Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

Christensen, Brock C.; Houseman, E. Andrés; Poage, Graham M.; Godleski, John J.; Bueno, Raphael; Sugarbaker, David J.; Wiencke, John K.; Nelson, Heather H.; Marsit, Carmen J.; Kelsey, Karl T.

doi:10.1158/0008-5472.can-10-0190

Cited by 49 publications

(38 citation statements)

References 43 publications

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“…Three genes ( Rab31 , Rps20 and Apool ) exhibited a cohort-dependent association with overall survival that is consistent with previously reported trends [74-76]. Lastly, the gender-dependent association between Gdf10 and progression-free survival is in agreement with reports of copy number loss of Gdf10 in mesothelioma [77]. …”

Section: Discussionsupporting

confidence: 90%

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

et al. 2011

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BackgroundGlioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival.MethodsA novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers.ResultsA total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events.Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death.ConclusionsKnown biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.

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Section: Discussionsupporting

confidence: 90%

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

et al. 2011

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“…Several other studies have reported correlation between the two mechanisms in different types of cells. Strong associations have been reported in urothelial carcinoma [34], head and neck squamous cell carcinomas [35], and mesothelioma [36]. Our study provides new evidence for association between methylation and copy-number on a global scale.…”

Section: Discussionsupporting

confidence: 65%

Epigenomic Alterations in Breast Carcinoma from Primary Tumor to Locoregional Recurrences

et al. 2014

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IntroductionEpigenetic modifications such as aberrant DNA methylation has long been associated with tumorogenesis. Little is known, however, about how these modifications appear in cancer progression. Comparing the methylome of breast carcinomas and locoregional evolutions could shed light on this process.MethodsThe methylome profiles of 48 primary breast carcinomas (PT) and their matched axillary metastases (PT/AM pairs, 20 cases), local recurrences (PT/LR pairs, 17 cases) or contralateral breast carcinomas (PT/CL pairs, 11 cases) were analyzed. Univariate and multivariate analyzes were performed to determine differentially methylated probes (DMPs), and a similarity score was defined to compare methylation profiles. Correlation with copy-number based score was calculated and metastatic-free survival was compared between methods.Results49 DMPs were found for the PT/AM set, but none for the others (FDR ). Hierarchical clustering clustered 75% of the PT/AM, 47% of the PT/LR, and none of the PT/CL pairs together. A methylation-based score (MS) was defined as a clonality measure. The PT/AM set contained a high proportion of clonal pairs while PT/LR pairs were evenly split between high and low MS score, suggesting two groups: true recurrences (TR) and new primary tumors (NP). CL were classified as new tumors. MS score was significantly correlated with copy-number based scores. There was no significant difference between the metastatic-free survival of groups of patients based on different classifications.ConclusionEpigenomic alterations are well suited to study clonality and track cancer progression. Methylation-based classification of TR and NP performed as well as clinical and copy-number based methods suggesting that these phenomenons are tightly linked.

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“…Notably, it was suggested in the literature that Knudson's two-hit hypothesis is often achieved through a combination of DNA methylation and copy number alteration to the same gene [62], [63]. Due to limitation of our studies, parallel detection of both types of somatic alterations was not achieved in primary melanomas.…”

Section: Discussionmentioning

confidence: 85%

Integrative Genomics Identifies Gene Signature Associated with Melanoma Ulceration

et al. 2013

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BackgroundDespite the extensive research approaches applied to characterise malignant melanoma, no specific molecular markers are available that are clearly related to the progression of this disease. In this study, our aims were to define a gene expression signature associated with the clinical outcome of melanoma patients and to provide an integrative interpretation of the gene expression -, copy number alterations -, and promoter methylation patterns that contribute to clinically relevant molecular functional alterations.MethodsGene expression profiles were determined using the Affymetrix U133 Plus2.0 array. The NimbleGen Human CGH Whole-Genome Tiling array was used to define CNAs, and the Illumina GoldenGate Methylation platform was applied to characterise the methylation patterns of overlapping genes.ResultsWe identified two subclasses of primary melanoma: one representing patients with better prognoses and the other being characteristic of patients with unfavourable outcomes. We assigned 1,080 genes as being significantly correlated with ulceration, 987 genes were downregulated and significantly enriched in the p53, Nf-kappaB, and WNT/beta-catenin pathways. Through integrated genome analysis, we defined 150 downregulated genes whose expression correlated with copy number losses in ulcerated samples. These genes were significantly enriched on chromosome 6q and 10q, which contained a total of 36 genes. Ten of these genes were downregulated and involved in cell-cell and cell-matrix adhesion or apoptosis. The expression and methylation patterns of additional genes exhibited an inverse correlation, suggesting that transcriptional silencing of these genes is driven by epigenetic events.ConclusionUsing an integrative genomic approach, we were able to identify functionally relevant molecular hotspots characterised by copy number losses and promoter hypermethylation in distinct molecular subtypes of melanoma that contribute to specific transcriptomic silencing and might indicate a poor clinical outcome of melanoma.

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Integrated Profiling Reveals a Global Correlation between Epigenetic and Genetic Alterations in Mesothelioma

Cited by 49 publications

References 43 publications

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival

Epigenomic Alterations in Breast Carcinoma from Primary Tumor to Locoregional Recurrences

Integrative Genomics Identifies Gene Signature Associated with Melanoma Ulceration

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