Recurrent PTPRZ1‐MET fusion and a high occurrence rate of MET exon 14 skipping in brain metastases

Abstract

Identifying molecular features is an essential component of the management and targeted therapy of brain metastases (BMs). The molecular features are different between primary lung cancers and BMs of lung cancer. Here we report the DNA and RNA mutational profiles of 43 pathological samples of BMs. In addition to previously reported mutational events associated with targeted therapy, PTPRZ1‐MET, which was previously exclusively identified in glioma, was present in two cases of BMs of lung cancer. Furthermore, MET exon 14 skipping may be more common (6/37 cases) in BMs of lung cancer than the frequency previously reported in lung cancer. These findings highlight the clinical significance of targeted DNA plus RNA sequencing for BMs and suggest PTPRZ1‐MET and MET exon 14 skipping as critical molecular events that may serve as targets of targeted therapy in BMs.

Molecular pathology and clinical implications of diffuse glioma

“…[60] RNA N6-methyladenosine (m 6 A) has also been shown to play an important role in the TMZ-resistance of gliomas. [61] Interestingly, m 6 A is dynamically regulated by methyltransferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). Increased levels of m 6 A modifications have been positively associated with glioma malignancy and chemotherapy resistance, and the elevated levels of expression of METTL3, a writer of m 6 A, have also been shown to be required for the malignant progression and TMZ resistance of gliomas.…”

“…With the increasing use of molecular markers in the diagnosis of gliomas, challenges have arisen regarding the methodology of molecular testing for gliomas; and the same is true for performing integrated diagnostics [26] . The traditional technologies used in pathological diagnosis, including light microscopy, histochemical stains, electron microscopy, immunohistochemistry, and DNA fluorescence in situ hybridization (FISH) cannot fulfill the requirements for the diagnosis of gliomas [6,17] . A variety of nucleic acid detection methods, such as DNA/RNA sequencing and RNA expression profiles, have clearly shown their contribution to the diagnosis and classification of gliomas [1] .…”

“…[61] Interestingly, m 6 A is dynamically regulated by methyltransferases ("writers"), binding proteins ("readers"), and demethylases ("erasers"). Increased levels of m 6 A modifications have been positively associated with glioma malignancy and chemotherapy resistance, and the elevated levels of expression of METTL3, a writer of m 6 A, have also been shown to be required for the malignant progression and TMZ resistance of gliomas. [62,63] These findings suggested that additional stratification based on transcriptome profiles holds promise for further improving the predictive accuracy of the TMZ response of gliomas.…”

“…[ 26 ] The traditional technologies used in pathological diagnosis, including light microscopy, histochemical stains, electron microscopy, immunohistochemistry, and DNA fluorescence in situ hybridization (FISH) cannot fulfill the requirements for the diagnosis of gliomas. [ 6 , 17 ] A variety of nucleic acid detection methods, such as DNA/RNA sequencing and RNA expression profiles, have clearly shown their contribution to the diagnosis and classification of gliomas. [ 1 ] However, the means by which to properly incorporate these novel methodologies into routine molecular testing of formalin-fixed paraffin-embedded samples remains a challenge.…”

“…This is largely attributed to the unique anatomic location, biological characteristics, developmental, genetic, epigenetic, and microenvironmental features of gliomas that render them resistant to conventional and novel treatments. [3][4][5][6] Additionally, the traditional classification of diffuse gliomas only by histological features cannot provide enough information for clinicians to have a better understanding of the prognosis and optimal therapy for patients with specific subgroups of gliomas. [7][8][9][10] However, the rapid development of molecular pathology brings new hope for improving prognosis and consequently the outcome of gliomas.…”