Sosipatros A. Boikos
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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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Overview

Overview

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


Overview1

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


Overview2

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


Wild type gist

Wild-Type GIST

85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA


Wild type gist1

Wild-Type GIST

85% of GIST occurring in young population is lacking mutations in KIT or PDGFRA

Stomach location, epithelioid histology


Wild type gist2

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)


Wild type gist3

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


Wild type gist4

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


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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


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

78 patients


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6 patients Have NF1 or BRAF mutations

NF1 (3)

BRAF (3)

78 patients


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44 Patients Have Mutations in SDHA, B, C, D

SDHA (22)

78 patients

SDHB (10)

SDHC (11)

SDHD (1)


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28 Patients Have No Detectable Mutation To Date

78 patients

None (28)


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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


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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


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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)


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  • 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)


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  • 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)


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  • 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)


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  • 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)


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Succinate Dehydrogenase Mutations lead to a hypermethylator phenotype in Gastrointestinal Stromal Tumor

Infinium 450 methylation data

Killian et al. Cancer Discovery 2013

78 patients


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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)


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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)


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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)


No disclosures

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)


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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)


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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)


Conclusions

Conclusions

3 distinct groups of Wildtype GIST


Conclusions1

Conclusions

Group B tumors have loss of SDHB staining without SDH mutations.

We assume these 20 tumors have alterations in SDH pathway.


Discussion

Discussion

Should we redefine Wildtype GIST as tumors having SDHB deficiency by IHC?

Should we use demethylating agents for SDHB deficient GIST?


Acknowledgements

Acknowledgements

Our patients!

Dr. Lee Helman lab

Lauren Long

Yeung Choh

Arnaldez Fernanda

Erin Gombos

Christine Heske

Amy McCalla-Martin

Anna Nkrumah

Wan Xiaolin


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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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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


No disclosures

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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