Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features

Abstract

Bronchioloalveolar carcinoma (BAC), a subtype of lung adenocarcinoma (ADC) without stromal, vascular, or pleural invasion, is considered an in situ tumor with a 100% survival rate. However, the histological criteria for invasion remain controversial. BAC-like areas may accompany otherwise invasive adenocarcinoma, referred to as mixed type adenocarcinoma with BAC features (AWBF). AWBF are considered to evolve from BAC, representing a paradigm for malignant progression in ADC. However, the supporting molecular evidence remains forthcoming. Here, we have studied the genomic changes of BAC and AWBF by array comparative genomic hybridization (CGH). We used submegabaseresolution tiling set array CGH to compare the genomic profiles of 14 BAC or BAC with focal area suspicious for invasion with those of 15 AWBF. Threshold-filtering and frequency-scoring analysis found that genomic profiles of noninvasive and focally invasive BAC are indistinguishable and show fewer aberrations than tumor cells in BAC-like areas of AWBF. These aberrations occurred mainly at the subtelomeric chromosomal regions. Increased genomic alterations were noted between BAC-like and invasive areas of AWBF. We identified 113 genes that best differentiated BAC from AWBF and were considered candidate marker genes for tumor invasion and progression. Correlative gene expression analyses demonstrated a high percentage of them to be poor prognosis markers in early stage ADC. Quantitative PCR also validated the amplification and overexpression of PDCD6 and TERT on chromosome 5p and the prognostic significance of PDCD6 in early stage ADC patients. We identified candidate genes that may be responsible for and are potential markers for malignant progression in AWBF.array comparative genomic hybridization ͉ bronchioloalveolar carcinoma ͉ microarray ͉ non-small-cell lung carcinoma ͉ prognostic markers

Upregulation of Notch2 and Six1 Is Associated with Progression of Early-Stage Lung Adenocarcinoma and a More Aggressive Phenotype at Advanced Stages

“…Aviel-Ronen and colleagues (2008) examined genomic changes associated with adenocarcinoma in situ and minimally invasive adenocarcinoma using array comparative genomic hybridization and found that genomic profiles are indistinguishable between adenocarcinoma in situ and minimally invasive adenocarcinoma, although they developed in distinct individuals (5). In contrast, this study successfully revealed that gene expression profiles substantially differed between lepidic growth and microinvasion cancer cells in a single minimally invasive adenocarcinoma.…”

“…The concept of progression from adenocarcinoma in situ to minimally invasive adenocarcinoma is widely accepted (4)(5)(6)(7)(8)(9). Noguchi and colleagues noted 2 types of small (maximum diameter, < 2 cm) adenocarcinomas.…”

Structure and function of ALG-2, a penta-EF-hand calcium-dependent adaptor protein

“…However, a cause-effect relationship is not clear. The gene of ALG-2 (PDCD6, chromosomal locus at 5p15.33) is a potential prognostic marker for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features, and patients with high expression levels of PDCD6 have low survival rates [70]. By contrast, low expression level of PDCD6 is correlated with poor overall survival of gastric cancer patients [71].…”

Variations in the PDCD6 Gene Are Associated with Increased Uterine Leiomyoma Risk in the Chinese

“…The role of PDCD6 in cancer development has been explored gradually, but the potential mechanism is still unknown. Previous studies found that PDCD6 is overexpressed in a variety of human tumors (la Cour et al, 2003;Mollerup et al, 2003;Aviel-Ronen et al, 2008;la Cour et al, 2008). However, Mel290 cells derived from a human tumor were found to express lower levels of PDCD6 mRNA and protein than normal melanocytes (Yamada et al, 2008).…”

“…Previous research showed that PDCD6-deficient mice develop normally without obvious abnormalities in the immune system ( Jang et al, 2002). Nonetheless, potential physiological roles of PDCD6 in the regulation of ER stress-induced apoptosis (Rao et al, 2004), neuronal cell death during development (Mahul-Mellier et al, 2006), and cancers (la Cour et al, 2003;Mollerup et al, 2003;Subramanian and Polans, 2004;Aviel-Ronen et al, 2008;la Cour et al, 2008;Yamada et al, 2008;Hoj et al, 2009) have been reported.…”