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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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Granzyme E alleles are associated with su sceptibility. (a) Log2 expression of Gzme in skin, papillomas, and carcinomas. Gzme mRNA is not detected in normal skin, and its level of expression is highest in papillomas from mice that are relatively resistant to papilloma development. Papillomas from resistant animals are plotted as blue circles, susceptible animals as red circles. (b) Expression of Gzme in papillomas and carcinomas is under germline genetic control. LOD plot for Gzme carcinoma eQTL significance on chromosome 14.
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Figure 5: Granzyme E alleles are associated with su sceptibility. (a) Log2 expression of Gzme in skin, papillomas, and carcinomas. Gzme mRNA is not detected in normal skin, and its level of expression is highest in papillomas from mice that are relatively resistant to papilloma development. Papillomas from resistant animals are plotted as blue circles, susceptible animals as red circles. (b) Expression of Gzme in papillomas and carcinomas is under germline genetic control. LOD plot for Gzme carcinoma eQTL significance on chromosome 14.

Mentions: Twenty-nine genes met these criteria (listed in Table 1). Of these genes, the serine protease Granzyme E (Gzme) showed the largest induction in papillomas from resistant mice. Gzme is expressed in granules released by cytotoxic T lymphocytes and together with perforin can destroy pathogen-infected or transformed cells [22,23]. Gzme was expressed at background levels in normal FVBBX skin, but at a range of detectable levels in papillomas and carcinomas (Figure 5a). The tumor-specific cis-eQTL for Gzme peaked at chromosome 14, 51 Mb in papillomas and carcinomas (raw P = 6.6e-7, permutation P < 0.001, q < 0.001; Figure 5b). Mice heterozygous at the eQTL locus (that is, with Gzme alleles inherited from both FVB/N and SPRET/Ei) had higher expression of Gzme in papillomas and carcinomas than mice homozygous for FVB/N at this allele. Although (as previously reported [8]) classical QTL analysis of papilloma counts for these FVBBX mice did not identify a locus significant after multiple test correction, the strongest linkage was to markers on chromosome 14, peaking at 62 Mb (linkage map plotted in Figure S4 in Additional file 1). The SPRET/Ei allele was protective at this locus, in agreement with the direction of the Gzme eQTL and susceptibility results. We conclude that Gzme is a strong candidate modifier of papilloma susceptibility based on genetic control of gene expression in tumor tissue, higher levels of expression in papillomas from resistant mice carrying the SPRET/Ei allele, and the documented biological activity of granzymes in killing of potential tumor cells.


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)

Granzyme E alleles are associated with su sceptibility. (a) Log2 expression of Gzme in skin, papillomas, and carcinomas. Gzme mRNA is not detected in normal skin, and its level of expression is highest in papillomas from mice that are relatively resistant to papilloma development. Papillomas from resistant animals are plotted as blue circles, susceptible animals as red circles. (b) Expression of Gzme in papillomas and carcinomas is under germline genetic control. LOD plot for Gzme carcinoma eQTL significance on chromosome 14.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Granzyme E alleles are associated with su sceptibility. (a) Log2 expression of Gzme in skin, papillomas, and carcinomas. Gzme mRNA is not detected in normal skin, and its level of expression is highest in papillomas from mice that are relatively resistant to papilloma development. Papillomas from resistant animals are plotted as blue circles, susceptible animals as red circles. (b) Expression of Gzme in papillomas and carcinomas is under germline genetic control. LOD plot for Gzme carcinoma eQTL significance on chromosome 14.
Mentions: Twenty-nine genes met these criteria (listed in Table 1). Of these genes, the serine protease Granzyme E (Gzme) showed the largest induction in papillomas from resistant mice. Gzme is expressed in granules released by cytotoxic T lymphocytes and together with perforin can destroy pathogen-infected or transformed cells [22,23]. Gzme was expressed at background levels in normal FVBBX skin, but at a range of detectable levels in papillomas and carcinomas (Figure 5a). The tumor-specific cis-eQTL for Gzme peaked at chromosome 14, 51 Mb in papillomas and carcinomas (raw P = 6.6e-7, permutation P < 0.001, q < 0.001; Figure 5b). Mice heterozygous at the eQTL locus (that is, with Gzme alleles inherited from both FVB/N and SPRET/Ei) had higher expression of Gzme in papillomas and carcinomas than mice homozygous for FVB/N at this allele. Although (as previously reported [8]) classical QTL analysis of papilloma counts for these FVBBX mice did not identify a locus significant after multiple test correction, the strongest linkage was to markers on chromosome 14, peaking at 62 Mb (linkage map plotted in Figure S4 in Additional file 1). The SPRET/Ei allele was protective at this locus, in agreement with the direction of the Gzme eQTL and susceptibility results. We conclude that Gzme is a strong candidate modifier of papilloma susceptibility based on genetic control of gene expression in tumor tissue, higher levels of expression in papillomas from resistant mice carrying the SPRET/Ei allele, and the documented biological activity of granzymes in killing of potential tumor cells.

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