Genome-Wide Screening of Genomic Alterations and Their Clinicopathologic Implications in Non–Small Cell Lung Cancers

Abstract

Purpose: Although many genomic alterations have been observed in lung cancer, their clinicopathologic significance has not been thoroughly investigated. This study screened the genomic aberrations across the whole genome of non^small cell lung cancer cells with high-resolution and investigated their clinicopathologic implications. Experimental Design: One-megabase resolution array comparative genomic hybridization was applied to 29 squamous cell carcinomas and 21adenocarcinomas of the lung. Tumor and normal tissues were microdissected and the extracted DNA was used directly for hybridization without genomic amplification. The recurrent genomic alterations were analyzed for their association with the clinicopathologic features of lung cancer. Results: Overall, 36 amplicons, 3 homozygous deletions, and 17 minimally altered regions common to many lung cancers were identified. Among them, genomic changes on 13q21, 1p32, Xq, and Yp were found to be significantly associated with clinical features such as age, stage, and disease recurrence. Kaplan-Meier survival analysis revealed that genomic changes on 10p, 16q, 9p, 13q, 6p21, and 19q13 were associated with poor survival. Multivariate analysis showed that alterations on 6p21, 7p, 9q, and 9p remained as independent predictors of poor outcome. In addition, significant correlations were observed for three pairs of minimally altered regions (19q13 and 6p21, 19p13 and 19q13, and 8p12 and 8q11), which indicated their possible collaborative roles. Conclusions: These results show that our approach is robust for high-resolution mapping of genomic alterations.The novel genomic alterations identified in this study, along with their clinicopathologic implications, would be useful to elucidate the molecular mechanisms of lung cancer and to identify reliable biomarkers for clinical application.Lung cancer is the most common incident form of malignancy and is also the leading cause of cancer death worldwide (1, 2). A primary lung cancer is classified into four major histologic subtypes; squamous cell carcinomas, adenocarcinomas, large cell and small cell lung cancers. The former three classes, which are grouped as non -small cell lung cancers (NSCLC), make up almost 80% of all total lung cancer cases. Among the NSCLC, squamous cell carcinomas and adenocarcinomas are the two major subtypes. Histologically different subtypes have different clinical courses, and might require individual therapeutic approaches.Some genomic aberrations in tumors have been suggested to be prognostic markers or can be used to identify the target genes for treatment or prevention (3, 4). Likewise, in other solid tumors, chromosomal aberrations are thought to be critical molecular events in the pathogenesis of lung cancer (5, 6). However, clinically applicable screening tools or prognostic markers are still underdeveloped. Because the lack of efficient screening methods and therapy accounts for the poor outcome of lung cancer, genome-wide assessment of aberrations could help in developing more accur...

Genetic Deletions in Sputum as Diagnostic Markers for Early Detection of Stage I Non–Small Cell Lung Cancer

“…This agrees with previous reports in which SFTPC gene is located in chromosome 8p21.3, and deletion of the 8p21 occurs later in the process of lung tumorigenesis and is associated with the metastatic phenotype of the disease (24). Thus, the detection of SFTPC deletions might not be a biomarker in sputum for lung cancer diagnosis.…”

Prediction of Clinical Outcome in Multiple Lung Cancer Cohorts by Integrative Genomics: Implications for Chemotherapy Selection

“…The PIK3CA gene, located at 3q26.3 locus, has been reported to be amplified in squamous cell carcinoma (4, 28) and, as expected, was not identified as a recurrent CNA in our series. In a similar vein, we observed recurrent gains of 6p and recurrent losses of 13, both of which have been shown to occur in lung adenocarcinomas (5,26).…”

“…Regions exhibiting copy number alterations (CNA) can affect the expression of cislocalized tumor suppressor genes and oncogenes. However, only few reports have suggested a potential relationship between recurrent CNAs and NSCLC patient prognosis (4,5). In addition, the architecture of CNAs is often complex (multiple ''subalterations '') and not all genes within a CNA region will necessarily show altered gene expression (''copy number-driven'' expression; refs.…”

Genetic Variants in Cell Cycle Control Pathway Confer Susceptibility to Lung Cancer

“…STK15 is a serine/threonine protein kinase modulating G 2 -M cell cycle progression through its regulation of mitotic spindle formation and centrosome duplication (42). Dysfunction of STK15 might result in aberrant chromosome segregation, a potential early event of lung carcinogenesis (42,43). Numerous reports have shown that p53 is one of the most frequently mutated genes in smoking-associated lung cancers (44,45).…”