Abstract 1417: Molecular abnormalities associated to the progression of lung adenocarcinomas with BAC features from non-invasive to invasive patterns
Authors: Solis Luisa M. , Raso Maria G. , Fujimoto Junya , Behrens Carmen , Woods Denise M. , Mendoza Gabriela , Kalhor Neda , Moran Cesar A. , Wistuba Ignacio I. 
Published: June 2012

Abstract
Background: Most invasive lung adenocarcinomas (LAC) consist of mixed histological growth patterns including a non-invasive component referred as bronchioloalveolar carcinoma (BAC). Invasive LACs with BAC features are suspected to evolve from pure non-invasive (BAC) tumors. However, in this tumor type there is limited information about the molecular abnormalities associated to the progression from non-invasive to the invasive components.
Materials and methods: To perform a detailed mapping analysis of molecular abnormalities comparing non-invasive and invasive sites in lung AC with BAC features we selected archival tumor tissue specimens from 77 LACs with more than 10% of non-invasive component out of 553 available tumors. Using whole histologic sections, we analyzed on each component (non-invasive and invasive) the immunohistochemical (IHC) expression of five markers known to be deregulated in lung AC, including EGFR, Her2-Neu, TTF-1, BRG1 and p53. We also compared in both tumor components the status of EGFR gene copy number gain (CNG) by fluorescent in situ hybridization and mutation of EGFR (exon 18-21) and KRAS (codons 12 and 13) by PCR-based sequencing using DNA extracted from microdissected tissue. For EGFR, we defined 2 types of CNGs: low (trysomy and low-polysomy), and high (high-polysomy and amplification).
Results: Most cases had similar levels of expression in the non-invasive and invasive components of LAC for all IHC markers: EGFR, 54/70, 77%; Her2-Neu, 56/71, 79%; p53, 58/72, 80%; TTF-1, 57/71, 80%; and BRG1, 70/73, 96%. In a subset of cases, we found that the invasive component of LAC showed higher frequency of overexpression than non-invasive sites of EGFR (invasive 14/70, 20% vs. non-invasive 2/70, 3%) and Her2Neu (13/71, 18% vs. 2/71, 3%). EGFR mutations of exons 18-21 were found in 11/44 (20%) LAC, and in 7 (64%) mutant tumors the mutations were detected only in the invasive component. KRAS mutations were found in 14/56 (25%) tumors, and in all mutant tumors the mutations were found in both the non-invasive and corresponding invasive components. Any EGFR CNG was found in the invasive component of 20/56 (36%) tumors, including 9 cases with high CNG (4 high-polysomy and 5 gene amplification). In most (16/20, 80%) tumors the invasive component demonstrated higher CNG levels than the corresponding non-invasive sites. Interestingly, all 5 invasive tumors with EGFR amplification did not show such of abnormality in the corresponding non-invasive site.
Conclusions: Our findings suggest that in LAC with BAC features the overexpression of EGFR and Her2Neu, and EGFR gene abnormalities (CNGs and mutations) are associated with the progression of non-invasive to invasive components of the tumors. In contrast, in LAC with KRAS mutation this abnormality commences at the non-invasive stage of tumor development. Supported by grant from Uniting Against Lung Cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1417. doi:10.1158/1538-7445.AM2011-1417