Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

Magali Michaut; Suet-Feung Chin; Ian Majewski; Tesa M Severson; Tycho Bismeijer; Leanne de Koning; Justine K Peeters; Philip C Schouten; Oscar M Rueda; Astrid J Bosma; Finbarr Tarrant; Yue Fan; Beilei He; Zheng Xue; Lorenza Mittempergher; Roelof J C Kluin; Jeroen Heijmans; Mireille Snel; Bernard Pereira; Andreas Schlicker; Elena Provenzano; Hamid Raza Ali; Alexander Gaber; Gillian O'Hurley; Sophie Lehn; Jettie J F Muris; Jelle Wesseling; Elaine Kay; Stephen John Sammut; Helen A Bardwell; Aurélie S Barbet; Floriane Bard; Caroline Lecerf; Darran P O'Connor; Daniël J Vis; Cyril H Benes; Ultan McDermott; Mathew J Garnett; Iris M Simon; Karin Jirström; Thierry Dubois; Sabine C Linn; William M Gallagher; Lodewyk F A Wessels; Carlos Caldas; Rene Bernards

doi:10.1038/srep18517

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

Magali Michaut, Suet-Feung Chin, Ian Majewski, Tesa M Severson, Tycho Bismeijer, Leanne de Koning, Justine K Peeters, Philip C Schouten, Oscar M Rueda, Astrid J Bosma, Finbarr Tarrant, Yue Fan, Beilei He, Zheng Xue, Lorenza Mittempergher, Roelof J C Kluin, Jeroen Heijmans, Mireille Snel, Bernard Pereira, Andreas SchlickerElena Provenzano, Hamid Raza Ali, Alexander Gaber, Gillian O'Hurley, Sophie Lehn, Jettie J F Muris, Jelle Wesseling, Elaine Kay, Stephen John Sammut, Helen A Bardwell, Aurélie S Barbet, Floriane Bard, Caroline Lecerf, Darran P O'Connor, Daniël J Vis, Cyril H Benes, Ultan McDermott, Mathew J Garnett, Iris M Simon, Karin Jirström, Thierry Dubois, Sabine C Linn, William M Gallagher, Lodewyk F A Wessels, Carlos Caldas, Rene Bernards

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Abstract

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

Original language	English
Article number	18517
Journal	Scientific Reports
Volume	6
DOIs	https://doi.org/10.1038/srep18517
Publication status	Published - 5 Jan 2016

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Michaut, M., Chin, S.-F., Majewski, I., Severson, T. M., Bismeijer, T., de Koning, L., Peeters, J. K., Schouten, P. C., Rueda, O. M., Bosma, A. J., Tarrant, F., Fan, Y., He, B., Xue, Z., Mittempergher, L., Kluin, R. J. C., Heijmans, J., Snel, M., Pereira, B., ... Bernards, R. (2016). Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer. Scientific Reports, 6, Article 18517. https://doi.org/10.1038/srep18517

@article{a0e4b6e1e9ce46ba815ba7e4dcaf7868,

title = "Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer",

abstract = "Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.",

author = "Magali Michaut and Suet-Feung Chin and Ian Majewski and Severson, {Tesa M} and Tycho Bismeijer and {de Koning}, Leanne and Peeters, {Justine K} and Schouten, {Philip C} and Rueda, {Oscar M} and Bosma, {Astrid J} and Finbarr Tarrant and Yue Fan and Beilei He and Zheng Xue and Lorenza Mittempergher and Kluin, {Roelof J C} and Jeroen Heijmans and Mireille Snel and Bernard Pereira and Andreas Schlicker and Elena Provenzano and Ali, {Hamid Raza} and Alexander Gaber and Gillian O'Hurley and Sophie Lehn and Muris, {Jettie J F} and Jelle Wesseling and Elaine Kay and Sammut, {Stephen John} and Bardwell, {Helen A} and Barbet, {Aur{\'e}lie S} and Floriane Bard and Caroline Lecerf and O'Connor, {Darran P} and Vis, {Dani{\"e}l J} and Benes, {Cyril H} and Ultan McDermott and Garnett, {Mathew J} and Simon, {Iris M} and Karin Jirstr{\"o}m and Thierry Dubois and Linn, {Sabine C} and Gallagher, {William M} and Wessels, {Lodewyk F A} and Carlos Caldas and Rene Bernards",

year = "2016",

month = jan,

day = "5",

doi = "10.1038/srep18517",

language = "English",

volume = "6",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

}

Michaut, M, Chin, S-F, Majewski, I, Severson, TM, Bismeijer, T, de Koning, L, Peeters, JK, Schouten, PC, Rueda, OM, Bosma, AJ, Tarrant, F, Fan, Y, He, B, Xue, Z, Mittempergher, L, Kluin, RJC, Heijmans, J, Snel, M, Pereira, B, Schlicker, A, Provenzano, E, Ali, HR, Gaber, A, O'Hurley, G, Lehn, S, Muris, JJF, Wesseling, J, Kay, E, Sammut, SJ, Bardwell, HA, Barbet, AS, Bard, F, Lecerf, C, O'Connor, DP, Vis, DJ, Benes, CH, McDermott, U, Garnett, MJ, Simon, IM, Jirström, K, Dubois, T, Linn, SC, Gallagher, WM, Wessels, LFA, Caldas, C & Bernards, R 2016, 'Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer', Scientific Reports, vol. 6, 18517. https://doi.org/10.1038/srep18517

TY - JOUR

T1 - Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

AU - Michaut, Magali

AU - Chin, Suet-Feung

AU - Majewski, Ian

AU - Severson, Tesa M

AU - Bismeijer, Tycho

AU - de Koning, Leanne

AU - Peeters, Justine K

AU - Schouten, Philip C

AU - Rueda, Oscar M

AU - Bosma, Astrid J

AU - Tarrant, Finbarr

AU - Fan, Yue

AU - He, Beilei

AU - Xue, Zheng

AU - Mittempergher, Lorenza

AU - Kluin, Roelof J C

AU - Heijmans, Jeroen

AU - Snel, Mireille

AU - Pereira, Bernard

AU - Schlicker, Andreas

AU - Provenzano, Elena

AU - Ali, Hamid Raza

AU - Gaber, Alexander

AU - O'Hurley, Gillian

AU - Lehn, Sophie

AU - Muris, Jettie J F

AU - Wesseling, Jelle

AU - Kay, Elaine

AU - Sammut, Stephen John

AU - Bardwell, Helen A

AU - Barbet, Aurélie S

AU - Bard, Floriane

AU - Lecerf, Caroline

AU - O'Connor, Darran P

AU - Vis, Daniël J

AU - Benes, Cyril H

AU - McDermott, Ultan

AU - Garnett, Mathew J

AU - Simon, Iris M

AU - Jirström, Karin

AU - Dubois, Thierry

AU - Linn, Sabine C

AU - Gallagher, William M

AU - Wessels, Lodewyk F A

AU - Caldas, Carlos

AU - Bernards, Rene

PY - 2016/1/5

Y1 - 2016/1/5

N2 - Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

AB - Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

U2 - 10.1038/srep18517

DO - 10.1038/srep18517

M3 - Article

C2 - 26729235

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 18517

ER -

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer

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