Molecular characterization ofMETfusions from a large real‐world Chinese population: A multicenter study

Abstract

Purpose MET is a notable driver gene in the diversity of aberrations with clinical relevance, including exon 14 skipping, copy number gain, point mutations, and gene fusions. Compared with the former two, MET fusions are severely under‐reported, leaving a series of unanswered questions. In this study, we addressed this gap by characterizing MET fusions in a large, real‐world Chinese cancer population. Methods We retrospectively included patients with solid tumors who had DNA‐based genome profiles acquired through targeted sequencing from August 2015 to May 2021. MET fusion‐positive (MET+) patients were subsequently selected for clinical and molecular characterization. Results We screened 79,803 patients across 27 tumor types and detected 155 putative MET fusions from 122 patients, resulting in an overall prevalence of 0.15%. Lung cancer comprised the majority of MET+ patients (92, 75.4%). Prevalence was markedly higher in liver cancer, biliary tract cancer, and renal cancer (range 0.52%–0.60%). It was lower in ovarian cancer (0.06%). A substantial proportion (48/58, 82.8%) of unique partners were reported for the first time. High heterogeneity was observed for partners, with ST7, HLA‐DRB1, and KIF5B as the three most common partners. Mutational landscape analysis of lung adenocarcinoma (n = 32) revealed a high prevalence of TP53 in MET+ alterations, EGFR L858R, EGFR L861Q, and MET amplification. Conclusion To our knowledge, this is currently the largest study in characterizing MET fusions. Our findings warrant that further clinical validation and mechanistic study may translate into therapeutic avenues for MET+ cancer patients.

Analytical validation and clinical utilization of K-4CARE™: a comprehensive genomic profiling assay with personalized MRD detection

“…Unlike other CGP assays that used RNA to detect gene rearrangement (White et al, 2021;Ng et al, 2022;Saldivar et al, 2023), we designed probes to target selected intron regions of commonly fused genes, and DNA libraries were used to hybridize with these probes. Our bioinformatic pipeline to detect gene fusion was robust and similar to those developed in previous studies (Wang et al, 2023;Xia et al, 2023;Ye et al, 2023). Since this eliminates the necessity to process tumor RNA, it expedites the result and makes the assay more cost-effective and feasible, particularly for developing countries like Vietnam where the quality of FFPE-derived RNA is often not sufficient for NGS (in-house data).…”

The role of molecular diagnostics in the choice of therapy for biliary tract cancers

“…Из нарушений, затрагивающих ген MET, в опухолях билиарного тракта описаны амплификации и перестройки. Частота обоих видов нарушений невелика: для амплификаций она составляет 1-2 %, для перестроек -около 0,5 % [19,43,44]. На примере единичных клинических наблюдений была показана возможность успешного применения таргетных ингибиторов киназы MET при лечении опухолей билиарного тракта c геном MET, активированным посредством амплификации или транслокации [45,46].…”

MET fusions are targetable genomic variants in the treatment of advanced malignancies

“…Search terms: MET, MET fusion, MET fusions, MET mutations, and MET alterations in PubMed; Period of search: August 2023 to September 2023. As concluded from the studies [ 11 – 19 , 23 – 32 ] listed in Table 1 , the average age of patients diagnosed with malignancies harboring MET fusions was 56.6 years, with a range of 27 to 74 years. Among these patients, 60% patients were female, and the MET fusion incidence showed no significant sex difference.…”

“… 71 74 Female Lung ADC IV NGS NA Primary HLA-DRB1-MET NA – 1 L Crizotinib (CR, greater than 8.0 m) Xia H, et al Cancer Med. 2023 [ 32 ] 72 67 Female Lung NA IV NGS NA NA HLA-DRB1-MET NA NA 5 L Crizotinib (PR, 12 m) 73 49 Female Lung ADC III NGS NA Acquired (EGFR) LINC01392-MET + NA 4 L Crizotinib+Osimertinib (PR, 3 m) 74 62 Female Lung ADC IV NGS NA NA KIF5B-MET NA NA 2 L Crizotinib (PD, 2 m) Abbreviations: ACC: acinic cell carcinoma; ADC: adenocarcinoma; ICC: intrahepatic cholangiocarcinoma; NGS: next generation sequencing; FFPE: formalin fixed paraffin embedded; CR: complete response; PR: partial response; PD: progressive disease; SD: stable disease; PFS: progression-free survival; DOR, duration of response; NA: not available; “+”: positive genetic variation; “-”: negative genetic variation …”

“…Abnormal MET protein expression could not only activate the classical downstream MAPK pathway, Akt pathway and STAT3 pathway, all of which participate in the inhibition of apoptosis induced by TKIs as concluded above, but also activate the MET/MYC/AXL axis and enhance resistance [ 40 – 42 ]. Given the critical role of acquired abnormal MET function in inducing resistance to TKIs, a previous study also shed new light on strategies for combination therapy, including therapies combining relevant TKIs and MET inhibitors (MET-TKIs), in improving the prognosis of patients [ 32 , 43 ]. As we summarized above, aberrant fusion of the MET gene could act as a trigger for the upregulation and activation of MET.…”