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Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility.

Quigley DA, To MD, Kim IJ, Lin KK, Albertson DG, Sjolund J, Pérez-Losada J, Balmain A - Genome Biol. (2011)

Bottom Line: The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin.However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4).We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.

ABSTRACT

Background: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown.

Results: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4).

Conclusions: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.

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Re-wiring of the Lgr5 hair follicle eQTL network. (a) Gene expression levels of Krt71, Krt25, Msx2, and Lgr5 in skin, papillomas, and carcinomas, showing that while Lgr5 is significantly correlated with Msx2 and Krt71 in normal skin, this association is lost during tumor progression. (b) A new eQTL network for hair follicle keratins in papillomas where the locus affects Gprc5d (yellow node) in cis and other genes (blue nodes) in trans. Green lines indicate significant influence of eQTL locus on all genes in the network (≤10% FDR); grey lines indicate significant gene-gene correlation.
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Figure 4: Re-wiring of the Lgr5 hair follicle eQTL network. (a) Gene expression levels of Krt71, Krt25, Msx2, and Lgr5 in skin, papillomas, and carcinomas, showing that while Lgr5 is significantly correlated with Msx2 and Krt71 in normal skin, this association is lost during tumor progression. (b) A new eQTL network for hair follicle keratins in papillomas where the locus affects Gprc5d (yellow node) in cis and other genes (blue nodes) in trans. Green lines indicate significant influence of eQTL locus on all genes in the network (≤10% FDR); grey lines indicate significant gene-gene correlation.

Mentions: We previously identified a hair follicle network in normal skin genetically linked to the G-protein coupled receptor gene Lgr5, known to mark hair follicle stem cells [8,20]. Papillomas do not produce hair follicles, although they continue to express hair follicle keratins (Figure 4a; Figure S2 in Additional file 1). Although Lgr5 is significantly expressed in papillomas and carcinomas, it is not under the control of a cis-eQTL in tumors, and also is not linked genetically to the hair follicle correlation network. A papilloma-specific eQTL network including hair follicle keratins and keratin-associated proteins was detected with a shared locus of control on distal chromosome six (Figure 4b), a locus that was not significantly associated with these genes in normal tissue. The G-protein coupled receptor family member Gprc5d was the only cis-eQTL in the new network (raw P = 5.4e-4, permutation P = 0.02, q = 0.02; linkage map plotted in Figure S3 in Additional file 1). Intriguingly, overexpression of Gprc5d promotes hair keratin gene expression, and Gprc5d is expressed in whn (hairless) nude mice [21], compatible with a role that would only be revealed when normal hair follicle control has been disrupted. These data suggest that the hair follicle stem cell network is significantly rewired during skin tumor development, but the possible role of Lgr5 as a marker of tumor initiating cells remains to be determined. We conclude that gene copy number changes, somatic mutations, and alterations in tissue composition in papillomas and carcinomas account for the loss of the Ccnd1, Hras1, and Lgr5 eQTL and likely are responsible for the loss of many other eQTL seen in normal skin.


Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility.

Quigley DA, To MD, Kim IJ, Lin KK, Albertson DG, Sjolund J, Pérez-Losada J, Balmain A - Genome Biol. (2011)

Re-wiring of the Lgr5 hair follicle eQTL network. (a) Gene expression levels of Krt71, Krt25, Msx2, and Lgr5 in skin, papillomas, and carcinomas, showing that while Lgr5 is significantly correlated with Msx2 and Krt71 in normal skin, this association is lost during tumor progression. (b) A new eQTL network for hair follicle keratins in papillomas where the locus affects Gprc5d (yellow node) in cis and other genes (blue nodes) in trans. Green lines indicate significant influence of eQTL locus on all genes in the network (≤10% FDR); grey lines indicate significant gene-gene correlation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3091303&req=5

Figure 4: Re-wiring of the Lgr5 hair follicle eQTL network. (a) Gene expression levels of Krt71, Krt25, Msx2, and Lgr5 in skin, papillomas, and carcinomas, showing that while Lgr5 is significantly correlated with Msx2 and Krt71 in normal skin, this association is lost during tumor progression. (b) A new eQTL network for hair follicle keratins in papillomas where the locus affects Gprc5d (yellow node) in cis and other genes (blue nodes) in trans. Green lines indicate significant influence of eQTL locus on all genes in the network (≤10% FDR); grey lines indicate significant gene-gene correlation.
Mentions: We previously identified a hair follicle network in normal skin genetically linked to the G-protein coupled receptor gene Lgr5, known to mark hair follicle stem cells [8,20]. Papillomas do not produce hair follicles, although they continue to express hair follicle keratins (Figure 4a; Figure S2 in Additional file 1). Although Lgr5 is significantly expressed in papillomas and carcinomas, it is not under the control of a cis-eQTL in tumors, and also is not linked genetically to the hair follicle correlation network. A papilloma-specific eQTL network including hair follicle keratins and keratin-associated proteins was detected with a shared locus of control on distal chromosome six (Figure 4b), a locus that was not significantly associated with these genes in normal tissue. The G-protein coupled receptor family member Gprc5d was the only cis-eQTL in the new network (raw P = 5.4e-4, permutation P = 0.02, q = 0.02; linkage map plotted in Figure S3 in Additional file 1). Intriguingly, overexpression of Gprc5d promotes hair keratin gene expression, and Gprc5d is expressed in whn (hairless) nude mice [21], compatible with a role that would only be revealed when normal hair follicle control has been disrupted. These data suggest that the hair follicle stem cell network is significantly rewired during skin tumor development, but the possible role of Lgr5 as a marker of tumor initiating cells remains to be determined. We conclude that gene copy number changes, somatic mutations, and alterations in tissue composition in papillomas and carcinomas account for the loss of the Ccnd1, Hras1, and Lgr5 eQTL and likely are responsible for the loss of many other eQTL seen in normal skin.

Bottom Line: The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin.However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4).We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.

View Article: PubMed Central - HTML - PubMed

Affiliation: Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.

ABSTRACT

Background: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown.

Results: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4).

Conclusions: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.

Show MeSH
Related in: MedlinePlus