Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project

Lukas Bubendorf; Urania Dafni; Martin Schobel; Stephen P. Finn; Verena Tischler; Aleksandra Sejda; Antonio Marchetti; Erik Thunnissen; Eric K. Verbeken; Arne Warth; Irene Sansano; Richard Cheney; Ernst Jan M. Speel; Daisuke Nonaka; Kim Monkhorst; Henrik Hager; Miguel Martorell; Spasenija Savic; Keith M. Kerr; Qiang Tan; Zoi Tsourti; Thomas R. Geiger; Roswitha Kammler; Katja Schulze; Ashis Das-Gupta; David Shames; Solange Peters; Rolf A. Stahel; Lungscape Consortium

doi:10.1016/j.lungcan.2017.07.021

Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project

Lukas Bubendorf^*, Urania Dafni, Martin Schobel, Stephen P. Finn, Verena Tischler, Aleksandra Sejda, Antonio Marchetti, Erik Thunnissen, Eric K. Verbeken, Arne Warth, Irene Sansano, Richard Cheney, Ernst Jan M. Speel, Daisuke Nonaka, Kim Monkhorst, Henrik Hager, Miguel Martorell, Spasenija Savic, Keith M. Kerr, Qiang TanZoi Tsourti, Thomas R. Geiger, Roswitha Kammler, Katja Schulze, Ashis Das-Gupta, David Shames, Solange Peters, Rolf A. Stahel, Lungscape Consortium

^*Corresponding author for this work

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

Abstract

Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.

Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio >= 2 (with average MET GCN >= 4), high MET GCN as CGN >= 5 and MET IHC + as >= 2 + intensity in >= 50% of tumor cells. A total of 182 MET IHC + and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.

Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN >= 5 in 4.1% of 1572 patients. MET amplification and MET GCN >= 5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p <0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC + WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR.

Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.

Original language	English
Pages (from-to)	143-149
Number of pages	7
Journal	Lung Cancer
Volume	111
DOIs	https://doi.org/10.1016/j.lungcan.2017.07.021
Publication status	Published - Sept 2017

Keywords

Non-small cell lung carcinoma
IHC MET overexpression
SISH MET amplification
MET exon14 mutation
CELL LUNG-CANCER
COPY NUMBER
PROTEIN EXPRESSION
TARGETING MET
IMMUNOHISTOCHEMISTRY
MUTATIONS
ADENOCARCINOMAS
CARCINOMAS
INHIBITORS
SURVIVAL

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10.1016/j.lungcan.2017.07.021

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Bubendorf, L., Dafni, U., Schobel, M., Finn, S. P., Tischler, V., Sejda, A., Marchetti, A., Thunnissen, E., Verbeken, E. K., Warth, A., Sansano, I., Cheney, R., Speel, E. J. M., Nonaka, D., Monkhorst, K., Hager, H., Martorell, M., Savic, S., Kerr, K. M., ... Lungscape Consortium (2017). Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project. Lung Cancer, 111, 143-149. https://doi.org/10.1016/j.lungcan.2017.07.021

@article{2f836bef8ba04b6a9813d88bf5c2f631,

title = "Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project",

abstract = "Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio >= 2 (with average MET GCN >= 4), high MET GCN as CGN >= 5 and MET IHC + as >= 2 + intensity in >= 50% of tumor cells. A total of 182 MET IHC + and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN >= 5 in 4.1% of 1572 patients. MET amplification and MET GCN >= 5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p <0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC + WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR.Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.",

keywords = "Non-small cell lung carcinoma, IHC MET overexpression, SISH MET amplification, MET exon14 mutation, CELL LUNG-CANCER, COPY NUMBER, PROTEIN EXPRESSION, TARGETING MET, IMMUNOHISTOCHEMISTRY, MUTATIONS, ADENOCARCINOMAS, CARCINOMAS, INHIBITORS, SURVIVAL",

author = "Lukas Bubendorf and Urania Dafni and Martin Schobel and Finn, {Stephen P.} and Verena Tischler and Aleksandra Sejda and Antonio Marchetti and Erik Thunnissen and Verbeken, {Eric K.} and Arne Warth and Irene Sansano and Richard Cheney and Speel, {Ernst Jan M.} and Daisuke Nonaka and Kim Monkhorst and Henrik Hager and Miguel Martorell and Spasenija Savic and Kerr, {Keith M.} and Qiang Tan and Zoi Tsourti and Geiger, {Thomas R.} and Roswitha Kammler and Katja Schulze and Ashis Das-Gupta and David Shames and Solange Peters and Stahel, {Rolf A.} and {Lungscape Consortium}",

year = "2017",

month = sep,

doi = "10.1016/j.lungcan.2017.07.021",

language = "English",

volume = "111",

pages = "143--149",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

Bubendorf, L, Dafni, U, Schobel, M, Finn, SP, Tischler, V, Sejda, A, Marchetti, A, Thunnissen, E, Verbeken, EK, Warth, A, Sansano, I, Cheney, R, Speel, EJM, Nonaka, D, Monkhorst, K, Hager, H, Martorell, M, Savic, S, Kerr, KM, Tan, Q, Tsourti, Z, Geiger, TR, Kammler, R, Schulze, K, Das-Gupta, A, Shames, D, Peters, S, Stahel, RA & Lungscape Consortium 2017, 'Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project', Lung Cancer, vol. 111, pp. 143-149. https://doi.org/10.1016/j.lungcan.2017.07.021

Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project. / Bubendorf, Lukas; Dafni, Urania; Schobel, Martin et al.
In: Lung Cancer, Vol. 111, 09.2017, p. 143-149.

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

TY - JOUR

T1 - Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC

T2 - Results from the European Thoracic Oncology Platform (ETOP) Lungscape project

AU - Bubendorf, Lukas

AU - Dafni, Urania

AU - Schobel, Martin

AU - Finn, Stephen P.

AU - Tischler, Verena

AU - Sejda, Aleksandra

AU - Marchetti, Antonio

AU - Thunnissen, Erik

AU - Verbeken, Eric K.

AU - Warth, Arne

AU - Sansano, Irene

AU - Cheney, Richard

AU - Speel, Ernst Jan M.

AU - Nonaka, Daisuke

AU - Monkhorst, Kim

AU - Hager, Henrik

AU - Martorell, Miguel

AU - Savic, Spasenija

AU - Kerr, Keith M.

AU - Tan, Qiang

AU - Tsourti, Zoi

AU - Geiger, Thomas R.

AU - Kammler, Roswitha

AU - Schulze, Katja

AU - Das-Gupta, Ashis

AU - Shames, David

AU - Peters, Solange

AU - Stahel, Rolf A.

AU - Lungscape Consortium

PY - 2017/9

Y1 - 2017/9

N2 - Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio >= 2 (with average MET GCN >= 4), high MET GCN as CGN >= 5 and MET IHC + as >= 2 + intensity in >= 50% of tumor cells. A total of 182 MET IHC + and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN >= 5 in 4.1% of 1572 patients. MET amplification and MET GCN >= 5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p <0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC + WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR.Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.

AB - Introduction: In a well-defined NSCLC cohort of the ETOP Lungscape program, we explored the epidemiology of IHC MET overexpression and amplification, their inter-correlation, and their association to outcome.Methods: Resected NSCLC were assessed for MET gene copy number (GCN) and expression using silver in-situ hybridization (SISH) and immunohistochemistry (IHC) on TMAs in a multicenter setting. MET amplification was defined as MET/centromere ratio >= 2 (with average MET GCN >= 4), high MET GCN as CGN >= 5 and MET IHC + as >= 2 + intensity in >= 50% of tumor cells. A total of 182 MET IHC + and EGFR/KRAS WT tumors were analyzed for METex14 skipping mutation.Results: MET IHC+ was found in 23.8% of 2432 patients, significantly associated with female gender, small tumor size, and adenocarcinoma histology. We observed a high inter-laboratory variability in IHC and SISH analysis. MET amplification prevailed in 4.6% and MET GCN >= 5 in 4.1% of 1572 patients. MET amplification and MET GCN >= 5 were not significantly associated with any tumor characteristics or stage. Both were significantly associated with IHC MET positivity (p <0.001). METex14 skipping mutation prevailed in 5 of 182 (2.7%) MET IHC + WT EGFR/KRAS NSCLC, 4 of which within the 88 adenocarcinomas (4.5%). No association of IHC MET overexpression, SISH MET amplification or high MET GCN was found with OS, RFS or TTR.Conclusion: MET overexpression is found in 23.8% of surgically resected NSCLC. MET amplification prevails in 4.6% and is associated with MET overexpression. Both have no influence on prognosis. The large inter-laboratory variability in IHC highlights the challenge of MET IHC analysis in routine practice.

KW - Non-small cell lung carcinoma

KW - IHC MET overexpression

KW - SISH MET amplification

KW - MET exon14 mutation

KW - CELL LUNG-CANCER

KW - COPY NUMBER

KW - PROTEIN EXPRESSION

KW - TARGETING MET

KW - IMMUNOHISTOCHEMISTRY

KW - MUTATIONS

KW - ADENOCARCINOMAS

KW - CARCINOMAS

KW - INHIBITORS

KW - SURVIVAL

U2 - 10.1016/j.lungcan.2017.07.021

DO - 10.1016/j.lungcan.2017.07.021

M3 - Article

C2 - 28838386

SN - 0169-5002

VL - 111

SP - 143

EP - 149

JO - Lung Cancer

JF - Lung Cancer

ER -

Prevalence and clinical association of MET gene overexpression and amplification in patients with NSCLC: Results from the European Thoracic Oncology Platform (ETOP) Lungscape project

Abstract

Keywords

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