestinal stromal tumors reveals distinct clinical phenotypes

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  3. Overview Presentation of the most recent genetic and clinical findings of the NIH Pediatric and Wildtype GIST clinic.

  4. Overview Presentation of the most recent genetic and clinical findings of the NIH Pediatric and Wildtype GIST clinic. Correlation of the genetic and epigenetic findings with the clinical phenotype

  5. Overview Presentation of the most recent genetic and clinical findings of the NIH Pediatric and Wildtype GIST clinic. Correlation of the genetic and epigenetic findings with the clinical phenotype Discussion

  6. Wild-Type GIST 85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA

  7. Wild-Type GIST 85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA Stomach location, epithelioid histology

  8. Wild-Type GIST 85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA Stomach location, epithelioid histology May be syndromic (Carney Triad, Stratakis-Carney Syndrome)

  9. Wild-Type GIST 85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA Stomach location, epithelioid histology May be syndromic (Carney Triad, Stratakis-Carney Syndrome) Tyrosine kinase inhibition is less effective compared to KIT or PDGFRA mutant tumors

  10. Wild-Type GIST 85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA Stomach location, epithelioid histology May be syndromic (Carney Triad, Stratakis-Carney Syndrome) Tyrosine kinase inhibition is less effective compared to KIT or PDGFRA mutant tumors Mutations in Succinate Dehydrogenase (SDH) genes have been found in some but not in all patients

  11. 10 WT GIST clinics; 115 patients have been seen till An international clinic twice a year 115 patients have been seen in 10 clinics since 2008. Objectives of the Wildtype Clinic at NIH • To bring together healthcare providers who have the most experience treating and studying GIST • To obtain clinical history, response to prior treatments, histopathologic results, radiographic assessments and genetic/molecular analyses • Continue long-term follow-up for these patients

  12. Summary of Mutation Analysis of 78 Patients with Wild-Type GIST Fully Analyzed for SDH, BRAF, and NF1 Mutations 78 patients

  13. 6 patients Have NF1 or BRAF mutations NF1 (3) BRAF (3) 78 patients

  14. 44 Patients Have Mutations in SDHA, B, C, D SDHA (22) 78 patients SDHB (10) SDHC (11) SDHD (1)

  15. 28 Patients Have No Detectable Mutation To Date 78 patients None (28)

  16. Mutations Distributed across all exons-90% Germline D118fs 1S 2S 3S 4S SDHD U 1 2 3 4 U 78 patients p54T H127R Splice Site G75D R133X R15X M1V 1L 2L 3L 4L 5L 3S 4S SDHC U U 1 2 3 4 5 c189F R46X Splice site W200C S92T c.17_42dup I127S R46Q R201fs 2Fe-2S 4Fe-4S SDHB U U 1 2 3 4 5 6 7 8 L511P S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  17. Wildtype GIST can have negative SDHB staining regardless of the status of mutations in SDH genes 78 patients NF1 (3) BRAF (3) SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) Janeway and Kim et al. 2011 PNAS 108:314

  18. 53 tumors had negative SDHB staining 9 had positive staining 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9)

  19. Tumors with SDHA, B, C, D mutations have always negative SDHB staining. 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9)

  20. Tumors with SDHA, B, C, D mutations have always negative SDHB staining. 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9)

  21. Tumors with SDHA, B, C, D mutations have always negative SDHB staining. • Tumors with negative SDHB staining and no mutations have probably alterations in SDH pathway. 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9)

  22. Tumors with SDHA, B, C, D mutations have always negative SDHB staining. • Tumors with no mutations and negative SDHB staining have probably alterations in SDH pathway. • Tumors with BRAF or NF1 mutations had SDHB positivity. • Tumors with SDHB positivity and no mutations likely have alterations outside the SDH pathway. 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9)

  23. Succinate Dehydrogenase Mutations lead to a hypermethylator phenotype in Gastrointestinal Stromal Tumor Infinium 450 methylation data Killian et al. Cancer Discovery 2013 78 patients

  24. Negative SDHB staining by IHC correlates with Hypermethylation in 66 tumors Infinium 450 methylation data Killian et al. Cancer Discovery 2013 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22)

  25. How SDHB loss is causing hypermethylation? 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9) 3rd Circle Methylation Yang M, Pollard PJ Cancer Cell 2013 Deviator (66) Centrist (12)

  26. Group A (n=12) Positive SDHB IHC Normal Methylation pattern Mutations in NF1, BRAF or other unknown genes Group A 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9) 3rd Circle Methylation Deviator (66) Centrist (12)

  27. Group B (n=22) Negative SDHB staining by IHC Hypermethylation (Deviator) Not known mutations 78 patients Group B NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9) 3rd Circle Methylation Deviator (66) Centrist (12)

  28. Group C (n=44) Negative SDHB staining by IHC Hypermethylation (Deviator) SDHA, B, C, D mutations Group C 78 patients NF1 (3) BRAF (3) 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9) 3rd Circle Methylation Deviator (66) Centrist (12)

  29. Comparison of Group B and C 1. Group B=young age Group C Age 78 patients Group B Years 60 40 20 0 NF1 (3) B C BRAF (3) 2. All patients in Group B are females while in Group C 65% are females. We have Carney Triad patients (chondroma, paraganglioma) or Carney-Stratakis Syndrome patients (paraganglioma) in both groups B and C. 1st Circle Mutated Genes: SDHA (22) SDHB (10) SDHC (11) SDHD (1) None (28) 2nd Circle SDHB staining: Negative (53) Positive (9) At the moment we have no statistically significant differences in overall Survival, Recurrence free Survival. 3rd Circle Methylation Deviator (66) Centrist (12)

  30. Conclusions 3 distinct groups of Wildtype GIST

  31. Conclusions Group B tumors have loss of SDHB staining without SDH mutations. We assume these 20 tumors have alterations in SDH pathway.

  32. Discussion Should we redefine Wildtype GIST as tumors having SDHB deficiency by IHC? Should we use demethylating agents for SDHB deficient GIST?

  33. Acknowledgements Our patients! Dr. Lee Helman lab Lauren Long Yeung Choh Arnaldez Fernanda Erin Gombos Christine Heske Amy McCalla-Martin Anna Nkrumah Wan Xiaolin

  34. SDHA FAD Binding Domain SDHB SDHC SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  35. T273I K589N A454E A454T L511P R188W SDHA R171C SDHB T256I SDHC A454L H99A SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223Fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  36. T273I K589N A454E A454T L511P FAD domain mutations R188W SDHA R171C SDHB T256I A445L SDHC H99A SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  37. T273I K589N A454E A454T L511P FAD domain mutations Protein-truncating mutations R188W SDHA R171C SDHB T256I A445L SDHC H99A SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  38. T273I K589N A454E A454T L511P FAD domain mutations Protein-truncating mutations Mutations disrupting the FAD domain R188W SDHA R171C SDHB T256I A445L SDHC H99A SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  39. T273I K589N A454E A454T L511P Correlation of Metastasis and site of mutation R188W SDHA R171C SDHB T256I SDHC A454L H99A SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X c.666delT A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  40. T273I K589N A454E A454T L511P Correlation of Metastasis and site of mutation R188W SDHA R171C SDHB T256I SDHC A454L H99A Similar analysis on SDHB, C and D subunits is ongoing SDHD S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X c.666delT A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U

  41. L511P S505fs R188W S445L K598N T256I A454E T273I R352X R31X Splice site H99Y R171C R512X A223fs A454T SDHA 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 U U c189F R46X Splice site W200C S92T c.17_42dup I127S R46Q R201fs 2Fe-2S 4Fe-4S SDHB U U 1 2 3 4 5 6 7 8 p54T H127R Splice Site G75D R133X R15X M1V 1L 2L 3L 4L 5L 3S 4S SDHC U U 1 2 3 4 5 D118fs 1S 2S 3S 4S SDHD U 1 2 3 4 U

  42. Wildtype GIST Phenotype Group B No mutations Hypermethylator phenotype Group C SDHx mutations Hypermethylator phenotype Age at diagnosis Female Gender Stomach Primary Multifocal Location Female Gender Paragangliomas Chondromas Carney Triad

  43. Age Almost all patients in group B are younger and female in comparison with group C Years 60 40 20 0 B C Group B No mutations Hypermethylator phenotype Group C SDHx mutations Hypermethylator phenotype Age at diagnosis Female Gender Stomach Primary Multifocal Location Female Gender Paragangliomas Chondromas Carney Triad

  44. We have Carney Triad patients (paraganglioma) or Carney-Stratakis Syndrome (chondroma, paraganglioma) in both groups B and C Group B No mutations Hypermethylator phenotype Group C SDHx mutations Hypermethylator phenotype Age at diagnosis Multifocal Location Female Gender Paragangliomas Chondromas Carney Triad

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