Researchers from The Cancer Genome Atlas (TCGA) Research Network have identified amplifications in MET and ERBB2 as well as mutations of NF1 and RIT1 as driver events in oncogene-negative lung adenocarcinomas. This analysis increases the fraction of lung adenocarcinoma cases with somatic evidence of RTK/RAS/RAF pathway activation. Knowledge of these genomic changes may expand the number of possible therapeutic targets and potentially identify a greater number of patients with treatable mutations because many potent cancer drugs that target these mutations already exist.
TCGA is jointly funded and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both part of the USA National Institutes of Health. A TCGA analysis of lung squamous cell carcinoma was reported in 2012. In this new study, published online July 9, 2014, in the journalNature, researchers examined the mutation profiles, structural rearrangements, copy number alterations, DNA methylation, mRNA, miRNA and protein expression of 230 lung adenocarcinomas.
They found high rates of somatic mutations, mean 8.9 mutations per megabase. In particular, 18 genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification.
EGFRmutations were more frequent in female patients, whereas mutations in RBM10 were more common in males.
Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours.
DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases.
MAPK and PI3K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation.
This analysis increases the fraction of lung adenocarcinoma cases with somatic evidence of RTK/RAS/RAF activation from 62% to 76%. The current study expands the range of possible targetable alterations within the RTK/RAS/RAF pathway in general and suggests increased implementation of MET and ERBB2/HER2 inhibitors in particular.
Discovery of inactivating mutations of MGA further underscores the importance of the MYC pathway in lung adenocarcinoma.
This study further implicates both chromatin modifications and splicing alterations in lung adenocarcinoma through the integration of DNA, transcriptome and methylome analysis. The researchers identified alternative splicing and mutation of splice sites incisled to activation of the MET gene.
Cluster analysis separated tumours based on single-gene driver events as well as large-scale aberrations, emphasising lung adenocarcinoma’s molecular heterogeneity and combinatorial alterations, including the identification of coincident SETD2 mutations and CDKN2A methylation in a subset of CIMP-H tumours, providing evidence of a somatic event associated with a genome-wide methylation phenotype.
The study provides new knowledge by illuminating modes of genomic alteration, highlighting previously unappreciated altered genes, and enabling further refinement in subclassification for the improved treatment personalisation in lung adenocarcinoma.
This work was supported by a number of NIH grants.
The Cancer Genome Atlas Network authors. Comprehensive molecular profiling of lung adenocarcinoma. Nature 2014; Published Online July 9. doi: 10.1038/nature13385.