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Systematical identifications of prognostic meaningful lung adenocarcinoma subtypes and the underlying mutational and expressional characters.

ABSTRACT: BACKGROUND:Lung adenocarcinoma (LUAD) is one of the most common cancer types, threatening the human health around the world. However, the high heterogeneity and complexity of LUAD limit the benefits of targeted therapies. This study aimed to identify the key prognosis impacting genes and relevant subtypes for LUAD. METHODS:We recognized significant mutations and prognosis-relevant genes based on the omics data of 515 LUAD samples from The Cancer Genome Atlas. Mutation significance was estimated by MutSigCV. Prognosis analysis was based on the cox proportional hazards regression (Coxph) model. Specifically, the Coxph model was combined with a causal regulatory network to help reveal which genes play master roles among numerous prognosis impacting genes. Based on expressional profiles of the master genes, LUAD patients were clustered into different sub-types by a consensus clustering method and the importance of master genes were further evaluated by random forest. RESULTS:Significant mutations did not influence the prognosis directly. However, a collection of prognosis relevant genes were recognized, where 75 genes like GAPDH and GGA2 which are involved in mTOR signaling, lysosome or other key pathways are further identified as the master ones. Interestingly, the master gene expressions help separate LUAD patients into two sub-types displaying remarkable differences in expressional profiles, prognostic outcomes and genomic mutations in certain genes, like SMARCA4 and COL11A1. Meanwhile, the subtypes were re-discovered from two additional LUAD cohorts based on the top-10 important master genes. CONCLUSIONS:This study can promote precision treatment of LUAD by providing a comprehensive description on the key prognosis-relevant genes and an alternative way to classify LUAD subtypes.

SUBMITTER: Lv Z

PROVIDER: S-EPMC6983970 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Systematical identifications of prognostic meaningful lung adenocarcinoma subtypes and the underlying mutational and expressional characters.

Lv Zhenyang Z Lei Ting T

BMC cancer 20200127 1

<h4>Background</h4>Lung adenocarcinoma (LUAD) is one of the most common cancer types, threatening the human health around the world. However, the high heterogeneity and complexity of LUAD limit the benefits of targeted therapies. This study aimed to identify the key prognosis impacting genes and relevant subtypes for LUAD.<h4>Methods</h4>We recognized significant mutations and prognosis-relevant genes based on the omics data of 515 LUAD samples from The Cancer Genome Atlas. Mutation significance ...[more]

PMID: 31987030

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Project description:IntroductionThe purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histologic subtypes in lung adenocarcinoma (LUAD).MethodsWe identified 604 patients with stage I to III LUAD who underwent complete resection and targeted next-generation sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations among clinicopathologic factors, genomic features, mutational signatures, and recurrence were evaluated within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection.ResultsMIP/SOL tumors had higher tumor mutational burden (p < 0.001), fraction of genome altered (p = 0.001), copy number amplifications (p = 0.021), rate of whole-genome doubling (p = 0.008), and number of oncogenic pathways altered ( p < 0.001) as compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p = 0.021) and SBS13 (p = 0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p = 0.046). Among ACI/PAP tumors, alterations in the cell cycle (p < 0.001) and PI3K (p = 0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were associated with recurrence (p = 0.049).ConclusionsThese results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.

Project description:BackgroundPancreatic adenocarcinoma (PDAC) is a malignant tumor with high heterogeneity and poor prognosis. In this study, we sought to identify the value of platelet-related genes in prognosis and heterogeneity of PDAC through multiple transcriptomic methods.MethodsBased on datasets from Gene Expression Omnibus and The Cancer Genome Atlas (TCGA), platelet-related genes were screened out, and the TCGA cohort (n = 171) was identified into two subtypes by unsupervised clustering. The platelet-related risk score model (PLRScore) was constructed by univariate Cox and LASSO regression, and the predictive ability was evaluated by Kaplan-Meier test and time-dependent receiver operating characteristic (ROC) curves. The results were validated in two other external validation sets, ICGC-CA (n = 140) and GSE62452 (n = 66). Furthermore, predictive nomogram containing clinical characteristics and PLRScore was established. In addition, we determined the possible correlation between PLRScore and immune infiltration and response of immunotherapy. Finally, we analyzed the heterogeneity of our signature in various types of cells using single-cell analysis.ResultsPlatelet-related subtypes that have significant difference of overall survival and immune states (p < 0.05) were identified. PLRScore model based on four-gene signature (CEP55, LAMA3, CA12, SCN8A) was constructed to predict patient prognosis. The AUCs of training cohort were 0.697, 0.687 and 0.675 for 1-, 3-and 5-year, respectively. Further evaluation of the validation cohorts yielded similar results. In addition, PLRScore was associated with immune cell infiltration and immune checkpoint expression, and had promising ability to predict response to immunotherapy of PDAC.ConclusionsIn this study, the platelet-related subtypes were identified and the four-gene signature was constructed and validated. It may provide new insights into the therapeutic decision-making and molecular targets of PDAC.

Project description:Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Project description:BackgroundAT-rich interaction domain 1A (ARID1A) is an essential subunit of the switch/sucrose non-fermentable chromatin remodeling complex and is considered to be a tumor suppressor. The Cancer Genome Atlas (TCGA) molecular classification has deepened our understanding of gastric cancer at the molecular level. This study explored the significance of ARID1A expression in TCGA subtypes of gastric adenocarcinoma.MethodsWe collected 1248 postoperative patients with gastric adenocarcinoma, constructed tissue microarrays, performed immunohistochemistry for ARID1A, and obtained correlations between ARID1A and clinicopathological variables. We then carried out the prognostic analysis of ARID1A in TCGA subtypes. Finally, we screened patients by random sampling and propensity score matching method and performed multiplex immunofluorescence to explore the effects of ARID1A on CD4, CD8, and PD-L1 expression in TCGA subtypes.ResultsSeven variables independently associated with ARID1A were screened out: mismatch repair proteins, PD-L1, T stage, differentiation status, p53, E-cadherin, and EBER. The independent prognostic variables in the genomically stable (GS) subtype were N stage, M stage, T stage, chemotherapy, size, and ARID1A. PD-L1 expression was higher in the ARID1A negative group than in the ARID1A positive group in all TCGA subgroups. CD4 showed higher expression in the ARID1A negative group in most subtypes, while CD8 did not show the difference in most subtypes. When ARID1A was negative, PD-L1 expression was positively correlated with CD4/CD8 expression; while when ARID1A was positive, this correlation disappeared.ConclusionsThe negative expression of ARID1A occurred more frequently in the Epstein-Barr virus and microsatellite instability subtypes and was an independent adverse prognostic factor in the GS subtype. In the TCGA subtypes, ARID1A negative expression caused increased CD4 and PD-L1 expression, whereas CD8 expression appeared independent of ARID1A. The expression of CD4/CD8 induced by ARID1A negativity was accompanied by an increase in PD-L1 expression.

Dataset Information

Systematical identifications of prognostic meaningful lung adenocarcinoma subtypes and the underlying mutational and expressional characters.

Publications

Systematical identifications of prognostic meaningful lung adenocarcinoma subtypes and the underlying mutational and expressional characters.

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