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Poster Display session 1

2596 - Driving solo? Investigation into collaborating mutations in SDH-deficient neoplasia

Date

28 Sep 2019

Session

Poster Display session 1

Topics

Pathology/Molecular Biology

Tumour Site

Presenters

Jonathan Killian

Citation

Annals of Oncology (2019) 30 (suppl_5): v797-v815. 10.1093/annonc/mdz269

Authors

J.K. Killian1, D.C. Pavlick2, E.S. Sokol3, M. Montesion4, D.X. Jin3, B. Kaplan3, D. Lin1, J. Vergilio1, J.A. Elvin1, N. Ngo1, E. Severson1, S. Ramkissoon1, D. Duncan1, C. Edgerly1, A. Hemmerich1, G.M. Frampton3, G. Bratslavsky5, V.A. Miller6, S.M. Ali6, J.S. Ross1

Author affiliations

  • 1 Pathology, Foundation Medicine, 02141 - Cambridge/US
  • 2 Cancer Genomics Research, Foundation Medicine, 02141 - Cambridge/US
  • 3 Cancer Genomics, Foundation Medicine, 02141 - Cambridge/US
  • 4 Dept. Cancer Genomics, Foundation Medicine, 02141 - Cambridge/US
  • 5 Urology, Upstate Medical University, 13210 - Syracuse/US
  • 6 Clinical Development, Foundation Medicine, 02141 - Cambridge/US

Resources

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Abstract 2596

Background

Succinate dehydrogenase (SDH) is a highly conserved component of energy production and metabolism. Genetic or epigenetic inactivation of SDH (dSDH) creates a state of intracellular pseudohypoxia that is uniquely oncogenic for subtypes of GIST, renal cell carcinoma (RCC), paraganglioma/pheochromocytoma (PGL/Pheo), and pituitary adenoma/carcinoma (PAC). dSHD stems from homozygous loss of one of four subunit encoding genes SDHA, SDHB, SDHC, or SDHD (aka, SDHx). dSDH is not targetable, and preclinical models are poorly viable. In the current study we analyze comprehensive genomic profiles (CGP) from a dSDH pan-tumor cohort for potential therapy-enabling non-SDHx genomic alterations and biomarkers (GA).

Methods

231,706 clinical grade CGP were searched for dSDH GIST, RCC, PGL/Pheo, and PAC. GA were determined on 1.1 Mb genome sequence encompassing up to 324 cancer genes. dSDH was further established by histopathology review and analysis of SDHx homozygous loss. Germline and zygosity status of SDHx variants were performed by SGZ algorithm. Non-SDHx GA were assessed for therapeutic actionability.

Results

82 SDH-deficient neoplasms were analyzed (Table). 0 of 38 GIST had highly actionable GA. In one case a subclonal KIT variant was identified in a recurrence of an SDHA-mutant GIST treated with Imatinib for several years. No clonal canonical driver kinase mutations were identified in KIT, PDGFRA, NF1, BRAF, FGFR1 or NTRK1-3. 0 of 36 dSDH PGL/Pheo and 0 of 1 PAC had potential therapeutic options. 2 of 7 dSDH RCC reported potential treatment options for oncogenic variants in EGFR and CDK4. No dSDH tumors had high TMB, microsatellite instability, or LOH score indicative of homologous recombination defect (HRD). Overall, 2 of 82 tumors (2.4%) harbored highly actionable GA.Table:

2039P

82 SDH-deficient tumors
GIST (n = 38)PGL/Pheo (n = 36)RCC (n = 7)PAC (n = 1)
Age (mean)33404944
Sex ratio (M/F)16/2124/124/30/1
SDHA111231
SDHB72130
SDHC4110
SDHD2200
SDHx-WT14000
%SDHx germline696410050
GA/tumor (pathogenic non-SDHx)0.580.892.290
MSI0000
TMB (mut/Mb, mean)1.862.430.9
HRD (LOHscore >16%)0000

Conclusions

This study identifies SDH deficiency as a lone driver of malignancy and without associated actionable GA in > 97% of cases, and underscores the need for novel therapeutic approaches targeting SDH deficiency itself.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Foundation Medicine.

Funding

Foundation Medicine.

Disclosure

J.K. Killian: Full / Part-time employment: Foundation Medicine. D.C. Pavlick: Full / Part-time employment: Foundation Medicine. E.S. Sokol: Full / Part-time employment: Foundation Medicine. M. Montesion: Full / Part-time employment: Foundation Medicine. D.X. Jin: Full / Part-time employment: Foundation Medicine. B. Kaplan: Full / Part-time employment: Foundation Medicine. D. Lin: Full / Part-time employment: Foundation Medicine. J. Vergilio: Full / Part-time employment: Foundation Medicine. J.A. Elvin: Full / Part-time employment: Foundation Medicine. N. Ngo: Full / Part-time employment: Foundation Medicine. E. Severson: Full / Part-time employment: Foundation Medicine. S. Ramkissoon: Full / Part-time employment: Foundation Medicine. D. Duncan: Full / Part-time employment: Foundation Medicine. C. Edgerly: Full / Part-time employment: Foundation Medicine. A. Hemmerich: Full / Part-time employment: Foundation Medicine. G.M. Frampton: Full / Part-time employment: Foundation Medicine. V.A. Miller: Full / Part-time employment: Foundation Medicine. S.M. Ali: Full / Part-time employment: Foundation Medicine. J.S. Ross: Full / Part-time employment: Foundation Medicine. All other authors have declared no conflicts of interest.

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