Top-level gene copy number gain defines a subtype of poorly differentiated pulmonary adenocarcinomas with poor prognosis.

BACKGROUND

amplifications occur in human tumors, including non-small cell lung cancer (NSCLC). MET inhibitors have demonstrated some clinical activity in amplified NSCLC, presumably with a gene dose effect. However, the definition of MET positivity or amplification as a potential oncogenic driver is still under debate. In this study, we aimed to establish the molecular subgroup of NSCLC with the highest unequivocal MET amplification level and to describe the prevalence, and histologic and clinical phenotype of this subgroup.

METHODS

A total of 373 unselected patients with NSCLC were consecutively tested for gene copy number (GCN) by FISH. Mean GCN, /CEN7 ratio and other FISH parameters were identified and correlated with morphological and molecular pathological characteristics of the tumors as well as with clinical data.

RESULTS

Based on the variability of obtained data a top-level category of amplification was newly defined (>90th percentile of average GCN; ≥10 gene copies per tumor cell). This criterion was fulfilled in 2% of analyzed tumors. These tumors were exclusively poorly differentiated adenocarcinomas with a predominant solid subtype and pleomorphic features. Rarely, co-alterations were detected ( mutation or exon 14 skipping mutation). In this top-level group, there were no mutations or or alterations. The most important clinical feature was a significantly shortened overall survival (HR 3.61; median OS 8.2 23.6 months). Worse prognosis did not depend on initial stage or treatment.

CONCLUSIONS

The newly defined top-level category of amplification in NSCLC defines a specific subgroup of pulmonary adenocarcinoma with adverse prognosis and characteristic morphological features. Lower levels of gene copy number seem to have probably no specific value as a prognostic or predictive biomarker.