New Genetic Culprits in Lung Cancer Identified

by Rajashri on Oct 23 2008 1:04 PM

Some 26 genes whose mutation plays a role in the commonest form of lung cancer have been identified by US scientists. The findings include genes that may be receptive to novel drugs or existing treatments used to tackle other tumours.

The haul, reported on Wednesday in the British-based science journal Nature, doubles the tally of genes fingered in lung adenocarcinoma, which accounts for around 40 percent of cases of lung cancer. Nearly nine out of every 10 cases occur among smokers or former heavy smokers.

"We found lung adenocarcinoma to be very diverse from a genetic standpoint," said a leading investigator, Matthew Meyerson, of the Broad Institute at the Massachusetts Institute of Technology (MIT).

"Our work uncovered many new targets for therapy of this deadly disease - oncogenes that drive particular forms of lung adenocarcinoma and tumour suppressor genes that would ordinarily prevent cancer cell growth."

The work entailed taking samples of lung tissue from 188 cancer patients in the United States and looking at 623 suspect genes. These were then compared to the same genes in healthy tissues from the same patients.

The team found more than 1,000 mutations among genes in the lung cancer samples, which pointed to a part in the molecular cascade by which cells become tumorous and then replicate unchecked.

Most of these alterations had never been spotted before in lung adenocarcinoma, but - an important finding - many are already implicated in other cancers.

The cross-linking genes include those that are common in colon cancer, types of leukaemia and lymphoma and a cancer of the nerve tissues called neurofibromastosis.

Meyerson said that these associations suggested that a small number of key genes operate together, forming molecular circuits, or pathways. A flaw in one or two of the genes could send the cellular machinery awry.

The work offers hope of new therapies that can be targeted against specific genes that so far are only associated with lung cancer, or at adapting existing therapies that are used for other cancer types to tackle lung adenocarcinoma.

For example, the researchers discovered that more than 80 percent of the 188 tumours involved a mutation in a pathway called mitogen-activated protein kinase, or MAPK.

Investigators are already getting promising results from drugs designed to block the MAPK machinery, although these prototype treatments are only being tested on mice so far, and not humans.

Another culprit circuit is called the mTOR pathway, which is implicated in 30 percent of lung tumours. A drug called rapamycin, which inhibits the mTOR genes, is already approved for use in kidney cancers.

Smokers with lung cancer, the researchers found, are likely to have many more genetic mutations in diseased tissue compared with non-smokers with a lung tumour. Smokers' cancers contained as many as 49 mutations, while non-smokers had five or fewer.

The paper was carried out by Tumour Sequencing Project - one of several major schemes to delve into the goldmine of data which is the human genome.