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Lynnette Fernandez-Cuesta
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ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)
- Event: WCLC 2019
- Type: Educational Session
- Track: Pathology
- Presentations: 1
- Now Available
- Moderators:Masayuki Noguchi, Beatriz Bellosillo
- Coordinates: 9/08/2019, 15:15 - 16:45, Toronto (1985)
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ES12.04 - Machine Learning and Integrative Multi-Omics Analysis Identify Novel Molecular Groups of Lung Neuroendocrine Tumors (Now Available) (ID 3221)
15:15 - 16:45 | Presenting Author(s): Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Abstract
This work is part of the lungNENomics project, a large multi-omic and multidisciplinary effort, built up on our previous published work (1-4). The lungNENomics project aims at the molecular characterization of rare lung neuroendocrine neoplasms through the integration of whole-genome sequencing, transcriptome sequencing and methylation data, as well as the correlation with epidemiological and clinical information, and taking advantage of unique biorepositories, advanced computational approaches, and state-of-the-art in vitro models. The talk would provide an overview of the global lungNENomics project, as well as presenting the identification of a novel molecular entity.The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compared and contrasted the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Integrative analyses on 257 lung neuroendocrine neoplasms stratified atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identified therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirmed the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveiled the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.
Funding: U.S. National Institutes of Health (NIH), French National Cancer Institute (INCa), French Ligue Nationale contre le Cancer (LNCC), and the Dutch Cancer Society (DCS)
Website: rarecancersgenomics.com
Twitter: @CancersRare
References
1. Peifer M*, Fernández-Cuesta L*, Sos ML, George J, Seidel D, Kasper LH, Plenker D, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012 PMID: 22941188
2. Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretić L, Seidal D, Zander T, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014 PMID: 24670920
3. George J*, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Müller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmüller J, Becker C, Nürnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland Å, Solberg S, Ansén S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sänger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Büttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L*, Thomas RK. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018 PMID: 29535388
4. Derks JL, Leblay N, Lantuejoul S, Dingemans AC, Speel EM, Fernandez-Cuesta L. New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management. J Thorac Oncol. 2018 Review. PMID: 29454048
5. Alcala N*, Leblay N*, Gabriel AAG*, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J, Ghantous A, Delhomme TM, Chabrier A, Cuenin C, Abedi-Ardekani B, Boland A, Olaso R, Meyer V, Altmuller J, Le Calvez-Kelm F, Durand G, Voegele C, Boyault S, Moonen L, Lemaitre N, Lorimier P, Toffart AC, Soltermann A, Clement JH, Saenger J, Field JK, Brevet M, Blanc-Fournier C, Galateau-Salle F, Le Stang N, Russell PA, Wright G, Sozzi G, Pastorino U, Lacomme S, Vignaud JM, Hofman V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, Muscarella LA, Graziano P, Popper H, Stojsic J, Deleuze JF, Herceg Z, Viari A, Nuernberg P, Pelosi G, Dingemans AMC, Milione M, Roz L, Brcic L, Volante M, Papotti MG, Caux C, Sandoval J, Hernandez-Vargas H, Brambilla E, Speel EJM, Girard N, Lantuejoul S, McKay JD, Foll M#, Fernandez-Cuesta L#. Integrative and comparative genomic analyses identify clinically relevant groups of pulmonary carcinoids and unveil the supra-carcinoids. Nat Commun. In Press
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ES17 - Molecular Alterations and Heterogeneity in Mesothelioma (ID 20)
- Event: WCLC 2019
- Type: Educational Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Steven Mutsaers, Emanuela Felley-Bosco
- Coordinates: 9/09/2019, 11:00 - 12:30, Tokyo (1982)
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ES17.04 - New Insights into the Molecular Characteristics and Intra-Tumor Heterogeneity of Malignant Pleural Mesothelioma from the MESOMICS Project (Now Available) (ID 3250)
11:00 - 12:30 | Presenting Author(s): Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Abstract
Malignant pleural mesothelioma (MPM) is a rare but deadly disease, which molecular characteristics have only recently been uncovered through large-scale genomic studies (Bueno Nat Genet 2016; Hmeljak Cancer Discov 2018). Although insightful and important, many questions are still unanswered, which could be addressed with additional comprehensive and integrative genomic analyses. In addition, we have recently performed a reanalysis of the transcriptome data of the two aforementioned cohorts with no assumption of discretness, in which we have uncovered the importance of angiogenesis and the immune system for understanding the diversity of MPM molecular phenotypes (Alcala et al. under review). Intra-tumour heterogeneity (ITH) is commonly reported in MPM at the histopathological level; however, the question of the molecular ITH of this disease has not been comprehensively addressed so far. Only one recent study has highlighted the enormous ITH at the microenvironment level (Thapa et al. JTO 2017), suggesting that MPM experience spatially heterogeneous selective pressures, or possibly that there exist MPM clones that differentially alter their micro-environment.
In close collaboration with the French MESOBANK/MESOPATH, we have started the MESOMICS project aiming at performing a molecular characterization of a large series of MPM through the integration of muti-omic data and detailed epidemiological and clinical information in order to better understand this understudied and deadly disease. For this we have collected 130 fresh frozen tumors and their matched-normals from all the three MPM types (epithelioid, biphasic, sarcomatoid) and the main morphological subtypes of the epithelioid MPM. We have performed whole-genome sequencing, transcriptome sequencing and 850K methylation arrays in all these samples. For 12 of them we had access to several regions of the tumor, which allowed us to perform ITH analyses. The preliminary analyses of these data will be presented and discussed.
Website: RareCancersGenomics.com
Twitter: @CancersRare
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MA12 - New Frontiers from Pathology to Genomics (ID 138)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:Prasad S Adusumilli, Francisco Perez Ochoa
- Coordinates: 9/09/2019, 14:00 - 15:30, Melbourne (1991)
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MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)
14:00 - 15:30 | Author(s): Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Background
Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.
Method
We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.
Result
A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.
Conclusion
In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.
1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work
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OA08 - Advanced Models and "Omics" for Therapeutic Development (ID 133)
- Event: WCLC 2019
- Type: Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Luis M Montuenga, Julie George
- Coordinates: 9/09/2019, 11:00 - 12:30, Interlaken (1988)
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OA08.02 - A Multidisciplinary Multi-Omics Study of Spatial and Temporal Tumor Evolution in Thoracic Cancers with Clinical Implications (Now Available) (ID 2365)
11:00 - 12:30 | Author(s): Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Background
In the context of the MESOMICS and lungNENomics projects1, we generated comprehensive molecular profiles of Malignant Pleural Mesothelioma (MPM)2 and pulmonary carcinoids (PCa)3. We showed that a continuous molecular model can better explain the prognosis of MPM than the three histologies, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples. We also identified a new entity of PCa (supra-carcinoids) with carcinoid-like morphology yet the molecular and clinical features of LCNEC, which challenges the general believe that PCa have no relationship or genetic, epidemiologic, and clinical traits in common with LCNEC and SCLC. These two studies suggest an important role of heterogeneity in the biology of these tumors.
Method
Much progress has been made in revealing the evolutionary history of individual cancers, in particular using multi-region sequencing. However, most studies focused on a single ‘omic technique, and lacked temporal samples. Here we present the results of an innovative approach to study spatial and temporal tumor evolution based on (i) integration of whole-genome and transcriptome sequencing and EPIC 850K methylation arrays on multiple regions from 12 MPM, and (ii) a novel tumor-derived organoid-based strategy for studying the evolution of PCa.
Figure 1. Multi-omic multi-regional profiling of a MPM patient. A) Somatic Copy Number Variants (CNV), somatic Structural Variants (SV), kernel density plots of (top) somatic single nucleotide variants (SNVs) allelic fractions, (middle) expression normalized read counts, and (bottom) methylation array M-values. B) Projection of the transcriptomic profile of two tumoral regions into the Principal Component Analysis (PCA) space computed from 284 malignant pleural mesotheliomas2C) Expression (z-score of normalized read counts) for two clinically relevant genes with substantial inter-regional differences.
Biorepositories: French MESOBANK; LungNEN Network
Result
In the data analyses of the 12 MPM we detected significant intra-tumor heterogeneity (ITH) in the expression of immune checkpoints and pro-angiogenic genes (see example in Fig. 1). This might explain the modest and variable response to treatment in clinical trials assessing immunotherapies and antiangiogenic drugs. In the case of PCa, we are currently analysing the organoids genomic data and we will present the preliminary data for the temporal evolution of these diseases.
Conclusion
We found that our approach can detect clinically and biologically meaningful ITH. All the computational methods we developed for these evolutionary studies are available to the scientific community4.
1RareCancersGenomics.com
2Alcala et al., under review in Cancer Res
3Alcala et al., under review in Nat Commun
4https://github.com/IARCbioinfoLFC and MF co-supervised this work
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WS02 - Mesothelioma Workshop (Ticketed Session) (ID 102)
- Event: WCLC 2019
- Type: Workshop
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/07/2019, 08:00 - 11:30, Interlaken (1988)
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WS02.04 - Molecular Section (Now Available) (ID 3833)
08:00 - 11:30 | Presenting Author(s): Lynnette Fernandez-Cuesta
- Abstract
- Presentation
Abstract
Molecular and immunologic breakthroughs are transforming the management of thoracic cancer, although advances have not been as marked for malignant pleural mesothelioma (MPM) where pathologic diagnosis has been essentially limited to three histologic subtypes. A multidisciplinary group (pathologists, molecular biologists, surgeons, radiologists and oncologists), sponsored by EURACAN/IASLC met in 2018, to critically review the current classification. Multidisciplinary recommendations for pathology classification and application were made, which will allow more informative pathologic reporting and potential risk stratification, to support clinical practice, research investigation and clinical trials. I will present the main points of the discussion around the use of molecular characteristics to inform and improve the current histopathological classification.
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