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TCGA Team Detects Signaling Pathway Alterations in Most Lung Adenocarcinoma Tumors

NEW YORK (GenomeWeb) – Members of the Cancer Genome Atlas today described driver mutations and potential drug targets detected in a common form of lung cancer called lung adenocarcinoma.

As they reported in Nature, the researchers identified new and known lung cancer driver genes through an integrated DNA sequence, RNA sequence, microRNA sequence, copy number, methylation, and proteomic analyses of tumor and normal samples from 230 individuals with lung adenocarcinoma.

As in past studies of other lung cancer types — including a TCGA analysis of 178 lung squamous cell carcinoma cases — the overall mutation rate was high in the lung adenocarcinoma tumors. Nevertheless, 18 recurrently mutated genes stood out in the analysis, including EGFR, NF1, and ERBB2.

And notably, around three-quarters of the tumors tested contained some type of glitch involving genes from the RTK/RAS/RAF signalling pathway, highlighting its importance as a lung cancer contributor and potential treatment target in many lung adenocarcinoma cases.

"It is remarkable how important the RTK/RAS/RAF pathway appears to be," Washington University's Ramaswamy Govindan, co-leader on the lung adenocarcima project, said in a statement. "Mutations in this particular pathway promote cancer cell proliferation. What is amazing is how many ways this pathway can be activated."

Govindan and his colleagues did exome sequencing on all 230 of the tumor-normal pairs included in the lung adenocarcinoma paper. They also tested the tumors, which came from lung adenocarcinoma patients who had not yet been treated, using array-based copy number profiling and methylation testing. Some of the tumor were was also assessed by proteomic profiling and/or whole-genome sequencing.

The team's analysis of this data uncovered almost nine somatic mutations in every million bases of tumor DNA sequence, on average. In particular, mutations tended to turn up in genes such as EGFR, RBM10, NF1, MET, ERBB2, MGA, and RIT1.

For example, some 13 percent of the tumors tested contained NF1, MET, ERBB2, or RIT1 mutations. Those alterations were particularly common in lung adenocarcinoma cases that did not involve mutations that activate other cancer-promoting oncogenes.

Tumors from female patients more frequently contain EGFR mutations, which appear to be mutually exclusive with KRAS mutations, researchers reported. Meanwhile, they found that tumors from male patients were more likely to carry loss-of-function mutations in RBM10, a gene that codes for an RNA-binding protein.

In some of the tumors that did not contain MYC amplifications, the team saw mutations in some genes not implicated in lung cancer in the past. Other recurrently amplified genes included TERT, MET, KRAS, and EGFR.

When they focused on pathways that were prone to glitches in lung adenocarcinoma, the researchers discovered that some 76 percent of the cases contained mutations expected to activate the RTK/RAS/RAF pathway.

"[T]he current study expands the range of possible targetable alterations within the RTK/RAS/RAF pathway in general," Govindan and co-authors wrote, "and suggests increased implementation of MET and ERBB2/HER2 inhibitors in particular."

A p53-containing pathway was altered in 63 percent of tumors, and 64 percent of tumors harbored mutations affecting pathways that regulate cell cycle activity. The group also saw recurrent mutations components of oxidative stress, chromatin, RNA splicing, and PI3-kinase signalling pathways.

Along with the more than 200 individuals assessed through the current and past TCGA analyses of lung cancer, the researchers plan to analyze samples from another 600 with lung cancer in the future.

For his part, Govindan is getting set to lead the so-called "Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial," or ALCHEMIST, a study focused on screening for EGFR and ALK gene mutations in thousands of lung cancer patients to target treatments against these alterations.