Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to EGFR and KRAS Mutation Status

Planck, Maria; Edlund, Karolina; Botling, Johan; Micke, Patrick; Isaksson, Sten; Staaf, Johan

doi:10.1371/journal.pone.0078614

Cited by 25 publications

(28 citation statements)

References 56 publications

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“…Notably, the enrichment of KRASmutated adenocarcinomas in a promoter hypermethylated cluster is consistent with previous reports (4,6). This enrichment is intriguing given that KRAS-mutated adenocarcinomas have been reported to display less distinctive mRNA and CNA patterns compared with, for example, EGFR-mutated adenocarcinomas (17,35). However, KRAS mutations have not been found to be the driver of such a promoter hypermethylated epitype in either lung adenocarcinoma or colorectal cancer, suggesting a more complex underlying mechanism (6,36).…”

Section: Discussionsupporting

confidence: 89%

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Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Karlsson

Jönsson

Lauss

et al. 2014

Clinical Cancer Research

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129

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Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear.Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles.Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome.Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. Clin Cancer Res; 20(23); 6127-40. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 89%

“…For the TCGA cohort, copy number estimates and CNAs were obtained from level 3 Affymetrix SNP6 data as described (16,17). Complex arm-wise aberration index (CAAI) scores were calculated similar to Russnes and colleagues (ref.…”

Section: Copy Number Analysismentioning

confidence: 99%

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Karlsson

Jönsson

Lauss

et al. 2014

Clinical Cancer Research

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129

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“…Published genomic profiles from 1,398 adenocarcinomas with available patient smoking history were collected into a genomic discovery cohort as previously described (29,30; Table 1 and Supplementary Tables S1 and S2). Heavy smokers were defined as smokers with >60 packyears consistent with Huang and colleagues (14).…”

Section: Genomic Tumor Cohortmentioning

confidence: 99%

“…Smokingrelated CNAs were identified through a genome-wide screen of 12,698 sequential 200-Kbp segments as described (29). Multinomial logistic regression analysis, similar to Broet and colleagues (11), was used to investigate the relationship with possible confounding factors (gender, EGFR mutation, cohort, and stage) for smoking-related CNAs.…”

Section: Genomic Analysesmentioning

confidence: 99%

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Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Karlsson

Ringnér

Lauss

et al. 2014

Clinical Cancer Research

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Purpose: Cigarette smoking is the major pathogenic factor for lung cancer. The precise mechanisms of tobacco-related carcinogenesis and its effect on the genomic and transcriptional landscape in lung cancer are not fully understood.Experimental Design: A total of 1,398 (277 never-smokers and 1,121 smokers) genomic and 1,449 (370 never-smokers and 1,079 smokers) transcriptional profiles were assembled from public lung adenocarcinoma cohorts, including matched next-generation DNA-sequencing data (n ¼ 423). Unsupervised and supervised methods were used to identify smoking-related copy-number alterations (CNAs), predictors of smoking status, and molecular subgroups.Results: Genomic meta-analyses showed that never-smokers and smokers harbored a similar frequency of total CNAs, although specific regions (5q, 8q, 16p, 19p, and 22q) displayed a 20% to 30% frequency difference between the two groups. Importantly, supervised classification analyses based on CNAs or gene expression could not accurately predict smoking status (balanced accuracies 60% to 80%). However, unsupervised multicohort transcriptional profiling stratified adenocarcinomas into distinct molecular subgroups with specific patterns of CNAs, oncogenic mutations, and mutation transversion frequencies that were independent of the smoking status. One subgroup included approximately 55% to 90% of neversmokers and approximately 20% to 40% of smokers (both current and former) with molecular and clinical features of a less aggressive and smoking-unrelated disease. Given the considerable intragroup heterogeneity in smoking-defined subgroups, especially among former smokers, our results emphasize the clinical importance of accurate molecular characterization of lung adenocarcinoma.Conclusions: The landscape of smoking-related CNAs and transcriptional alterations in adenocarcinomas is complex, heterogeneous, and with moderate differences. Our results support a molecularly distinct less aggressive adenocarcinoma entity, arising in never-smokers and a subset of smokers. Clin Cancer Res; 20(18); 4912-24. Ó2014 AACR.

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Monitoring pediatric CNS non‐germinomatous germ cell tumors via cerebrospinal fluid circulating tumor DNA

Zhang,

Jin,

Zhong

et al. 2024

Pediatric Blood & Cancer

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BackgroundAccurate molecular and clinical stratification of patients with central nervous system (CNS) non‐germinomatous germ cell tumors (NGGCTs) remains challenging, impeding the development of personalized therapeutic approaches. Herein, we investigated the translational significance of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) in pediatric NGGCTs to identify characteristic features of CNS NGGCTs and to identify a subset of patients for whom the presence of residual disease is a risk factor and an indicator of shorter progression‐free survival (PFS) and overall survival (OS).MethodsMedical records of patients with CNS NGGCTs between January 1, 2018 and December 31, 2022 were reviewed retrospectively.ResultsThe cohort consisted of 11 male and six female patients. Tumor markers were elevated in four of the five people who underwent surgery. The remaining 12 patients were diagnosed with malignant NGGCTs according to elevated tumor markers. Among them, ctDNA before chemotherapy as well as ctDNA clearance were consistently associated with PFS and OS (p < .05). By setting a ctDNA positivity threshold of 6%, patients with high ctDNA (above the threshold) levels, which had limitation due to the selection based on optimal statistic from the survival analysis, had significantly inferior 5‐year PFS and OS compared to those with low levels (below the threshold). ctDNA or ctDNA clearance combined with the presence of residual disease predicted significantly worse OS and PFS (p < .05).ConclusionsCSF ctDNA might allow the study of genomic evolution and the characterization of tumors in pediatric NGGCTs. CSF ctDNA analysis may facilitate the clinical management of pediatric NGGCT patients, and aid in designing personalized therapeutic strategies.

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Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to EGFR and KRAS Mutation Status

Cited by 25 publications

References 56 publications

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome

Genomic and Transcriptional Alterations in Lung Adenocarcinoma in Relation to Smoking History

Monitoring pediatric CNS non‐germinomatous germ cell tumors via cerebrospinal fluid circulating tumor DNA

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