Dataset Information

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

ABSTRACT:

Background

Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.

Methods and findings

We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 [8.9%] samples) and ZKSCAN1 (mutated in 6 [5.9%] samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10-50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10-4) were associated with increased risk of distant metastasis. Our study's limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.

Conclusions

These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD's high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.

SUBMITTER: Shi J

PROVIDER: S-EPMC5140047 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

Shi Jianxin J Hua Xing X Zhu Bin B Ravichandran Sarangan S Wang Mingyi M Nguyen Cu C Brodie Seth A SA Palleschi Alessandro A Alloisio Marco M Alloisio Marco M Pariscenti Gianluca G Jones Kristine K Zhou Weiyin W Bouk Aaron J AJ Boland Joseph J Hicks Belynda B Risch Adam A Bennett Hunter H Luke Brian T BT Song Lei L Duan Jubao J Liu Pengyuan P Kohno Takashi T Chen Qingrong Q Meerzaman Daoud D Marconett Crystal C Laird-Offringa Ite I Mills Ian I Caporaso Neil E NE Gail Mitchell H MH Pesatori Angela C AC Consonni Dario D Bertazzi Pier Alberto PA Chanock Stephen J SJ Landi Maria Teresa MT

PLoS medicine 20161206 12

<h4>Background</h4>Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of LUAD and identify mutation signatures associated with tumor progression.<h4>Methods and findings</h4>We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUA ...[more]

PMID: 27923066

Similar Datasets

Project description:Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-associated mortality. Lung adenocarcinoma (LAC) is the most prevalent pathological subtype of NSCLC and accounts for ~40% of all lung cancer mortalities. There remains an urgent demand for the identification of novel biomarkers for the diagnosis and development of therapeutic strategies for LAC. In the present study, the profiles of the differentially-expressed circular RNAs (circRNAs) in LAC tissues compared with those in their corresponding non-cancerous tissues were obtained after analyzing the circRNA microarray dataset GSE101586. The expression pattern of the indicated circRNAs in the LAC tissues were subsequently verified using reverse transcription-quantitative PCR (RT-qPCR). The potential prognostic significance of these circRNAs in patients with LAC were then analyzed in a retrospective clinical study. A circRNA-microRNA (miR or miRNA)-mRNA regulatory network in LAC was established by using Cytoscape. In addition, a protein-protein interaction (PPI) network was plotted using the Search Tool for the Retrieval of Interacting Genes/Proteins and visualized through Cytoscape. The prognostic value of the hub genes found was then analyzed based on the Gene Expression Profiling Interactive Analysis database. In total, four differentially-expressed circRNAs were obtained from the GSE101586 microarray dataset, three of which (hsa_circ_0006220, hsa_circ_0072088 and hsa_circ_0001666) were confirmed by RT-qPCR to be highly expressed in LAC tissues. This retrospective clinical study revealed that higher expression levels of these three circRNAs were associated with poorer prognoses in patients with LAC. In addition, siRNA-mediated knockdown of these circRNAs was found to inhibit cell proliferation, migration and invasion in LAC cells. Following analysis of the molecular mechanism underlying these circRNAs, eight miRNAs, namely miR-520f, miR-1261, miR-1270, miR-620, miR-188-3p, miR-516b, miR-940 and miR-661, were identified with potential binding sites for these three circRNAs. Subsequently, 232 overlapped genes from the 795 upregulated genes in the LAC samples from The Cancer Genome Atlas database and 7,829 predicted target genes of the list of eight aforementioned miRNAs were obtained. A circRNA-miRNA-mRNA network was then constructed. A PPI network was established, with six hub genes, namely kinesin family member (KIF) 2C, KIF18B, maternal embryonic leucine zipper kinase, baculoviral IAP repeat-containing 5, polo-like kinase 1 and cytoskeleton-associated protein 2-like, determined from this network. Higher expression levels of each of these hub genes were found to be associated with poorer prognoses of patients with LAC. To conclude, data from the present study suggested that circRNAs hsa_circ_0006220, hsa_circ_0072088 and hsa_circ_0001666 have the potential to be viable biomarkers and therapeutic targets for LAC.

Project description:BACKGROUND: The sensitivity of Papanicolaou smears for detecting endocervical adenocarcinoma in situ (AIS) is very low. A comprehensive cytological analysis of endocervical AIS is necessary to increase diagnostic accuracy. METHODS: The subjects were 74 patients with pathologically-diagnosed AIS. A total of 140 Papanicolaou smears were reviewed to calculate the sensitivity of the Papanicolaou smears for detecting AIS and the incidence of sampling/screening/diagnostic errors. The cytological review was performed by 6 cytotechnologists, and the final cytological diagnosis was obtained at the consensus meeting. We classified the cases into three differentiation types; typical type (well-differentiated AIS), polymorphic type (poorly differentiated AIS), and mixed typical and polymorphic type. Three cytological subtypes (endocervical, endometrioid and intestinal subtypes) of AIS were also analyzed. RESULTS: The sensitivity of the original Papanicolaou smears for the detection of AIS was 44.6%, while that for the detection of AIS and adenocarcinoma was 63.5%. The diagnostic accuracy of AIS increased to 78.5% in the final diagnosis. The common characteristic features were microbiopsies/hyperchromatic crowded groups (HCG) (82.0%) and mitotic figures (72.2%). The appearance of single cells (2.8%) was rare, and all the cervical cytology smears showed no evidence of necrotic tumor diathesis. The most common AIS was the typical type (41 cases, 67.2%) among all cytologically-diagnosed AIS or adenocarcinoma cases (61 cases). Although mixed typical and polymorphic AIS existed in 17 cases (27.9%), pure polymorphic AIS was very rare (3 cases, 4.9%). The endocervical subtype was the most predominant subtype (67.2%), followed by a few mixed subtypes. The important diagnostic keys for AIS cytology are as follows: (1) The appearance of microbiopsies/HCG (single-cell pattern is rare), (2) mitotic figures in the microbiopsies/HCG, (3) a lack of necrotic tumor diathesis in cases with polymorphic AIS, and (4) recognition of typical cytological subtypes. CONCLUSIONS: The relatively low diagnostic accuracy AIS was caused by the underestimation of microbiopsies/HCG and the overestimation of polymorphic components. The typical cytological features of AIS are the presence of microbiopsies/HCG with mitotic figures in the absence of necrotic tumor diathesis in specimens containing endocervical samples. The recognition of infrequent AIS subtypes (endometrioid and intestinal subtypes) is also important.

Dataset Information

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

Background

Methods and findings

Conclusions

Publications

Somatic Genomics and Clinical Features of Lung Adenocarcinoma: A Retrospective Study.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets