Dr. Kim was awarded a two-year grant (2012-2014) for the following project from Uniting Against Lung Cancer.
Identification of novel fusion genes and tumor-specific isoforms in triple- or quadruple-negative lung adenocarcinoma patients
Lung cancer is the leading cause of cancer death in men and women in the U.S. and world-wide, causing approximately 157,300 American deaths in 2010, more than breast, prostate, and colorectal cancers combined. While genetic susceptibility genes have been identified in lung cancer patients that have strong associations with many clinical outcomes, there have been no major breakthroughs in lung cancer therapeutics in the area of targeted personalized medicine.
We have developed a fast and robust mutation assay to screen most frequently mutated genes and applied to a total of 192 lung adenocarcinoma (AD) patients. With this new assay screening, we have identified 102 triple- (EGFR, K-ras, and EML4-ALK fusion) and 78 quadruple- (triple plus TP53) negative lung AD patients. There is no currently effective treatment for these triple- or quadruple-negative (wild-type) patients. The triple-negative concept has been emphasized in breast cancer. This type of breast cancer is known to be more aggressive, non-responsive to receptor targeted treatment, and prone to later recurrence.
The clinical differences between patients with triple- or quadruple-negative lung AD and those with previously identified mutations are not clear yet. A preliminary study was done with 141 normal and matched lung ADs, in addition to 68 pairs of lung squamous cell carcinomas (SCC) and 24 malignant mesotheliomas (MM) using Affymetrix microarray with probes in each human coding exons. This microarray analysis can suggest both splicing isoforms and potential fusion genes by the 'breakpoint' analysis.
We identified 22 unknown fusion and 12 tumor-specific isoform candidates in AD patients. We aim to validate these 22 novel fusion candidate genes using the next generation sequencing (NGS) and 5'-RACE (Rapid Amplification of cDNA Ends) approaches in this proposal. Inhibitors of some of these fusion candidates are under clinical trials in other diseases. The validation of these markers can support an initiation of a new clinical trial with the currently available inhibitors in patients with the fusion. The success of this proposal would provide a new therapeutic and diagnostic paradigm to patients with triple- or quadruple-negative lung AD patients.