Comprehensive Molecular Profiling of Lung Adenocarcinoma
The Cancer Genome Atlas Research Network has recently reported its comprehensive molecular profiling of lung adenocarcinoma in Nature. Findings included a high rate of somatic mutations including alterations in tumor-suppressor genes, chromatin-modifying genes, and RNA-splicing genes and suggested novel or as-yet unidentified mechanisms in pathway activation.
Study Details
In the analysis, tumor and matched normal tissue from 230 patients with previously untreated resected adenocarcinomas were profiled using messenger RNA, microRNA and DNA sequencing integrated with copy number, and methylation and proteomic analyses. All major histologic types of adenocarcinoma were included, including acinar in 33% of cases, solid in 25%, micropapillary in 14%, papillary in 9%, lepidic in 5%, invasive mucinous in 4%, colloid in 0.4%, and unclassifiable in 8%.
Past or present smoking was reported by 83% of patients. Median follow-up was 19 months, with 163 patients remaining alive at last follow-up.
Common Alterations
There were high rates of somatic mutations, with a mean of 8.9 mutations per DNA megabase. TP53 was frequently mutated (46%). Mutations in KRAS (33%) were mutually exclusive with those in EGFR (14%). Mutations were also common in BRAF (10%), PIK3CA (7%), MET (7%), and the small GTPase gene RIT1 (2%). Mutations were observed in the tumor-suppressor genes STK11 (17%), KEAP1 (17%), NF1 (11%), RB1 (4%), and CDKN2A (4%), in the chromatin-modifying genes SETD2 (9%), ARID1A (7%) and SMARCA4 (6%), and in the RNA-splicing genes RBM10 (8%) and U2AF1 (3%).
Recurrent mutations in the MGA gene (which encodes a Max-interacting protein in the MYC pathway) were found in 8% of tumors. Loss-of-function (frameshift and nonsense) mutations in MGA were mutually exclusive with focal MYC amplification, suggesting a novel potential mechanism for MYC pathway activation.
Other Highlights
EGFR mutations were more common in women, and loss-of-function mutations in RBM10 (RNA-binding protein located on the X chromosome) were more common in men.
Alterations in NF1, MET, ERBB2, and RIT1 were found in 13% of tumors and were enriched in those that lacked an identified activated oncogene, with these findings suggesting that these events may act as drivers in certain tumors.
DNA and mRNA sequencing in the same tumor revealed splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases.
At the protein level, MAPK and PI(3)K pathway activity could be explained by known mutations in only a small proportion of cases, suggesting as-yet unidentified mechanisms of pathway activation.
The investigators concluded, “These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.”
Matthew Meyerson, MD, PhD, of the Dana-Farber Cancer Institute, Harvard Medical School, and the Broad Institute, is the corresponding author for the Nature article.
The study was supported by grants from the National Institutes of Health.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
