Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers uncover mutated genes involved in lung cancer; one affects nonsmokers

02.03.2005


Lung cancer patients who have never smoked are more likely than smokers to harbor one of two genetic mutations that researchers at UT Southwestern Medical Center have now linked to the disease.



"This study describes the first known mutation to occur in lung cancer patients who have never smoked," said Dr. Adi Gazdar, professor of pathology in the Nancy B. and Jake L. Hamon Center for Therapeutic Oncology Research and senior author of the study in today’s issue of the Journal of the National Cancer Institute. "These findings may help explain why certain lung cancer patients respond dramatically to a specific form of targeted therapy while others have little or no response."

Mutations in the epidermal growth factor receptor (EGFR) gene are present mainly in adenocarcinomas, the most common form of lung cancer found in smokers and non-smokers, as well in women and people under 45. These mutations have shown increased sensitivity to gefitinib (Iressa) and erlotinib (Tarceva), drugs targeting the gene.


To understand better the role of the EGFR mutation in the development of lung cancer, Dr. Gazdar and his colleagues analyzed tissue samples from primary tumors of 519 patients in the United States, Japan, Taiwan and Australia. Mutations in the DNA of nonmalignant lung tissue from many of these patients and from other separate cancer tissues also were examined.

The researchers found mutations in the EGFR gene were much more common:

  • in people with lung cancer who never smoked compared to smokers (51 percent vs. 10 percent, 85 of 166 non smokers vs. 35 of 353 smokers);
  • in adenocarcinomas compared to other lung cancers (40 percent vs. 3 percent, 114 of 289 adenocarcinomas vs. 6 of 230 other cancers);
  • in women compared to men (42 percent vs. 14 percent, 72 of 171 women vs. 48 of 348 men);
  • in patients of Asian ancestry compared to other ethnicities (30 percent vs. 8 percent, 107 of 361 Asians vs. 13 of 158 in other ethnicities).

Mutations in the KRAS gene – a gene in the EGFR signaling pathway – were found in 8 percent of lung cancers but in none with the EGFR mutation. This mutation was more common in males, Caucasians, and current or former smokers.

As a result, it appears that two distinct molecular pathways are involved in formation of lung cancer, Dr. Gazdar said. The pathway in smokers involves KRAS gene mutations, while the pathway in people who never smoked involves EGFR gene mutations. The next step is to move these findings toward development of better treatments for lung cancer, said Dr. Gazdar.

He and Dr. John Minna, director of the W.A. "Tex" and Deborah Moncrief Jr. Center for Cancer Genetics and the Hamon Center for Therapeutic Oncology Research and a contributing author, have established eight lung cancer cell lines that harbor several types of EGFR mutations and are now establishing another line from a patient who relapsed after initially responding well to the gefitinib drug. "These lines will prove invaluable in understanding both the response to gefitinib and erlotinib and the mechanisms by which resistance eventually develops," Dr. Gazdar said. "The cell lines may help identify strategies to overcome this drug resistance that eventually develops in most responders."

A related study in the current issue of Cancer Research with Dr. Gazdar and his colleagues found that mutations in EGFR and HER2, another gene in the EGFR pathway that is associated with certain cancers, targeted the same patient subpopulations. The discovery that HER2 also is a mutation occurring mainly in tumors of people who never smoked suggests different pathways may be involved in lung cancer formation in smokers and nonsmokers. "Our work is very important because if you have a mutation in the EGFR gene in the tumor, a patient likely will have a dramatic response to a relatively nontoxic once-daily oral therapy," Dr. Minna said.

"The research has found these tumors can vary by several thousandfold on how sensitive they are to a drug," said Dr. Minna. "We also have been able to identify in advance a pattern of gene expression that tells whether a tumor is going to be resistant or sensitive to a particular drug. We want to be capable of examining a patient’s tumor, profile each human gene and then select the best current therapy." Dr. Minna and Dr. Jonathan Dowell, assistant professor of internal medicine, contributed to an editorial in the Feb. 24 issue of The New England Journal of Medicine commenting on a study headed by Dan Farber Cancer Research Center. Researchers there found a lung cancer that initially was very sensitive to gefitinib because of a mutation in the EGFR gene developed resistance to the drug because of a second EGFR mutation.

The enhanced understanding of EGFR and these mutations reported in the NEJM study will allow new drugs to be designed to combat these drug-resistant receptors, enabling effective second-line therapy to then be directed at the same target, Dr. Minna wrote.

Scott Maier | EurekAlert!
Further information:
http://www.utsouthwestern.edu

More articles from Life Sciences:

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

nachricht Party discipline for jumping genes
22.09.2017 | Veterinärmedizinische Universität Wien

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

Hope to discover sure signs of life on Mars? New research says look for the element vanadium

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>