Early Events in the Molecular Pathogenesis of Lung Cancer

Abstract

The majority of cancer-related deaths in the United States and worldwide are attributed to lung cancer. There are more than 90 million smokers in the United States who represent a significant population at elevated risk for lung malignancy. In other epithelial tumors, it has been shown that if neoplastic lesions can be detected and treated at their intraepithelial stage, patient prognosis is significantly improved. Thus, new strategies to detect and treat lung preinvasive lesions are urgently needed in order to decrease the overwhelming public health burden of lung cancer. Limiting these advances is a poor knowledge of the earliest events that underlie lung cancer development and that would constitute markers and targets for early detection and prevention. This review summarizes the state of knowledge of human lung cancer pathogenesis and the molecular pathology of premalignant lung lesions, with a focus on the molecular premalignant field that associates with lung cancer development. Lastly, we highlight new approaches and models to study genome-wide alterations in human lung premalignancy in order to facilitate the discovery of new markers for early detection and prevention of this fatal disease. Cancer Prev Res; 9(7); 518-27. Ó2016 AACR.

Genomic Landscape of Atypical Adenomatous Hyperplasia Reveals Divergent Modes to Lung Adenocarcinoma

“…This is largely attributed to late diagnosis after locoregional or distant spread [1]. Advances (e.g., molecular-based) in early detection and prevention of NSCLC have been limited by a poor understanding of early changes in NSCLC pathogenesis [3]. …”

“…Studies have demonstrated that LUADs and LUSCs carry different genomic landscapes of driver mutations as well as disparate clinicopathological features [3]. While LUSCs are diagnosed almost exclusively in smokers, LUADs are known to develop in both smokers and non-smokers [3].…”

“…Studies have demonstrated that LUADs and LUSCs carry different genomic landscapes of driver mutations as well as disparate clinicopathological features [3]. While LUSCs are diagnosed almost exclusively in smokers, LUADs are known to develop in both smokers and non-smokers [3]. In contrast to the well characterized histopathological sequence of various lesions (bronchial hyperplasias, metaplasias and dysplasias, as well as carcinomas in situ ) associated with LUSC pathogenesis, atypical adenomatous hyperplasias (AAHs) are the only known precursor (premalignant) lesions in the development of LUAD [3,4].…”

“…Further, it has also been shown that KRAS -mutant AAHs are more prevalent in smokers while EGFR -mutant AAHs do not show association with smoking status [5]. Loss-of-heterozygosity of chromosome arms 3p, 9p, 16p, 17q, and 17p have been shown in AAH, and in common with corresponding primary LUADs [3]. Other molecular aberrations that have been identified in AAH include overexpression of Cyclin D1, survivin, ERBB2 oncoproteins and NKX2-1 [3].…”

“…Loss-of-heterozygosity of chromosome arms 3p, 9p, 16p, 17q, and 17p have been shown in AAH, and in common with corresponding primary LUADs [3]. Other molecular aberrations that have been identified in AAH include overexpression of Cyclin D1, survivin, ERBB2 oncoproteins and NKX2-1 [3]. Epigenetic modifications such as increased promoter hypermethylation of genes implicated in lung cancer (e.g., p16 ) with histologic progression from normal to AAH and finally LUAD [6], as well as DNA methylation of CDKN2A and PTPRN2, have also been reported in AAHs [7].…”