Whole Genome Comparison of Allelic Imbalance between Noninvasive and Invasive Small-Sized Lung Adenocarcinomas

Abstract

Seventy-two small-sized (V2 cm in diameter) lung adenocarcinomas consisting of 15 noninvasive and 57 invasive tumors were subjected to whole genome allelic imbalance (AI) scanning and mutational analysis of the EGFR, KRAS, and TP53 genes to elucidate genetic pathways of early-stage lung adenocarcinomas. The chromosome 13q13 region showed the most frequent AI (58%) and was affected at similar frequencies between noninvasive and invasive tumors (53% and 60%, respectively), as EGFR and KRAS mutations were. The number of AI regions as well as the frequency of TP53 mutations in invasive tumors was significantly higher than those in noninvasive ones [9.8 F 5.6 versus 4.8 F 2.8 (P = 0.00002) and 61% versus 13% (P = 0.001), respectively]. In particular, AIs at the chromosome 11p11-p12, 17p12-p13, and 18p11 regions in invasive tumors were significantly more frequent than those in noninvasive ones (P < 0.01). The results indicated that noninvasive tumors were developed by EGFR, KRAS, and 13q alterations and progressed to invasive ones by subsequent alterations of several tumor suppressor genes, including those on 11p11-p12, 17p12-p13, and 18p11 and TP53. AI at 8p21 was significantly more frequent in advanced stages (>IA) and associated with worse prognoses (P = 0.04) and, thus, would be involved in invasion and/or metastasis of adenocarcinoma cells and useful for the prediction of prognosis of patients with small-sized lung adenocarcinoma.

MYC Amplification as a Prognostic Marker of Early-Stage Lung Adenocarcinoma Identified by Whole Genome Copy Number Analysis

“…In 92 cases of small-sized lung ADCs, cancer cells were obtained by laser capture microdissection using the PixCell Laser Capture Microdissection System (Arcturus Engineering) as previously described (17), and noncancerous lung tissues were obtained from regions greater than 5 cm from tumors with macroscopically normal morphology in the resected lobes of the lungs. Sixty-five cases were subjected to 10-K singlenucleotide polymorphism (SNP) array analysis as reported previously (12), and 60 cases were subjected to real-time genomic PCR (RT-G-PCR) analysis. Thirtythree of the 92 cases were subjected to both analyses.…”

“…Type A localized bronchioloalveolar carcinoma (LBAC), and type B LBAC with foci of alveolar structural collapse, are noninvasive tumors, while type C, LBAC with foci of active fibroblastic proliferation, and type D, poorly differentiated ADC, are invasive tumors. To efficiently detect the association of copy number alterations with prognosis, all type C cases with relapse and random type C cases without relapse were selected for this cohort; therefore, the relapse-free survival rate of type C cases selected was considerably lower than that of all type C cases, and the population of advanced stages (>IA) in type C cases was higher than that in all type C cases, as previously described (12). In 162 cases of stage I lung ADCs, the cancer cells and the corresponding noncancerous cells were macrodissected.…”

“…Because stepwise progression of lung ADC has been thought to be attributed to accumulation of multiple genetic alterations in lung epithelial cells, we have attempted to identify genetic alterations associated with prognosis of patients with small-sized lung ADC by using several molecular biologic methods (12). In this study, we attempted to identify genes commonly amplified in lung ADCs that show association with prognosis of patients because amplified genes and/or their products could be molecular targets not only for diagnosis but also for therapy of patients with lung ADC.…”

Bioinformatics Analysis Reveals Connection of Squamous Cell Carcinoma and Adenocarcinoma of the Lung

“…TP53 was identified to mutate in lung carcinoma (Le Calvez et al, 2005). Furthermore, the frequency of TP53 mutations in invasive tumors was significantly higher than those in noninvasive ones (Nakanishi et al, 2009). SP3 belongs to a family of 16 different transcription factors containing a highly conserved zinc finger DNA-binding domain (Philipsen and Suske, 1999).…”

Correlation between computed tomography findings and epidermal growth factor receptor and Kras gene mutations in patients with pulmonary adenocarcinoma

“…We found that KRas mutations occurred significantly more frequently in patients who had a tumor >31 mm in diameter than in patients who had a tumor ≤30 mm. The KRas mutation is thought to be an early event that plays a role in tumor initiation (34,35). Woo et al (36) reported that the KRas mutation and a tumor size >30 mm were independent prognostic factors in stage I lung adenocarcinoma (KRas mutation; Hr 4.51, 95% cI 1.68-12.06, p=0.003, tumor size >30 mm; Hr 4.55, 95% cI 1.61-12.82, p=0.004, respectively).…”