MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC)

被引:55
作者
Casadevall, David [1 ,6 ]
Gimeno, Javier [2 ]
Clave, Sergi [3 ,4 ]
Taus, Alvaro [1 ]
Pijuan, Lara [2 ]
Arumi, Miriam [1 ]
Lorenzo, Marta [4 ]
Menendez, Silvia [4 ]
Canadas, Israel [4 ]
Albanell, Joan [1 ,4 ,5 ]
Serrano, Sergio [2 ]
Espinet, Blanca [3 ,4 ]
Salido, Marta [3 ,4 ]
Arriola, Edurne [1 ,4 ,7 ]
机构
[1] Hosp del Mar, Serv Oncol Med, Barcelona, Spain
[2] Hosp del Mar, Serv Patol, Barcelona, Spain
[3] Hosp del Mar, Serv Patol, Lab Citogenet Mol, Barcelona, Spain
[4] IMIM Hosp del Mar Med Res Inst, Canc Res Program, Barcelona, Spain
[5] Univ Pompeu Fabra, Barcelona, Spain
[6] Univ Autonoma Barcelona, Bellaterra, Spain
[7] Univ Southampton, Canc Sci Unit, Southampton, Hants, England
关键词
c-MET; immunohistochemistry; fish; non-small-cell lung cancer; heterogeneity; GROWTH-FACTOR RECEPTOR; TO-MESENCHYMAL TRANSITION; IN-SITU HYBRIDIZATION; RANDOMIZED PHASE-II; C-MET; INTRATUMOR HETEROGENEITY; STANDARD CHEMOTHERAPY; PROTEIN EXPRESSION; ALK TRANSLOCATION; ERLOTINIB;
D O I
10.18632/oncotarget.3976
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Objective: We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. Methods: Our study included 120 patients with non-squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/ +3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio >= 2.0 and/or MET >= 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. Results: Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H-scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). Conclusions: MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation.
引用
收藏
页码:16215 / 16226
页数:12
相关论文
共 53 条
[1]  
[Anonymous], 2020, CA Cancer J Clin, DOI DOI 10.3322/CAAC.21590
[2]   MET phosphorylation predicts poor outcome in small cell lung carcinoma and its inhibition blocks HGF-induced effects in MET mutant cell lines [J].
Arriola, E. ;
Canadas, I. ;
Arumi-Uria, M. ;
Domine, M. ;
Lopez-Vilarino, J. A. ;
Arpi, O. ;
Salido, M. ;
Menendez, S. ;
Grande, E. ;
Hirsch, F. R. ;
Serrano, S. ;
Bellosillo, B. ;
Rojo, F. ;
Rovira, A. ;
Albanell, J. .
BRITISH JOURNAL OF CANCER, 2011, 105 (06) :814-823
[3]   Measuring the Role for Met Endosomal Signaling in Tumorigenesis [J].
Barrow, Rachel ;
Joffre, Carine ;
Menard, Ludovic ;
Kermorgant, Stephanie .
ENDOSOME SIGNALING, PT B, 2014, 535 :121-140
[4]   Met, metastasis, motility and more [J].
Birchmeier, C ;
Birchmeier, W ;
Gherardi, E ;
Vande Woude, GF .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (12) :915-925
[5]   Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non-small cell lung cancer (NSCLC) [J].
Camidge, D. Ross ;
Ou, Sai-Hong Ignatius ;
Shapiro, Geoffrey ;
Otterson, Gregory Alan ;
Villaruz, Liza Cosca ;
Villalona-Calero, Miguel Angel ;
Iafrate, A. John ;
Varella-Garcia, Marileila ;
Dacic, Sanja ;
Cardarella, Stephanie ;
Zhao, Weiqiang ;
Tye, Lesley ;
Stephenson, Patricia ;
Wilner, Keith D. ;
James, Leonard Philip ;
Socinski, Mark A. .
JOURNAL OF CLINICAL ONCOLOGY, 2014, 32 (15)
[6]   Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study [J].
Camidge, D. Ross ;
Bang, Yung-Jue ;
Kwak, Eunice L. ;
Iafrate, A. John ;
Varella-Garcia, Marileila ;
Fox, Stephen B. ;
Riely, Gregory J. ;
Solomon, Benjamin ;
Ou, Sai-Hong I. ;
Kim, Dong-Wan ;
Salgia, Ravi ;
Fidias, Panagiotis ;
Engelman, Jeffrey A. ;
Gandhi, Leena ;
Jaenne, Pasi A. ;
Costa, Daniel B. ;
Shapiro, Geoffrey I. ;
LoRusso, Patricia ;
Ruffner, Katherine ;
Stephenson, Patricia ;
Tang, Yiyun ;
Wilner, Keith ;
Clark, Jeffrey W. ;
Shaw, Alice T. .
LANCET ONCOLOGY, 2012, 13 (10) :1011-1019
[7]   Optimizing the Detection of Lung Cancer Patients Harboring Anaplastic Lymphoma Kinase (ALK) Gene Rearrangements Potentially Suitable for ALK Inhibitor Treatment [J].
Camidge, D. Ross ;
Kono, Scott A. ;
Flacco, Antonella ;
Tan, Aik-Choon ;
Doebele, Robert C. ;
Zhou, Qing ;
Crino, Lucio ;
Franklin, Wilbur A. ;
Varella-Garcia, Marileila .
CLINICAL CANCER RESEARCH, 2010, 16 (22) :5581-5590
[8]   Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer [J].
Canadas, Israel ;
Rojo, Federico ;
Taus, Alvaro ;
Arpi, Oriol ;
Arumi-Uria, Montserrat ;
Pijuan, Lara ;
Menendez, Silvia ;
Zazo, Sandra ;
Domine, Manuel ;
Salido, Marta ;
Mojal, Sergi ;
Garcia de Herreros, Antonio ;
Rovira, Ana ;
Albanell, Joan ;
Arriola, Edurne .
CLINICAL CANCER RESEARCH, 2014, 20 (04) :938-950
[9]   Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer [J].
Cappuzzo, F ;
Hirsch, FR ;
Rossi, E ;
Bartolini, S ;
Ceresoli, GL ;
Bemis, L ;
Haney, J ;
Witta, S ;
Danenberg, K ;
Domenichini, I ;
Ludovini, V ;
Magrini, E ;
Gregorc, V ;
Doglioni, C ;
Sidoni, A ;
Tonato, M ;
Franklin, WA ;
Crino, L ;
Bunn, PA ;
Varella-Garcia, M .
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2005, 97 (09) :643-655
[10]   Increased MET Gene Copy Number Negatively Affects Survival of Surgically Resected Non-Small-Cell Lung Cancer Patients [J].
Cappuzzo, Federico ;
Marchetti, Antonio ;
Skokan, Margaret ;
Rossi, Elisa ;
Gajapathy, Sujatha ;
Felicioni, Lara ;
del Grammastro, Maela ;
Sciarrotta, Maria Grazia ;
Buttitta, Fiamma ;
Incarbone, Matteo ;
Toschi, Luca ;
Finocchiaro, Giovanna ;
Destro, Annarita ;
Terracciano, Luigi ;
Roncalli, Massimo ;
Alloisio, Marco ;
Santoro, Armando ;
Varella-Garcia, Marileila .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (10) :1667-1674