Genomic characterization of squamous cell lung cancers
New potential targets discovered for treating squamous cell lung cancers
- Date : 11 Sep 2012
- Topic : Carcinoma of unknown primary site
In the September 9, 2012 early online edition of Nature, scientists of The Cancer Genome Atlas report that they have characterized the lung squamous cell carcinoma genome. It is ranking second only to lung adenocarcinoma in the number of deaths it causes, but unlike the most common form of lung cancer, squamous cell carcinoma has no treatments aimed at the specific genetic alterations that drive it.
That picture may change. The Cancer Genome Atlas Research Network has identified many potential therapeutic targets based on the large number and variety of molecular alterations discovered in most of the tumours studied. This study clearly shows that squamous cell carcinoma, like lung adenocarcinoma, is a cancer with diverse genomic causes, many of which are potentially susceptible to drug inhibition.
New therapeutic opportunities for squamous cell carcinoma
The first targeted treatments for lung adenocarcinoma, erlotinib and gefitinib, were aimed at mutations in the EGFR gene. Unfortunately, and like other drugs being tested in clinical trials that target several other genes altered in lung adenocarcinoma, they do not help patients with squamous cell carcinoma.The Cancer Genome Atlas effort, a multicenter consortium funded by the USA National Institutes of Health, is the first comprehensive genomic characterization of this lung cancer subtype. Squamous cell carcinoma causes approximately 400,000 deaths per year worldwide.
As in the three previous reports of the Cancer Genome Atlas on glioblastoma, ovarian cancer, and colorectal cancer, the scientists used multiple large-scale approaches to highlight key molecular defects. They sequenced the protein-coding segments of the genomes of 178 squamous cell carcinoma tumours, along with normal tissue from the same patients. The researchers also sequenced the whole genomes of 19 tumour and normal tissue pairs. They mapped a diverse catalogue of genomic alterations, including the rearrangements of chromosomes and other structural changes in regions of the genome that might not encode proteins but could control nearby genes involved in cancer development.
The comprehensive study confirmed some previously identified genomic alterations. For example, the p53 gene was altered in 90% of the tumours. The CDKN2A gene was inactivated in 72% of tumours. These genes normally prevent cancer, but when they are switched off, tumours can grow unimpeded. CDKN2A may be susceptible to a kinase inhibitor, presenting an opportunity for clinical trials.
The report documents a long list of mutations that could be targeted therapeutically, some even now with drugs currently available or in clinical trials
Overall the researchers identified mutations or amplifications in three families of tyrosine kinases. Frequently altered in cancer, they are already being investigated as therapeutic targets in other cancers. The researchers also found genomic alterations in signalling pathways that could present important opportunities for treatment.
In another striking finding, the researchers discovered mutations in the HLA-A gene that hampered its function in tumours. HLA genes direct the arm of the immune system that discriminates between its own tissues and foreign invaders. This is the first cancer in which these mutations have been found, but they are likely to occur in other cancers.
This is the first example of a tumour that has a genomic mechanism for evading an immune response. This may be important in understanding the immune response to squamous cell carcinoma and also in envisioning how immune-regulatory therapy might be used for this disease.
While much works needs to be done, the scientists see many opportunities. Patients with squamous cell lung cancer get today the same treatment they got 10 years ago. The researchers hope that their findings will catalyse a large new set of clinical trials in squamous cell carcinoma.
This and other studies from the Cancer Genome Atlas show the powers of a multi-institutional and multi-technological approach. For lung squamous cell carcinoma, the researchers not only studied the tumour DNA, but also the tumour RNA, with the integration of these data types yielded far more information that either type alone. These data identified numerous new and old drug targets, which is setting the stage for the next generation of clinical trials in these patients.
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