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TCGA Team Reports on Squamous Cell Lung Cancer Findings

NEW YORK (GenomeWeb News) – In a study appearing online yesterday in Nature, members of The Cancer Genome Atlas reported on the progress they've made in characterizing a form of lung cancer called squamous cell carcinoma.

Through an integrated analysis of copy number, mutation, gene expression, and other data from 178 lung squamous cell carcinomas, the TCGA team defined several pathways that were frequently affected by genetic glitches and identified nearly a dozen recurrently mutated genes — among them, TP53, which was altered in almost all of the tumors.

In addition to showing that some of the lung squamous cell carcinoma mutations overlapped with those found in other squamous cell carcinoma tumors — namely those appearing in the head and neck — the investigators highlighted the possibility of finding new treatments for the squamous lung tumors by grouping them according to genetic profiles.

"The current study has identified a targetable gene or pathway alteration in most lung [squamous cell carcinoma] samples studied," corresponding author Matthew Meyerson, a researcher affiliated with the Broad Institute, the Dana-Farber Cancer Institute, and Harvard Medical School, and colleagues wrote.

"The data … can help to organize efforts to analyze lung [squamous cell carcinoma] clinical tumor specimens for a panel of specific, actionable mutations to select patients for appropriately targeted clinical trials," they added. "These data could thereby help to facilitate effective personalized therapy for this deadly disease."

After lung adenocarcinoma, researchers explained, lung squamous cell carcinoma is the most common form of lung cancer, accounting for almost one-third of lung cancer cases and some 400,000 deaths around the world annually.

In contrast to treatments for lung adenocarcinoma, which are sometimes targeted based on genetic profiles previously detected in that lung cancer subtype, squamous cell lung tumor treatments are still limited to non-specific methods such as chemotherapy and radiation. Such treatments target cancer cells, but have not been designed with lung squamous cell carcinoma-specific pathways in mind, primarily owing to a limited understanding of the molecular alterations that exist in the squamous cell subtype.

For the current effort to characterize the disease and to find its potential genetic vulnerabilities, the TCGA team did exome sequencing and array-based copy number analyses on 178 untreated lung squamous cell carcinoma tumor samples from individuals with stage I to stage IV cancers. The samples were also subjected to messenger RNA sequencing, gene expression, and promoter methylation analyses.

To round out their analyses, the researchers interrogated 19 lung squamous cell carcinoma samples by whole-genome sequencing and subjected 159 tumors to microRNA sequencing.

As in other lung cancer types, the team found fairly high mutation rates overall: on the order of around eight mutations for every million bases of genome sequence. The mean tally of exonic mutations per tumor was 360, for instance, and tumors averaged more than 300 copy number changes and 165 rearrangements apiece.

Most of the squamous cell lung tumors tested contained mutations involving the known cancer gene TP53.

Other recurrently mutated genes included some of the same players altered in forms of head and neck squamous cell carcinoma that are not accompanied by human papillomavirus infection, underscoring the notion that genetic profiles provide a different level of resolution compared to classification schemes based on a tumor's tissue of origin.

"This reinforces something that we've been seeing in a lot of our cancer genomics work," co-author Richard Wilson, director of Washington University's Genome Institute, said in a statement. "It's really less about what type of tissue the tumor arises in — lung, breast, skin, prostate — and more about what genes and pathways are affected."

Also altered in a significant number of the tumors were the tumor suppressor genes CDKN2A and RB1, the class I major histocompatibility immune gene HLA-A, fibroblast growth factor receptor, or FGFR, family genes, and genes involved in tyrosine kinase signaling.

Other tyrosine kinases tended to be affected in the tumors too, as were genes from pathways involved in processes such as cell cycle regulation, apoptosis, oxidative stress response, and squamous cell differentiation.

Now, researchers say, the goal is to begin trying to use some of the new mutation information and translate it into molecularly focused treatments for groups of squamous cell lung tumors sharing recognizable mutation patterns.

"We found that almost 75 percent of the patients' cancers have mutations that can be targeted with existing drugs — drugs that are available commercially or for clinical trials," Washington University oncology researcher Ramaswamy Govindan, a study author and co-chair of TCGA's lung cancer group, said in a statement.

"With this analysis, we are just starting to understand the molecular biology of lung squamous cell carcinoma," Govindan added. "And now we have identified potential targets for therapies to study in future clinical trials."

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