Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer

Newnham, Genni M; Conron, Matthew; McLachlan, Sue‐Anne; Dobrovic, Alexander; Do, Hongdo; Li, Jason; Opeskin, Kenneth; Thompson, Natalie; Wright, Gavin; Thomas, David M.

doi:10.1186/1471-2407-11-93

Cited by 18 publications

(13 citation statements)

References 42 publications

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“…Reasons for the lower number of significant genes in the independent cohorts likely include smaller sample sizes and different microarray platforms compared with the discovery cohorts. The low number of differentially expressed genes between the mutation groups (only 21 genes consistently differentially expressed in all five discovery cohorts) is similar to results from other studies [8,12,14,16]. This low number of differentially expressed genes argues against that the mutational subgroups represent distinct transcriptional groups.…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2013

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IntroductionIn lung adenocarcinoma, the mutational spectrum is dominated by EGFR and KRAS mutations. Improved knowledge about genomic and transcriptional alterations in and between mutation-defined subgroups may identify genes involved in disease development or progression.MethodsGenomic profiles from 457 adenocarcinomas, including 113 EGFR-mutated, 134 KRAS-mutated and 210 EGFR and KRAS-wild type tumors (EGFRwt/KRASwt), and gene expression profiles from 914 adenocarcinomas, including 309 EGFR-mutated, 192 KRAS-mutated, and 413 EGFRwt/KRASwt tumors, were assembled from different repositories. Genomic and transcriptional differences between the three mutational groups were analyzed by both supervised and unsupervised methods.Results EGFR-mutated adenocarcinomas displayed a larger number of copy number alterations and recurrent amplifications, a higher fraction of total loss-of-heterozygosity, higher genomic complexity, and a more distinct expression pattern than EGFR-wild type adenocarcinomas. Several of these differences were also consistent when the three mutational groups were stratified by stage, gender and smoking status. Specific copy number alterations were associated with mutation status, predominantly including regions of gain with the highest frequency in EGFR-mutated tumors. Differential regions included both large and small regions of gain on 1p, 5q34-q35.3, 7p, 7q11.21, 12p12.1, 16p, and 21q, and losses on 6q16.3-q21, 8p, and 9p, with 20-40% frequency differences between the mutational groups. Supervised gene expression analyses identified 96 consistently differentially expressed genes between the mutational groups, and together with unsupervised analyses these analyses highlighted the difficulty in broadly resolving the three mutational groups into distinct transcriptional entities.ConclusionsWe provide a comprehensive overview of the genomic and transcriptional landscape in lung adenocarcinoma stratified by EGFR and KRAS mutations. Our analyses suggest that the overall genomic and transcriptional landscape of lung adenocarcinoma is affected, but only to a minor extent, by EGFR and KRAS mutation status.

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Section: Discussionsupporting

confidence: 86%

“…Several studies have reported KRAS mutant signatures or differentially expressed genes between adenocarcinomas with EGFR and/or KRAS mutations and respective wild type cases [8,10,12,14,16,26,33,40]. However, the overlap between these public signatures is very poor when directly compared (Figures S3B and C).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…In another study of KRAS and EGFR mutations in adenosquamous lung carcinoma, one out of three tumors had an EGFR mutation detected only in the glandular (adeno) component and not in the squamous component [16]. This is not surprising as lung adenocarcinomas and lung squamous cell carcinomas have markedly different genomic and gene expression profiles [17,18]. In accordance with Swanton's trunk and branch evolutionary model [7], the two histotypes could have diverged from their pluripotential stem cell origin by the acquisition of an EGFR mutation in one subclone (leading to invasive adenocarcinoma), but a different genomic event in the eventual squamous or pleomorphic component.…”

Section: Discussionmentioning

confidence: 99%

Mapping of actionable mutations to histological subtype domains in lung adenocarcinoma: implications for precision medicine

Wright

Weiss

et al. 2014

Oncotarget

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Precision medicine depends on the accurate identification of actionable mutations in a tumor sample. It is unknown how heterogeneous the distribution of such mutations can be in a tumor. Morphological (i.e. histopathological) heterogeneity is well described in lung adenocarcinoma and has been specifically recognized in the most recent official clinico-pathological classification. The most predominant subtype present is now used to classify each lung adenocarcinoma. No molecular profile exists to explain the intratumoral differences in lung adenocarcinoma morphology, despite the consistently observed association between specific predominant subtypes and poorer survival. Given a recent proposal stratifying lung adenocarcinoma into subtypes of differing metastatic potential, we questioned the assumption that major mutations are present uniformly throughout tumors; especially those showing discrete different subtypes.We selected formalin-fixed paraffin embedded lung adenocarcinoma specimens that showed discrete areas of different subtypes, extracted subtype DNA samples from those areas and screened for mutations in hotspot regions of the EGFR, KRAS and BRAF genes using high resolution melting. Sanger sequencing was used to confirm all identified mutations. Chromogenic in situ hybridization (CISH) was used to identify mutant allele specific imbalances in tumors with EGFR mutations.Interestingly, we found that KRAS and BRAF mutations could be confined to morphological domains of higher grade. On the other hand, EGFR mutations were found through all histological subtypes in each tumor consistent with the driver status of this mutation.Intratumoral heterogeneity has major implications for tumorigenesis, chemoresistance and the role of histopathology in molecular screening for precision medicine. This study not only confirms that intratumoral mutational heterogeneity does occur, but also that it is associated with morphologically distinct regions in some tumors. From a practical perspective, small biopsies may not adequately represent a tumor's full mutational profile, particularly for later arising but prognostically important mutations such as those in the KRAS and BRAF genes.

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“…1) and silencing of gene expression [17]. Studies have also found that SHOX2 gene hypermethylation was accompanied by other genomic rearrangements, such as increased gene copy number and amplification [14,16,49], while the amplification did not lead to an increase in SHOX2 gene expression. This observation suggests that multiple abnormalities exist in lung cancer, while the precedence relationship and causality of these abnormalities are not clear yet.…”

Section: Relationship Between Shox2 Gene Methylation and Lung Cancermentioning

confidence: 94%

Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay

Song

Yu²,

Li³

2015

Mol Diagn Ther

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Lung cancer is the most prevalent cancer in the world. Few effective and cheap methods are available so far for early detection and screening of lung cancer. Although histological and cytological examinations are gold standards in lung cancer diagnosis, patients are always at late stages when diagnosis is confirmed. Therefore, new diagnostic methods are needed urgently to increase the early diagnostic rate, enhance the confirmed diagnostic rate, and reduce mortality. The SHOX2 gene methylation assay has become a promising option for the above purposes. It has been shown to enhance the confirmed diagnostic rate of lung cancer in several clinical trials when combined with histological or cytological assays, and has the potential to become an early diagnostic tool. This article reviews the outcome of clinical trials using the SHOX2 gene methylation assay alone or in combination with other examinations, and suggests its future applications and research directions.

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Integrated mutation, copy number and expression profiling in resectable non-small cell lung cancer

Cited by 18 publications

References 42 publications

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

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

Mapping of actionable mutations to histological subtype domains in lung adenocarcinoma: implications for precision medicine

Diagnosis of Lung Cancer by SHOX2 Gene Methylation Assay

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