Genomic and clinical characteristics of <i>MET</i> exon14 alterations in a large cohort of Chinese cancer patients revealed distinct features and a novel resistance mechanism for crizotinib
Bibliographic record
Abstract
Background: Alterations in MET exon 14 (METex14) and its flanking intronic regions have been identified in a variety of cancers.Patients with METex14 alterations often benefit from MET inhibitors such as crizotinib.Given the unique mutation profiles of Chinese lung cancer patients, it is necessary to investigate the prevalence of METex14 alterations in a large cohort of cancer patients.Patients and methods: Cases carrying METex14 alterations were screened from 26,391 Chinese cancer patients by next-generation sequencing (NGS), and the clinicopathologic and molecular characteristics were reviewed.Results: Compared to Western population (~3%), the frequency of METex14 alterations is much lower in Chinese cancer patients (0.7%, n=184) and lung cancer patients (1.1%, n=175).Seventy-eight distinct METex14 alterations, including several novel alteration types were detected.Concurrent MET copy gain and non-exon14 MET mutations were also found.EGFR copy gain (11%) and mutations (8%), KRAS (5%) and PIK3CA (5%), appeared in a mutually exclusive pattern.Female patients contain much less TP53 mutations than male patients (65% vs. 24%, FDR = 0.01).Co-amplification of CDK4 and MDM2, CDK6 and EGFR were identified, which indicated cell cycle dysregulation and EGFR alteration are important co-occurring features in patients with METex 14 alteration.Of 9 tissue specimens having PD-L1 immunohistochemistry (IHC) results, 5 of them (55.5%) were found PD-L1 positive, which is comparable to other types of tumor.In 14 crizotinib-treated patients, the median progression free survival (mPFS) was 7 months.Upon resistance to crizotinib, two patients acquired secondary mutations in MET and one patient acquired BRAF p.K601E that can be a novel resistance mechanism.Conclusion: Chinese cancer patients have a relatively lower frequency of METex14 alterations compared to Western patients.Patients with METex14 alterations showed distinct molecular characteristics and the representative case study showed responses to MET tyrosine kinase inhibitor (TKI).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".