Mutational events that lead to MET exon 14 skipping occur frequently and may be targetable events in patients with pulmonary sarcomatoid carcinoma (PSC), according to a recent study published online ahead of print in the Journal of Clinical Oncology.
Balazs Halmos, MD, of Columbia University Medical Center, in New York, NY, and fellow researchers conducted whole-exome sequencing as well as targeted MET mutation screening in patients with PSC in order to further understand molecular pathogenesis of the disease.
With regard to MET exon 14 skipping,, which was validated through reverse transcriptase polymerase chain reaction and Western blotting , they also performed functional studies for validation of its oncogenic roles in lung adenosquamous cell line H596 as well as gastric adenocarcinoma cell line Hs746T.
The researchers found and validated several novel mutations in genes that had since been unknown to be cancer-associated, including RASA1, CDH4, CDH7, LAMB4, SCAF1, and LMTK2. They also confirmed mutations in genes that were previously known, such as TP53, KRAS, PIK3CA, MET, NOTCH, STK11, and RB1.
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Mutations that led to exon 14 skipping were identified in eight out of 36 patient cases.
Furthermore, RNA silencing of MET and MET inhibition with crizotinib demonstrated an effect on cell viability and a decrease in downstream AKT and mitogen-activated protein kinase activation in Hs746T and Hh596.
- Liu X, Jia Y, Stoopler MB, et al. Next-generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations. Journal of Clinical Oncology. 2015. [epub ahead of print]. doi: 10.1200/JCO.2015.62.0674.