Genetic and Epigenetic Tumor Suppressor Gene Silencing Are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Nonsmall Cell Lung Cancer

Carmen J Marsit,Karl T Kelsey,Heather H Nelson,E Andres Houseman

doi:10.1155/2008/215809

Abstract

Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

Highlights

Lung cancer remains one of the most incident cancers and the leading cause of cancer death in both men and women in the United States
We examined the effect of mutation of the KRAS gene which has been previously reported in this population of tumors [25, 45], as mutation of this pathway is associated with a methylator phenotype in colon cancer [46]
We found that only KRAS mutation status and fraction allelic loss score of loss of heterozygosity (LOH) at 3p21 were significantly associated with the propensity for hypermethylation

Summary

Introduction

Lung cancer remains one of the most incident cancers and the leading cause of cancer death in both men and women in the United States. In 2006, there were over 162 000 deaths attributable to lung cancer in the U.S [1]. Nonsmall cell lung cancer (NSCLC) is derived from the epithelial cells of the lung and bronchus and is characterized by a wide variety of molecular alterations. Included among these are activating mutations in oncogenes (such as cMYC, KRAS, EGFR, CCND1, and BCL2) and inactivating lesions in tumor suppressor genes [3, 4]. The inactivation of tumor suppressor genes occurs through allele loss (both single allele loss and homozygous gene deletion) or epigenetic silencing associated with promoter hypermethylation of CpG islands in the promoters of many of these genes [5,6,7]

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Conclusion