Comprehensive Genomic Profiling of Circulating Cell-Free DNA Distinguishes Focal MET Amplification from Aneuploidy in Diverse Advanced Cancers

Amplification (amp) of MET can be observed in cases of focal gene copy number gain, such as MET-driven amp, or with a gain of chromosome 7, such as aneuploidy. Several studies have shown that only high-level focal MET amp (MET/CEP7 ratio ≥5) is oncogenic, with such tumors responding to targeted therapy. However, there are few reports on how to distinguish between focal amplification and aneuploidy using next-generation sequencing (NGS). A total of 1025 patients with advanced solid tumors (typically pre-treated) were tested with a non-invasive comprehensive cfDNA NGS panel (Guardant360) from July 2014 to June 2019. Since bioinformatics upgrades of Guardant360 were undergoing in September 2018, focal MET amp was determined by our independent algorithm using the cohorts tested before September 2018 (291 patients), and validation was performed in the remaining cohort (734 patients). MET alterations (alts) associated with aberrant signaling were found in 110 patients (10.7%) among nine different cancer types, most commonly in non-small cell (12.2%, 62/510) and small cell (33.3%, 3/9) lung cancers, gastroesophageal cancer (19.4%, 7/36), and prostate adenocarcinoma (15.6%; 5/32). Among 291 patients tested before September 2018, 37 (12.7%) had MET alts. Among these, 24 (64.9%) had amps, 5 (13.5%) had exon 14 skipping, and 13 (35.1%) had single nucleotide variants (SNVs). Co-alterations, such as amp + SNVs, were found in four samples (10.8%). Among 24 MET amps, 29.2% (7/24) were focal according to our algorithm. MET copy number was significantly higher with focal amp compared to non-focal amp (mean copy number 3.26 vs. 2.44, respectively, p = 0.00304). In 734 patients tested after September 2018, our definition of focal MET amp was detected in 4.2% (31/734). Overall, focal amplification based on our algorithm was 3.7% (=38/1025). This study describes an approach to distinguish focal and non-focal MET amplification using comprehensive genomic profiling of cfDNA in advanced cancer patients. Focal MET amp accounted for ~30% of all MET amp, which was found in 3.7% of patients with diverse cancers and was associated with a higher plasma copy number. Clinical studies are warranted to assess the clinical utility of targeted therapies for tumors with focal MET amplification detected by NGS of cfDNA.

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Clinicopathologic Implications of ALK Gene Copy Number Gain in Non-small Cell Lung Cancer

Journal of Lung Cancer ◽

10.6058/jlc.2011.10.2.87 ◽

2011 ◽

Vol 10 (2) ◽

pp. 87 ◽

Cited By ~ 1

Author(s):

Seol-Bong Yoo ◽

Hyojin Kim ◽

Xianhua Xu ◽

Ping-Li Sun ◽

Yan Jin ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Copy Number Gain ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Gene Copy Number Gain

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MYC and human telomerase gene (TERC) gene copy number gain in resected in non-small cell lung cancer (NSCLC).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.10580 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 10580-10580 ◽

Cited By ~ 1

Author(s):

A. Flacco ◽

V. Ludovini ◽

F. R. Tofanetti ◽

F. Bianconi ◽

G. Bellezza ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Copy Number ◽

Gene Copy Number ◽

Copy Number Gain ◽

Small Cell ◽

Gene Copy ◽

Small Cell Lung ◽

Human Telomerase ◽

Gene Copy Number Gain

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Immunohistochemical Overexpression of Platelet-Derived Growth Factor Receptor–Beta (PDGFR-β) is Associated With PDGFRB Gene Copy Number Gain in Sarcomatoid Non–Small-Cell Lung Cancer

Clinical Lung Cancer ◽

10.1016/j.cllc.2011.02.002 ◽

2011 ◽

Vol 12 (6) ◽

pp. 369-374 ◽

Cited By ~ 22

Author(s):

Anne S. Tsao ◽

Wei Wei ◽

Elisabetta Kuhn ◽

Loreto Spencer ◽

Luisa M. Solis ◽

...

Keyword(s):

Copy Number ◽

Gene Copy Number ◽

Growth Factor Receptor ◽

Copy Number Gain ◽

Small Cell ◽

Platelet Derived Growth Factor ◽

Gene Copy ◽

Small Cell Lung ◽

Gene Copy Number Gain ◽

Receptor Beta

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Comprehensive genomic profiling of circulating cell-free DNA (cfDNA) distinguishes focal amplification (amp) from aneuploidy among MET amps in diverse advanced cancer types.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3046 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3046-3046

Author(s):

Yuichi Kumaki ◽

Sadakatsu Ikeda ◽

Thereasa A. Rich ◽

Jing Zhao ◽

Takayuki Yoshino ◽

...

Keyword(s):

Copy Number ◽

Gene Copy Number ◽

Copy Number Gain ◽

Chromosome 7 ◽

Gene Copy ◽

Cancer Type ◽

Single Nucleotide Variants ◽

Gene Assay ◽

Cancer Types ◽

Egfr Mutated

3046 Background: MET amps can occur from focal gene copy number gain (e.g. MET-driven) or gain of chromosome 7 (e.g. aneuploidy); however, the contribution of each to MET amp is not well established. MET inhibitor-sensitive lung cancers harboring high-level MET amp have been reported in the absence of other sensitizing MET alterations (alts), e.g. exon 14 skipping, particularly among those with higher MET to chromosome 7 ratios. Methods: 3,114 samples from 2,902 Asian patients with advanced solid tumors were tested with a comprehensive cfDNA NGS panel (Guardant360) between Oct 2015-Dec 2018. This 70-73 gene assay evaluates single nucleotide variants (SNV), selected insertion-deletions (indels), fusions, and copy number gains. Focal amp was determined bioinformatically as having statistically higher copy number relative to other genes, such as BRAF, or CDK6, in the same chromosome arm. Results: MET alts associated with aberrant signaling were found in 223 pts (7.7%) with 18 different cancer types, most commonly lung (128/1,678), colorectal (36/349), and prostate (11/48). Among 223 pts, 189 pts (84.8%) had amps, 38(17.0%) had exon 14 skipping, and 8 (3.6%) had activating SNVs. 39.7% of MET amp was focal but differed by cancer type; highest prevalence was in gastroesophageal (80%) and lowest in prostate cancers (9%). Samples with focal MET amp had higher plasma copy number compared to those with non-focal MET amp (mean 5.8 vs. 2.5; p < 0.0001) and lower total number of alts per sample (8.8 vs. 11; p = 0.0122). Focal MET amp was more common than non-focal MET amp among 419 EGFR mutated samples (6.9% vs. 3.8%, p = 0.05) suggesting focal MET amp may be biologically more relevant as a mechanism of EGFR TKI resistance. Conclusions: This is the first study to use cfDNA to examine focal vs. non-focal MET amp. Focal MET amp accounted for ~40% of all MET amps, was found in 2.6% of pts with diverse cancers, was associated with higher plasma copy number, and found in a higher proportion of EGFR mutated lung cancer samples. The ability to differentiate may be clinically relevant given higher MET to chromosome 7 ratios have been associated with improved therapeutic response.

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