MET Testing

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

MET aberrations and their corresponding potential testing methods
c-Met Protein Overexpression1–3
MET Gene Amplification4–7
METex14 Skipping Mutations4,8,9
PROTEIN
OVEREXPRESSION
c-Met overexpression icon
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
MET Gene Amplification icon
FISH
FISH10
Utilizes fluorescent probes that bind to specific DNA sequences to identify chromosomal abnormalities
FISH10

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

VARIANT
DETECTION
METex14 and MET Gene icon
NGS
NGS11
High-throughput method used to determine the nucleotide sequence of entire genomes or a broad panel of target genes
METex14 and MET Gene icon
NGS11

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

VARIANT
DETECTION
METex14 and MET Gene icon
RT-PCR
RT-PCR12
Used to amplify specific targets and detect alternative variants that lead to exon skipping
METex14 and MET Gene icon
RT-PCR12

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

VARIANT
DETECTION
METex14 icon
Sanger Sequencing
Sanger Sequencing11
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 Sequencing11

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; FDA=Food and Drug Administration; 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
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IHC
c-Met Protein Overexpression
FISH
MET Gene Amplification
NGS
METex14 Skipping Mutations
NGS
MET Gene Amplification
Tissue Requirements14,15
FFPE tissue and cell blocks
4 μm section
Turnaround Time14,15
1- to 2-day turnaround*
Testing16–21
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

*Turnaround times are approximate and may vary for individual tests/assays.

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

View c-Met IHC staining intensity22

Scoring/Interpretation16†
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 representative and for illustrative purposes only and not intended for clinical use.22

FDA=Food and Drug Administration; IHC=immunohistochemistry; MET=mesenchymal-epithelial transition.

Tissue Requirements14,15,23
FFPE tissue and cell blocks
4 μm section
Turnaround Time14,15
3- to 7-day turnaround*
Testing24,25
FISH signal counts can be determined in targeted tumor areas using MET and CEP7 DNA probes

*Turnaround times are approximate and may vary for individual tests/assays. 

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

View representative cells with MET/CEP7 probes

Scoring/Interpretation25†
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; Chr=chromosome; FDA=Food and Drug Administration; FISH=fluorescence in situ hybridization; MET=mesenchymal-epithelial transition; WT=wildtype.

Tissue Requirements14,15
FFPE tissue blocks or slides
6–8 slides of 7–10 μm sections
Turnaround Time14,15
10- to 21-day turnaround*
Testing4,27
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 alternations that can lead to METex14 skipping, hybrid capture can be a preferred library preparation approach compared to amplicon-based methods

*Turnaround times are approximate and may vary for individual tests/assays. 

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

View METex14 skipping sites and their prevalence

Scoring/Interpretation5,27†
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 NSCLC27‡

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 Requirements14,15
FFPE tissue blocks or slides
6–8 slides of 7–10 μm sections
Turnaround Time14,15
10- to 21-day turnaround*
Testing24,25
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

*Turnaround times are approximate and may vary for individual tests/assays. 

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

View sample MET amplification results

Scoring/Interpretation5,27,28†
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.7.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed June 26, 2024. 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; FDA=Food and Drug Administration; MET=mesenchymal-epithelial transition; NGS=next-generation sequencing.

Learn more about the testing
journey and its challenges
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References
  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
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  9. 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
  10. NGS vs. Sanger Sequencing. Illumina. Accessed August 10, 2023. https://www.illumina.com/science/technology/next-generation-sequencing/ngs-vs-sanger-sequencing.html
  11. 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
  12. 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
  13. List of cleared or approved companion diagnostic devices. US Food and Drug Administration. Updated May 1, 2024. Accessed June 4, 2024. https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools
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  15. 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
  16. 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
  17. 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
  18. 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
  19. 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
  20. 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
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  22. Images are provided on behalf of Roche Diagnostics
  23. c-Met Oncology Fish. Labcorp. Accessed February 27, 2024. https://www.labcorp.com/tests/510890/c-met-oncology-fish
  24. 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
  25. 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
  26. 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
  27. 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
  28. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell lung Cancer V.7.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed June 26, 2024. 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.
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c-Met protein overexpression and MET amplification are emerging biomarkers and in clinical research as potential therapeutic targets. There are no FDA-approved tests for c-Met protein overexpression or MET amplification. The shown images are for illustrative purposes only. †Method results should be interpreted by a qualified pathologist in conjunction with histologic examination, relevant clinical information, and proper controls.