Mutated Tumor Suppressor Gene in Lung Tissue Has Oncogenic Potential

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(ChemotherapyAdvisor) – Mutations in the tumor suppressor gene EPHA3 have oncogenic potential in lung tissue, according to a team of researchers from Vanderbilt University, Nashville, TN. This conclusion is based on an article entitled “Effects of Cancer-Associated EPHA3 Mutations on Lung Cancer,” which was published online in the Journal of the National Cancer Institute on July 24.

More people in the United States die from lung cancer than any other type of cancer. This is true for both men and women. According to the most currently available epidemiologic data from the US Centers for Disease Control and Prevention, 208,493 people were diagnosed with lung cancer in 2008, including 111,886 men and 96,607 women; among those, there were a total of 158,592 deaths from lung cancer. In accordance with this high mortality rate, dedicated researchers have sequenced numerous cancer types. According to the investigators, a recent sequencing effort identified the gene EPHA3, which encodes the EPHA3 receptor tyrosine kinase, one of the most frequently mutated genes in lung cancer. The normal (wild type) copy of EPHA3 functions as a tumor suppressor gene.

In the current study, the investigators aimed to uncover the oncogenic potential of the EPHA3 mutations in lung cancer. By employing a battery of laboratory methods, including   immunoprecipitation, western blotting, and kinase assays, it was possible to investigate the activity and signaling of mutant EPHA3 receptors. “A mutation-associated gene signature was generated from one large dataset, mapped to another training dataset with survival information, and tested in a third independent dataset,” the investigators wrote regarding their methods. “We assessed tumor growth in vivo using A549 and H1299 human lung carcinoma cell xenografts in mice (n=7–8 mice per group),” they wrote.

Interestingly, the investigators reported that ≥2 cancer-associated EPHA3 somatic mutations inhibited the normal (wild type) EPHA3 protein and identified an EPHA3 mutation-associated gene signature that was associated with a low survival rate. The more clinically-relevant findings came from experiments involving large cohorts of lung cancer patients and lung tumor xenografts in mouse models. In fact, the investigators reported that EPHA3 gene copy numbers and/or expression levels were decreased in tumors from patient cohorts. Additionally, wild type EPHA3 increased apoptosis in human lung cancer lines and inhibited the growth of tumor xenografts (For example, for H1299 cells, mean tumor volume with wild-type EPHA3 = 437.4mm3 vs control = 774.7mm3, P<.001).

The investigators concluded: “Cancer-associated EPHA3 mutations attenuate the tumor-suppressive effects of normal EPHA3 in lung cancer.”


Lung Cancer Epidemiology

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