Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium; Thanos P Mourikis; Lorena Benedetti; Elizabeth Foxall; Damjan Temelkovski; Joel Nulsen; Juliane Perner; Matteo Cereda; Jesper Lagergren; Michael Howell; Christopher Yau; Rebecca C Fitzgerald; Paola Scaffidi; Francesca D Ciccarelli

doi:10.1038/s41467-019-10898-3

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Thanos P Mourikis, Lorena Benedetti, Elizabeth Foxall, Damjan Temelkovski, Joel Nulsen, Juliane Perner, Matteo Cereda, Jesper Lagergren, Michael Howell, Christopher Yau, Rebecca C Fitzgerald, Paola Scaffidi, Francesca D Ciccarelli

Comprehensive Cancer Centre

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Abstract

The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.

Original language	English
Article number	3101
Number of pages	17
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	15 Jul 2019
DOIs	https://doi.org/10.1038/s41467-019-10898-3
Publication status	Published - 1 Dec 2019

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Patient-specific cancer genes_BENEDETTI_Accepted4May2019_GOLD AAMAccepted author manuscript, 418 KBLicence: CC BY
Patient-specific cancer genes contribute to recurrently perturbed pathways_CICCARELLI_Publishedonline15July2019_GOLD CORRECTED PROOF (CC BY)Proof, 4.16 MBLicence: CC BY
Patient-specific cancer genes_MOURIKIS_Accepted4June2019Publishedonline15July2019_GOLD VoR (CC BY)Final published version, 4.16 MBLicence: CC BY

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Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Mourikis, T. P., Benedetti, L., Foxall, E., Temelkovski, D., Nulsen, J., Perner, J., Cereda, M., Lagergren, J., Howell, M., Yau, C., Fitzgerald, R. C., Scaffidi, P., & Ciccarelli, F. D. (2019). Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma. Nature Communications, 10(1), Article 3101. https://doi.org/10.1038/s41467-019-10898-3

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title = "Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma",

abstract = "The identification of cancer-promoting genetic alterations is challenging particularly in highly unstable and heterogeneous cancers, such as esophageal adenocarcinoma (EAC). Here we describe a machine learning algorithm to identify cancer genes in individual patients considering all types of damaging alterations simultaneously. Analysing 261 EACs from the OCCAMS Consortium, we discover helper genes that, alongside well-known drivers, promote cancer. We confirm the robustness of our approach in 107 additional EACs. Unlike recurrent alterations of known drivers, these cancer helper genes are rare or patient-specific. However, they converge towards perturbations of well-known cancer processes. Recurrence of the same process perturbations, rather than individual genes, divides EACs into six clusters differing in their molecular and clinical features. Experimentally mimicking the alterations of predicted helper genes in cancer and pre-cancer cells validates their contribution to disease progression, while reverting their alterations reveals EAC acquired dependencies that can be exploited in therapy.",

author = "{Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium} and Mourikis, {Thanos P} and Lorena Benedetti and Elizabeth Foxall and Damjan Temelkovski and Joel Nulsen and Juliane Perner and Matteo Cereda and Jesper Lagergren and Michael Howell and Christopher Yau and Fitzgerald, {Rebecca C} and Paola Scaffidi and Ciccarelli, {Francesca D}",

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Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Mourikis, TP , Benedetti, L , Foxall, E , Temelkovski, D , Nulsen, J, Perner, J, Cereda, M, Lagergren, J, Howell, M, Yau, C, Fitzgerald, RC, Scaffidi, P & Ciccarelli, FD 2019, 'Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma', Nature Communications, vol. 10, no. 1, 3101. https://doi.org/10.1038/s41467-019-10898-3

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma. / Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium ; Mourikis, Thanos P ; Benedetti, Lorena et al.
In: Nature Communications, Vol. 10, No. 1, 3101, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

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AU - Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

AU - Mourikis, Thanos P

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AU - Foxall, Elizabeth

AU - Temelkovski, Damjan

AU - Nulsen, Joel

AU - Perner, Juliane

AU - Cereda, Matteo

AU - Lagergren, Jesper

AU - Howell, Michael

AU - Yau, Christopher

AU - Fitzgerald, Rebecca C

AU - Scaffidi, Paola

AU - Ciccarelli, Francesca D

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Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Mourikis TP , Benedetti L , Foxall E , Temelkovski D , Nulsen J et al. Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma. Nature Communications. 2019 Dec 1;10(1):3101. Epub 2019 Jul 15. doi: 10.1038/s41467-019-10898-3

Patient-specific cancer genes contribute to recurrently perturbed pathways and establish therapeutic vulnerabilities in esophageal adenocarcinoma

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