Discover MET in NSCLC

MET aberrations and their corresponding potential testing methods

c-Met Protein Expression^1-3

MET Gene Amplification^4-7

METex14 Skipping Mutations^4,8,9

PROTEIN
EXPRESSION

IHC

IHC¹

Uses antibodies against tumor antigens to measure levels of protein

IHC¹

Uses antibodies against tumor antigens to measure levels of protein

CHROMOSOMAL
ABNORMALITIES

FISH

FISH¹²

Utilizes fluorescent probes that bind to specific DNA sequences to identify chromosomal abnormalities

FISH¹²

Utilizes fluorescent probes that bind to specific DNA sequences to identify chromosomal abnormalities

VARIANT
DETECTION

NGS

NGS^9,10

High-throughput method used to determine the nucleotide sequence of entire genomes or a broad panel of target genes

NGS^9,10

High-throughput method used to determine the nucleotide sequence of entire genomes or a broad panel of target genes

VARIANT
DETECTION

RT-PCR

RT-PCR¹¹

Used to amplify specific targets and detect alternative variants that lead to exon skipping

RT-PCR¹¹

Used to amplify specific targets and detect alternative variants that lead to exon skipping

VARIANT
DETECTION

Sanger Sequencing

Sanger Sequencing¹⁰

Determines the nucleotide sequence of DNA and is used when analyzing small regions of the DNA on a limited number of samples or genomic targets

Sanger Sequencing¹⁰

Determines the nucleotide sequence of DNA and is used when analyzing small regions of the DNA on a limited number of samples or genomic targets

ex14=exon 14; FISH=fluorescence in situ hybridization; IHC=immunohistochemistry; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer; RT-PCR=reverse transcription polymerase chain reaction.

Explore IHC, FISH, and NGS detection methods
and view image galleries for each testing method

Scroll down to learn more

MET Image Gallery

Tissue Requirements^14,15

FFPE tissue and cell blocks
4–5 μm section

Testing^16-21

3 serial tissue sections are used per sample:

H&E: to visualize morphology
Negative control: to determine levels of non‑specific background staining
Anti–c-Met antibody: binds to c-Met receptor with high specificity

A tissue sample with known c-Met protein expression can be used as a positive control for staining

FFPE=formalin-fixed paraffin-embedded; H&E=hematoxylin and eosin; MET=mesenchymal-epithelial transition.

View c-Met IHC staining intensity²²

Assessment¹⁶*
c-Met protein expression can be defined as the percentage of tumor cells with no (0), weak (1+), moderate (2+), or strong (3+) staining intensity

TAP TO VIEW WHOLE-SLIDE IMAGES

c-Met 0

No staining¹⁶

c-Met 1+

Weak c-Met protein staining intensity¹⁶

c-Met 2+

Moderate c-Met protein staining intensity¹⁶

c-Met 3+

Strong c-Met protein staining intensity¹⁶

*Images are for illustrative purposes only and are not intended for diagnostic purposes.²²

Stain images are provided by Roche Diagnostics.

IHC=immunohistochemistry; MET=mesenchymal-epithelial transition.

Tissue Requirements^14,15,23

FFPE tissue and cell blocks
4 μm section

Testing^24,25

FISH signal counts can be determined in targeted tumor areas using MET and CEP7 DNA probes

CEP7=centromere 7; FFPE=formalin-fixed paraffin-embedded; FISH=fluorescence in situ hybridization; MET=mesenchymal-epithelial transition.

View representative cells with MET/CEP7 probes

Assessment²⁵*
The MET/CEP7 ratio can distinguish between true focal amplification versus polysomy of chromosome 7, which is less likely to result in oncogenicity. MET gene amplification can be defined as a ratio of ≥2.0

Control

MET negative²⁶

MET Amplification

Copy number gain in MET, not in CEP7. Ratio ≥2.0²⁶

Polysomy 7

Copy number gain detected in both MET and CEP7. Ratio <2.0²⁶

*Images are representative and for illustrative purposes only and not intended for clinical use.

CEP7=centromere 7; FISH=fluorescence in situ hybridization; MET=mesenchymal-epithelial transition; WT=wild type.

Tissue Requirements^14,15

FFPE tissue blocks or slides
6–8 slides of 7–10 μm sections

Testing^4,27

Mutations can be detected using DNA- and/or RNA-based NGS:

To ensure detection of low allele frequency variants, most NGS assays employ a form of target enrichment
Given the diversity of alterations that can lead to METex14 skipping, hybrid capture can be a preferred library preparation approach compared to amplicon-based methods

ex14=exon 14; FFPE=formalin-fixed paraffin-embedded; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing.

View METex14 skipping sites and their prevalence

Assessment^5,27*
Alterations can be within exon 14, in the intronic region surrounding exon 14,
or the total deletion of exon 14

METex14 skipping mutation sites in NSCLC^27†

*Images are for illustrative purposes only. ^†Figure adapted from Socinski MA, et al. JCO Precis Oncol. 2021;5:PO.20.00516.

METex14 skipping mutation site prevalence data can vary among studies and data sets because of detection methodology used, patient sample sizes and/or demographics/characteristics.

ex14=exon 14; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing; NSCLC=non-small cell lung cancer.

Tissue Requirements^14,15

FFPE tissue blocks or slides
6–8 slides of 7–10 μm sections

Testing^24,25

Gene copy number (GCN) can be assessed using DNA-based NGS:

The definition of MET amplification varies by NGS platform
GCN cutoff values can range from 2.3–10
Focal MET amplifications can be distinguished from broad chromosomal gains that include MET using NGS
Focal MET amplifications are associated with a greater likelihood of dependence on MET

FFPE=formalin-fixed paraffin-embedded; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing.

View sample MET amplification results

Assessment^5,27,28*
For NGS based results, a copy number ≥10 can be consistent with high-level MET amplification^†

*Images are for illustrative purposes only. ^‡Figure adapted from Guo R, et al. Nat Rev Clin Oncol. 2020;17(9):569-587.

^†The definition of high-level MET amplification is evolving and may differ according to the assay used for testing. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V.3.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed March 31, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

CAPZA2=capping actin protein of muscle z-line subunit alpha 2; Chr=chromosome; LINC01510=long intergenic non-protein coding RNA 1510; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing.

Learn more about the testing
journey and its challenges

References

Magaki S, Hojat SA, Wei B, So A, Yong WH. An introduction to the performance of immunohistochemistry. Methods Mol Biol. 2019;1897:289-298. doi:10.1007/978-1-4939-8935-5_25.
Park S, Choi YL, Sung CO, et al. High MET copy number and MET overexpression: poor outcome in non-small cell lung cancer patients. Histol Histopathol. 2012;27(2):197-207. doi:10.14670/HH-27.197.
Sun W, Song L, Ai T, et al. Prognostic value of MET, cyclin D1 and MET gene copy number in non-small cell lung cancer. J Biomed Res. 2013;27(3):220-230. doi:10.7555/JBR.27.20130004.
Michaels E, Bestvina CM. Meeting an un-MET need: targeting MET in non-small cell lung cancer. Front Oncol. 2022;12:1004198. doi:10.3389/fonc.2022.1004198.
Das R, Jakubowski MA, Spildener J, Cheng YW. Identification of novel MET exon 14 skipping variants in non-small cell lung cancer patients: a prototype workflow involving in silico prediction and RT-PCR. Cancers (Basel). 2022;14(19):4814. doi:10.3390/cancers14194814.
Kim EK, Kim KA, Lee CY, et al. Molecular diagnostic assays and clinicopathologic implications of MET exon 14 skipping mutation in non-small-cell lung cancer. Clin Lung Cancer. 2019;20(1):e123-e132. doi:10.1016/j.cllc.2018.10.004.
Cai YR, Zhang HQ, Zhang ZD, Mu J, Li ZH. Detection of MET and SOX2 amplification by quantitative real-time PCR in non-small cell lung carcinoma. Oncol Lett. 2011;2(2):257-264. doi:10.3892/ol.2010.229.
Fang L, Chen H, Tang Z, et al. MET amplification assessed using optimized FISH reporting criteria predicts early distant metastasis in patients with non-small cell lung cancer. Oncotarget. 2018;9(16):12959-12970. doi:10.18632/oncotarget.24430.
Peng LX, Jie GL, Li AN, et al. MET amplification identified by next-generation sequencing and its clinical relevance for MET inhibitors. Exp Hematol Oncol. 2021;10(1):52. doi:10.1186/s40164-021-00245-y.
NGS vs. Sanger Sequencing. Illumina. Accessed August 10, 2023. https://www.illumina.com/science/technology/next-generation-sequencing/ngs-vs-sanger-sequencing.html.
The basics: RT-PCR. Thermo Fisher Scientific. Accessed August 10, 2023. https://www.thermofisher.com/us/en/home/references/ambion-tech-support/rtpcr-analysis/general-articles/rt--pcr-the-basics.html.
Fluorescence in situ hybridization (FISH). Genome.gov. Updated August 21, 2023. Accessed August 22, 2023. https://www.genome.gov/genetics-glossary/Fluorescence-In-Situ-Hybridization.
List of cleared or approved companion diagnostic devices. US Food and Drug Administration. Updated March 5, 2025. Accessed March 31, 2025. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools.
Mino-Kenudson M. Immunohistochemistry for predictive biomarkers in non-small cell lung cancer. Transl Lung Cancer Res. 2017;6(5):570-587. doi:10.21037/tlcr.2017.07.06.
Tsao MS, Yatabe Y. Old soldiers never die: is there still a role for immunohistochemistry in the era of next-generation sequencing panel testing? J Thorac Oncol. 2019;14(12):2035-2038. doi:10.1016/j.jtho.2019.09.007.
Ding C, Qiu Y, Zhang J, et al. Clinicopathological characteristics of Non-Small Cell Lung Cancer (NSCLC) patients with c-MET exon 14 skipping mutation, MET overexpression and amplification. BMC Pulm Med. 2023;23(1):240. doi:10.1186/s12890-023-02482-9.
Prat M, Narsimhan RP, Crepaldi T, Nicotra MR, Natali PG, Comoglio PM. The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer. 1991;49(3):323-328. doi:10.1002/ijc.2910490302.
Hewitt SM, Baskin DG, Frevert CW, Stahl WL, Rosa-Molinar E. Controls for immunohistochemistry: the Histochemical Society’s standards of practice for validation of immunohistochemical assays. J Histochem Cytochem. 2014;62(10):693-697. doi:10.1369/0022155414545224.
Casadevall D, Gimeno J, Clavé S, et al. MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC). Oncotarget. 2015;6(18):16215-16226. doi:10.18632/oncotarget.3976.
H and E staining. NCI Dictionary of Cancer Terms. Accessed April 18, 2024. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/h-and-e-staining.
Watermann I, Schmitt B, Stellmacher F, et al. Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation?. Diagn Pathol. 2015;10:130. doi:10.1186/s13000-015-0362-5.
Images are provided on behalf of Roche Diagnostics.
c-Met Oncology Fish. Labcorp. Accessed February 27, 2024. https://www.labcorp.com/tests/510890/c-met-oncology-fish.
Qin K, Hong L, Zhang J, Le X. MET amplification as a resistance driver to TKI therapies in lung cancer: Clinical challenges and opportunities. Cancers (Basel). 2023;15(3):612. doi:10.3390/cancers15030612.
Guo R, Luo J, Chang J, et al. MET-dependent solid tumours - molecular diagnosis and targeted therapy. Nat Rev Clin Oncol. 2020;17(9):569-587. doi:10.1038/s41571-020-0377‑z.
Yin W, Guo M, Tang Z, et al. MET expression level in lung adenocarcinoma loosely correlates with MET copy number gain/amplification and is a poor predictor of patient outcome. Cancers (Basel). 2022;14(10):2433. doi:10.3390/cancers14102433.
Socinski MA, Pennell NA, Davies KD. MET exon 14 skipping mutations in non-small-cell lung cancer: An overview of biology, clinical outcomes, and testing considerations. JCO Precis Oncol. 2021;5:PO.20.00516. doi:10.1200/PO.20.00516.
Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer V.3.2025. © National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed March 31, 2025. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

MET Testing

The method used for detecting MET aberrations in NSCLC depends on the type of aberration present