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Analysis of Matched Tumor and Normal Profiles Reveals Common Transcriptional and Epigenetic Signals Shared across Cancer Types.

Gross AM, Kreisberg JF, Ideker T - PLoS ONE (2015)

Bottom Line: Frequent tumor-associated alterations were identified using a simple statistical approach.Nearly all of the GABA receptors are frequently downregulated, with the gene encoding the delta subunit (GABRD) strongly upregulated as the notable exception.Metabolic genes are also frequently downregulated, particularly alcohol dehydrogenases and others consistent with the decreased role of oxidative phosphorylation in cancerous cells.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
To identify the transcriptional regulatory changes that are most widespread in solid tumors, we performed a pan-cancer analysis using over 600 pairs of tumors and adjacent normal tissues profiled in The Cancer Genome Atlas (TCGA). Frequency of upregulation was calculated across mRNA expression levels, microRNA expression levels and CpG methylation sites and is provided here as a resource. Frequent tumor-associated alterations were identified using a simple statistical approach. Many of the identified changes were consistent with the increased rate of cell division in cancer, such as the overexpression of cell cycle genes and hypermethylation of PRC2 binding sites. However, we also identified proliferation-independent alterations, which highlight novel pathways essential to tumor formation. Nearly all of the GABA receptors are frequently downregulated, with the gene encoding the delta subunit (GABRD) strongly upregulated as the notable exception. Metabolic genes are also frequently downregulated, particularly alcohol dehydrogenases and others consistent with the decreased role of oxidative phosphorylation in cancerous cells. Alterations in the composition of GABA receptors and metabolism may play a key role in the differentiation of cancer cells, independent of proliferation.

No MeSH data available.


Related in: MedlinePlus

GABRD is tumor-associated, independent of proliferation.(a) Scatter-plot comparing GABRD gene expression profiles to proliferation scores across matched tumor and normal samples. Lines indicate linear regression figs of tumor (red) and normal (blue) samples, shaded regions indicate 95% confidence intervals. (b) Comparison of matched tumor and normal profiles for GABRD expression, grouped by tissue type. (c) Comparison of matched tumor and normal profiles for all GABA protein subunits in renal cell carcinoma. Cancer acronyms are defined as follows: KIRC, kidney renal clear cell carcinoma; THCA, thyroid carcinoma; BRCA, breast invasive carcinoma; LIHC, liver hepatocellular carcinoma; KICH, kidney chromophobe; STAD, stomach adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; COAD, colon adenocarcinoma; UCEC, uterine corpus endometrioid carcinoma; LUSC, lung squamous cell carcinoma; BLCA, bladder urothelial carcinoma; HNSC, head and neck squamous cell carcinoma; PRAD, prostate adenocarcinoma; KIRP, kidney renal papillary cell carcinoma.
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pone.0142618.g003: GABRD is tumor-associated, independent of proliferation.(a) Scatter-plot comparing GABRD gene expression profiles to proliferation scores across matched tumor and normal samples. Lines indicate linear regression figs of tumor (red) and normal (blue) samples, shaded regions indicate 95% confidence intervals. (b) Comparison of matched tumor and normal profiles for GABRD expression, grouped by tissue type. (c) Comparison of matched tumor and normal profiles for all GABA protein subunits in renal cell carcinoma. Cancer acronyms are defined as follows: KIRC, kidney renal clear cell carcinoma; THCA, thyroid carcinoma; BRCA, breast invasive carcinoma; LIHC, liver hepatocellular carcinoma; KICH, kidney chromophobe; STAD, stomach adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; COAD, colon adenocarcinoma; UCEC, uterine corpus endometrioid carcinoma; LUSC, lung squamous cell carcinoma; BLCA, bladder urothelial carcinoma; HNSC, head and neck squamous cell carcinoma; PRAD, prostate adenocarcinoma; KIRP, kidney renal papillary cell carcinoma.

Mentions: The most upregulated, proliferation-independent genes in tumors were SEMA5B (detrended fup = 0.82 [0.74–0.88], S4 Fig), the GABA receptor subunit GABRD (detrended fup = 0.82 [0.64–0.80], Fig 3), and the well-studied tumor suppressor CDKN2A (detrended fup = 0.72 [0.63–0.79]). SEMA5B is a gene in the semaphorin family, whose main roles are to serve as guidance signals in various stages of development. These genes have recently been shown have a role in cancer signaling [20]. This GABAA subunit is primarily expressed in the cerebellum where its receptor is located extrasynaptically [21–22], but it is also expressed in the testes (S5 Fig) and CD4+ T-cells [22–23]. In the TCGA dataset, GABRD is overexpressed in 89% (CIBonf 81%-93%) of subjects and has a slight negative association with proliferation in tumors (Fig 3). In contrast, most other GABA subunit genes are downregulated across many cancers (Fig 3c, S6 Fig). We observed a particularly large effect in renal cell carcinoma where there is a ten-fold median decrease in GABRA2 alongside a six-fold increase in expression of GABRD (Fig 4e). Similar effects were observed in a paired microarray dataset (S7 Fig).


Analysis of Matched Tumor and Normal Profiles Reveals Common Transcriptional and Epigenetic Signals Shared across Cancer Types.

Gross AM, Kreisberg JF, Ideker T - PLoS ONE (2015)

GABRD is tumor-associated, independent of proliferation.(a) Scatter-plot comparing GABRD gene expression profiles to proliferation scores across matched tumor and normal samples. Lines indicate linear regression figs of tumor (red) and normal (blue) samples, shaded regions indicate 95% confidence intervals. (b) Comparison of matched tumor and normal profiles for GABRD expression, grouped by tissue type. (c) Comparison of matched tumor and normal profiles for all GABA protein subunits in renal cell carcinoma. Cancer acronyms are defined as follows: KIRC, kidney renal clear cell carcinoma; THCA, thyroid carcinoma; BRCA, breast invasive carcinoma; LIHC, liver hepatocellular carcinoma; KICH, kidney chromophobe; STAD, stomach adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; COAD, colon adenocarcinoma; UCEC, uterine corpus endometrioid carcinoma; LUSC, lung squamous cell carcinoma; BLCA, bladder urothelial carcinoma; HNSC, head and neck squamous cell carcinoma; PRAD, prostate adenocarcinoma; KIRP, kidney renal papillary cell carcinoma.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4640835&req=5

pone.0142618.g003: GABRD is tumor-associated, independent of proliferation.(a) Scatter-plot comparing GABRD gene expression profiles to proliferation scores across matched tumor and normal samples. Lines indicate linear regression figs of tumor (red) and normal (blue) samples, shaded regions indicate 95% confidence intervals. (b) Comparison of matched tumor and normal profiles for GABRD expression, grouped by tissue type. (c) Comparison of matched tumor and normal profiles for all GABA protein subunits in renal cell carcinoma. Cancer acronyms are defined as follows: KIRC, kidney renal clear cell carcinoma; THCA, thyroid carcinoma; BRCA, breast invasive carcinoma; LIHC, liver hepatocellular carcinoma; KICH, kidney chromophobe; STAD, stomach adenocarcinoma; READ, rectum adenocarcinoma; LUAD, lung adenocarcinoma; COAD, colon adenocarcinoma; UCEC, uterine corpus endometrioid carcinoma; LUSC, lung squamous cell carcinoma; BLCA, bladder urothelial carcinoma; HNSC, head and neck squamous cell carcinoma; PRAD, prostate adenocarcinoma; KIRP, kidney renal papillary cell carcinoma.
Mentions: The most upregulated, proliferation-independent genes in tumors were SEMA5B (detrended fup = 0.82 [0.74–0.88], S4 Fig), the GABA receptor subunit GABRD (detrended fup = 0.82 [0.64–0.80], Fig 3), and the well-studied tumor suppressor CDKN2A (detrended fup = 0.72 [0.63–0.79]). SEMA5B is a gene in the semaphorin family, whose main roles are to serve as guidance signals in various stages of development. These genes have recently been shown have a role in cancer signaling [20]. This GABAA subunit is primarily expressed in the cerebellum where its receptor is located extrasynaptically [21–22], but it is also expressed in the testes (S5 Fig) and CD4+ T-cells [22–23]. In the TCGA dataset, GABRD is overexpressed in 89% (CIBonf 81%-93%) of subjects and has a slight negative association with proliferation in tumors (Fig 3). In contrast, most other GABA subunit genes are downregulated across many cancers (Fig 3c, S6 Fig). We observed a particularly large effect in renal cell carcinoma where there is a ten-fold median decrease in GABRA2 alongside a six-fold increase in expression of GABRD (Fig 4e). Similar effects were observed in a paired microarray dataset (S7 Fig).

Bottom Line: Frequent tumor-associated alterations were identified using a simple statistical approach.Nearly all of the GABA receptors are frequently downregulated, with the gene encoding the delta subunit (GABRD) strongly upregulated as the notable exception.Metabolic genes are also frequently downregulated, particularly alcohol dehydrogenases and others consistent with the decreased role of oxidative phosphorylation in cancerous cells.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics and Systems Biology Program, University of California San Diego, La Jolla, California, United States of America.

ABSTRACT
To identify the transcriptional regulatory changes that are most widespread in solid tumors, we performed a pan-cancer analysis using over 600 pairs of tumors and adjacent normal tissues profiled in The Cancer Genome Atlas (TCGA). Frequency of upregulation was calculated across mRNA expression levels, microRNA expression levels and CpG methylation sites and is provided here as a resource. Frequent tumor-associated alterations were identified using a simple statistical approach. Many of the identified changes were consistent with the increased rate of cell division in cancer, such as the overexpression of cell cycle genes and hypermethylation of PRC2 binding sites. However, we also identified proliferation-independent alterations, which highlight novel pathways essential to tumor formation. Nearly all of the GABA receptors are frequently downregulated, with the gene encoding the delta subunit (GABRD) strongly upregulated as the notable exception. Metabolic genes are also frequently downregulated, particularly alcohol dehydrogenases and others consistent with the decreased role of oxidative phosphorylation in cancerous cells. Alterations in the composition of GABA receptors and metabolism may play a key role in the differentiation of cancer cells, independent of proliferation.

No MeSH data available.


Related in: MedlinePlus