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CTF 2017 Cutaneous Neurofibroma Resource Sage Bionetworks
- 1. The molecular landscape of cutaneous neurofibroma Robert Allaway, PhD CTF Conference 2017 @allawayr
- 2. The molecular landscape of cutaneous neurofibroma Robert Allaway, PhD CTF Conference 2017 @allawayr accelerating biomedical research through open practices and collaborative research efforts
- 3. CME Disclosure • I have no financial relationships to disclose • I will not be discussing off-label or investigational uses of drugs or devices
- 4. Cutaneous/dermal neurofibromas • Grow from nerves in the skin • Late childhood throughout adulthood • Can range in both size and amount (few to 1000s) • Do not progress to malignancy • Cause lifelong struggle for NF1 patients • Can itch or be painful, cause superficial infections • Cosmetic, social concerns • Significant patient burden
- 5. Ongoing questions in cNF • Key driving components? • How do cutaneous NF differ from plexiform NF (molecular, microenvironment, endocrine, other)? • Diversity among patients? • Ideal therapeutic approaches?
- 6. Ongoing questions in cNF • Developing new treatments requires knowing why and how NFs grow • How best to facilitate & accelerate the pace of this research?
- 7. Hurdles in cNF research •What are some hurdles for the neurofibroma research community? • Few open datasets with comprehensively characterized biological samples
- 8. Hurdles in cNF research •What are some hurdles for the neurofibroma research community? • Few open datasets with comprehensively characterized biological samples • Identifying critical molecular features
- 9. Hurdles in cNF research •What are some hurdles for the neurofibroma research community? • Few open datasets with comprehensively characterized biological samples • Identifying critical molecular features • Patients are very diverse
- 10. CTF Biobank & Data Resource • CTF Biobank: • Neurofibroma and blood samples donated by patients
- 11. CTF Biobank & Data Resource •Data Resource: •Clinical and ‘omic data from biobank samples •Analysis •Share data and our analysis with NF researchers • CTF Biobank: • Neurofibroma and blood samples donated by patients
- 12. CTF Biobank & Data Resource
- 21. neurofibroma sample neurofibroma sample neurofibroma sample NF patient data analysis data analysis NF Research Community
- 24. Demographics Gosline et al, Scientific Data, 2017 11 patients 52 cNFs profiled
- 25. Data Type Number of Samples WGS 42 Patient matched PBMC for germline variants RNASeq 33 SNP Array 40 Patient matched PBMC for germline variants Proteomics 41 Currently being reprocessed Publically available data
- 26. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis
- 27. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis
- 28. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis
- 29. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis
- 30. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis What genetic variants predominate across patients and tumors?
- 31. Broad array of germline and somatic NF1 mutations Germline
- 32. Broad array of germline and somatic NF1 mutations Germline Somatic
- 33. Landscape of germline mutations
- 34. Landscape of somatic mutations in cNF
- 35. WGS mutation profiling RNASeq WGS + RNASeq immune estimation pathway analysis integrative analysis Can we detect RNA-based signatures of immune components?
- 36. Immune population estimation • CIBERSORT (Newman et al 2015) • Estimation of immune cell fractions in tumor samples • Deconvolution method for RNA expression data • Identification of immune cell subtypes (LM22 signature set)
- 38. WGS mutation profiling RNASeq WGS + RNASeq immune estimation pathway analysis integrative analysis Can we detect signaling pathway signatures?
- 39. Pathway analysis • ssGSEA: test for pathway enrichment across samples • Candidate-finding approach to discovering pathways for further investigation Barbie et al 2009, Hänzelmann et al 2013
- 40. enriched pathway signatures in cNF
- 41. WGS mutation profiling RNASeq WGS + RNASeq pathway analysis immune estimation integrative analysis What signatures correlate with mutations found in cNF?
- 42. Hotnet 2 42
- 43. When filtering for high-impact mutations, only 1 somatic network
- 44. When filtering for high-impact mutations, only 1 somatic network Highly mutated nodes
- 45. CDC27 and CREBBP have a broad mutation spectrum
- 46. Immune signatures correlate with CREBBP/CDC27 mutation Interferon 𝛄 Response signature Complement signature
- 47. Immune signatures correlate with CREBBP/CDC27 mutation Interferon 𝛄 Response signature Complement signature Can we leverage information like this to identify therapeutic approaches?
- 49. Conclusions Biobank and data resource are a resource for scientists studying cNF and other NF1-related tumors •Data sharing: • Eliminates hurdles for researchers • Enables stronger conclusions • Faciliates generation of new hypotheses • Allows the whole NF research community to participate, explore and ask new and different questions that may not have been tested
- 50. Conclusions Biobank and data resource are a resource for scientists studying cNF and other NF1-related tumors •Data sharing: • Eliminates hurdles for researchers • Enables stronger conclusions • Faciliates generation of new hypotheses • Allows the whole NF research community to participate, explore and ask new and different questions that may not have been tested •New discoveries may: • Answer our fundamental questions about cNF • Help researchers better identify and develop treatments
- 51. Sara Gosline, PhD Justin Guinney, PhD Xindi Guo Thomas Yu Annette Bakker, PhD Salvo La Rosa, PhD Pamela Knight, MS Hubert Weinberg, MD Nripesh Prasad, PhD Lu Le, MD-PhD robert.allaway@sagebase.org @allawayr
Editor's Notes
- Hi everyone, I’m … and I’ll be talking today about cutaneous neurofibroma, and a new CTF-sponsored public omics data resource for research projects involving these tumors
- Hi everyone, I’m … and I’ll be talking today about cutaneous neurofibroma, and a new CTF-sponsored public omics data resource for research projects involving these tumors
- Which features are common across most or all patients?
- Which features are common across most or all patients?
- Which features are common across most or all patients?
- Share data and our analysis with NF researchers so they can study the data and integrate it into their own research
- Share data and our analysis with NF researchers so they can study the data and integrate it into their own research
- The demographics of enrolled patients are as follows…… we have characterized tumors from 11 patients fulfiling NF1 diagnostic criteria. From these patients, we profiled 52 cNFs
- Of those 52 cNFs, 42 were characterized by WGS, 33 by RNAseq, 40 by SNP array, and 41 by proteomics
- We think this data sharing model will faciliate new discoveries that could help answer …. And help researcherrs better …