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An integrated analysis of molecular aberrations in NCI-60 cell lines.

Yeang CH - BMC Bioinformatics (2010)

Bottom Line: To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions.For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3) Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4) Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes.Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan. chyeang@webmail.stat.sinica.edu.tw

ABSTRACT

Background: Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.

Results: We propose an integrated modeling framework to identify the statistical and putative causal relations of various molecular aberrations and gene expressions in cancer. To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions. Layer 1 models associate gene expressions with the molecular aberrations on the same loci. Layer 2 models associate expressions with the aberrations on different loci but have known mechanistic links. Layer 3 models associate expressions with nonlocal aberrations which have unknown mechanistic links. We applied the layered models to the integrated datasets of NCI-60 cancer cell lines and validated the results with large-scale statistical analysis. Furthermore, we discovered/reaffirmed the following prominent links: (1) Protein expressions are generally consistent with mRNA expressions. (2) Several gene expressions are modulated by composite local aberrations. For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3) Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4) Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes.

Conclusions: The analysis results on NCI-60 data justify the utility of the layered models for the incoming flow of cancer genomic data. Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.

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Two examples of cis and trans acting effects of CNVs on gene expressions. Left: Two modules are associated with putative regulators and external segment CNVs. The upper half of the heatmap shows the CNV of segment 9 (chr3p 13-14.2), the expression of MITF (chr3p 14.1) and associated genes on other chromosomes. The module is expressed in melanoma cell lines (ME). The lower half of the heatmap shows the CNV of segment 17 (chr6q 21-27), the expressions of MYB (chr6q 22) and associated genes on other chromosomes. The module is expressed in leukemia cell lines (LE). Right: mRNA expressions of the MYB module under unperturbed and radiation conditions. The upper half of the heatmap shows the CNV of segment 17, expressions of MYB and associated genes under the unperturbed condition. The lower half of the heatmap shows the expressions of MYB and associated genes under radiation.
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Figure 4: Two examples of cis and trans acting effects of CNVs on gene expressions. Left: Two modules are associated with putative regulators and external segment CNVs. The upper half of the heatmap shows the CNV of segment 9 (chr3p 13-14.2), the expression of MITF (chr3p 14.1) and associated genes on other chromosomes. The module is expressed in melanoma cell lines (ME). The lower half of the heatmap shows the CNV of segment 17 (chr6q 21-27), the expressions of MYB (chr6q 22) and associated genes on other chromosomes. The module is expressed in leukemia cell lines (LE). Right: mRNA expressions of the MYB module under unperturbed and radiation conditions. The upper half of the heatmap shows the CNV of segment 17, expressions of MYB and associated genes under the unperturbed condition. The lower half of the heatmap shows the expressions of MYB and associated genes under radiation.

Mentions: MITF encodes a transcription factor that regulates the differentiation and development of melanocytes and pigment cell-specific transcription of the melanogenesis enzyme genes [50]. It is located on segment 9 (chromosome 3p 13-14.2). Both segment 9 CNV and MITF mRNA expression undergo melanoma-specific amplification. Moreover, MITF expression is associated with the 246 melanoma-specific gene expressions. This number far exceeds the 9 MITF targets from TRANSFAC. To gather a more complete information of MITF targets we extracted 106 experimentally validated MITF targets from [51] and found they intersected with our MITF-associated genes on 41 genes (hyper-geometric p-value < 5.1 × 10-46). Indeed, the causal chain from the amplification of chromosome 3p to the disregulation of MITF and its targets in NCI-60 was previously reported [31]. The upper left panel of Figure 4 shows the CNV of segment 9 and expressions of MITF and its associated genes.


An integrated analysis of molecular aberrations in NCI-60 cell lines.

Yeang CH - BMC Bioinformatics (2010)

Two examples of cis and trans acting effects of CNVs on gene expressions. Left: Two modules are associated with putative regulators and external segment CNVs. The upper half of the heatmap shows the CNV of segment 9 (chr3p 13-14.2), the expression of MITF (chr3p 14.1) and associated genes on other chromosomes. The module is expressed in melanoma cell lines (ME). The lower half of the heatmap shows the CNV of segment 17 (chr6q 21-27), the expressions of MYB (chr6q 22) and associated genes on other chromosomes. The module is expressed in leukemia cell lines (LE). Right: mRNA expressions of the MYB module under unperturbed and radiation conditions. The upper half of the heatmap shows the CNV of segment 17, expressions of MYB and associated genes under the unperturbed condition. The lower half of the heatmap shows the expressions of MYB and associated genes under radiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984587&req=5

Figure 4: Two examples of cis and trans acting effects of CNVs on gene expressions. Left: Two modules are associated with putative regulators and external segment CNVs. The upper half of the heatmap shows the CNV of segment 9 (chr3p 13-14.2), the expression of MITF (chr3p 14.1) and associated genes on other chromosomes. The module is expressed in melanoma cell lines (ME). The lower half of the heatmap shows the CNV of segment 17 (chr6q 21-27), the expressions of MYB (chr6q 22) and associated genes on other chromosomes. The module is expressed in leukemia cell lines (LE). Right: mRNA expressions of the MYB module under unperturbed and radiation conditions. The upper half of the heatmap shows the CNV of segment 17, expressions of MYB and associated genes under the unperturbed condition. The lower half of the heatmap shows the expressions of MYB and associated genes under radiation.
Mentions: MITF encodes a transcription factor that regulates the differentiation and development of melanocytes and pigment cell-specific transcription of the melanogenesis enzyme genes [50]. It is located on segment 9 (chromosome 3p 13-14.2). Both segment 9 CNV and MITF mRNA expression undergo melanoma-specific amplification. Moreover, MITF expression is associated with the 246 melanoma-specific gene expressions. This number far exceeds the 9 MITF targets from TRANSFAC. To gather a more complete information of MITF targets we extracted 106 experimentally validated MITF targets from [51] and found they intersected with our MITF-associated genes on 41 genes (hyper-geometric p-value < 5.1 × 10-46). Indeed, the causal chain from the amplification of chromosome 3p to the disregulation of MITF and its targets in NCI-60 was previously reported [31]. The upper left panel of Figure 4 shows the CNV of segment 9 and expressions of MITF and its associated genes.

Bottom Line: To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions.For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3) Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4) Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes.Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.

View Article: PubMed Central - HTML - PubMed

Affiliation: Institute of Statistical Science, Academia Sinica, Taipei, Taiwan. chyeang@webmail.stat.sinica.edu.tw

ABSTRACT

Background: Cancer is a complex disease where various types of molecular aberrations drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.

Results: We propose an integrated modeling framework to identify the statistical and putative causal relations of various molecular aberrations and gene expressions in cancer. To reduce spurious associations among the massive number of probed features, we sequentially applied three layers of logistic regression models with increasing complexity and uncertainty regarding the possible mechanisms connecting molecular aberrations and gene expressions. Layer 1 models associate gene expressions with the molecular aberrations on the same loci. Layer 2 models associate expressions with the aberrations on different loci but have known mechanistic links. Layer 3 models associate expressions with nonlocal aberrations which have unknown mechanistic links. We applied the layered models to the integrated datasets of NCI-60 cancer cell lines and validated the results with large-scale statistical analysis. Furthermore, we discovered/reaffirmed the following prominent links: (1) Protein expressions are generally consistent with mRNA expressions. (2) Several gene expressions are modulated by composite local aberrations. For instance, CDKN2A expressions are repressed by either frame-shift mutations or DNA methylations. (3) Amplification of chromosome 6q in leukemia elevates the expression of MYB, and the downstream targets of MYB on other chromosomes are up-regulated accordingly. (4) Amplification of chromosome 3p and hypo-methylation of PAX3 together elevate MITF expression in melanoma, which up-regulates the downstream targets of MITF. (5)Mutations of TP53 are negatively associated with its direct target genes.

Conclusions: The analysis results on NCI-60 data justify the utility of the layered models for the incoming flow of cancer genomic data. Experimental validations on selected prominent links and application of the layered modeling framework to other integrated datasets will be carried out subsequently.

Show MeSH
Related in: MedlinePlus