High-throughput oncogene mutation profiling in human cancer

Abstract

Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention.

Molecular pathology of lung cancer: key to personalized medicine

“…205 Of the 100 samples studied, 51 and 18 samples harbored high and low abundances of EGFR mutations, respectively, and 31 carried wild-type EGFR. Differences in overall survival and objective response rate in patients with high and low abundances of EGFR mutations were not significant.…”

“…63 EGFR and KRAS mutations are rarely detected in the same tumor, suggesting that they may perform functionally equivalent roles in lung tumorigenesis. 205,206 KRAS mutation is a negative predictor of response to anti-EGFR monoclonal antibodies and is also an important mechanism of resistance to TKIs in lung adenocarcinomas. 55 A meta-analysis by Linardou et al 207 provided empirical evidence that somatic mutations of the KRAS oncogene are highly specific negative predictors of response to single-agent EGFR TKIs in advanced lung cancers, mostly adenocarcinomas.…”

The FGFR4 Y367C mutant is a dominant oncogene in MDA-MB453 breast cancer cells

“…Such activation often arises from genetic alterations, either by mutation or by amplification of genes that have a pivotal role in the maintenance of cellular homeostasis. As such, genome-wide screening has been used extensively for the discovery of novel mutations in cell signalling molecules such as the tyrosine kinase superfamily to better understand the pathophysiology of cancers and to identify new drug targets (Bardelli et al, 2003;Stephens et al, 2004Stephens et al, , 2005Bignell et al, 2006;Greenman et al, 2007;Ruhe et al, 2007;Thomas et al, 2007). However, a major constraint in this process is the difficulty in establishing the functional significance of newly discovered genetic lesions for cancer formation and progression.…”

Gene expression profiling of Non-small cell lung cancer

“…Array technology permits us to study multiple genetic alterations and patterns of gene expression changes in lung cancers. Gene expression arrays can be used to screen cancerous tissues to simultaneously localize hundreds of molecular alterations [13]. Furthermore, bioinformatics potentially has the ability to describe the genetic alterations in lung cancer more globally in pathways such as metastasis [14], apoptosis [15] and cell cycle [16].…”