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PTCH1 +/- dermal fibroblasts isolated from healthy skin of Gorlin syndrome patients exhibit features of carcinoma associated fibroblasts.

Valin A, Barnay-Verdier S, Robert T, Ripoche H, Brellier F, Chevallier-Lagente O, Avril MF, Magnaldo T - PLoS ONE (2009)

Bottom Line: Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome.They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts.These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

View Article: PubMed Central - PubMed

Affiliation: CNRS FRE2939, Université Paris Sud-Institut Gustave Roussy, Villejuif, France.

ABSTRACT
Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

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Comparison plot of the missense and the nonsense signatures revealed by the microarray analysis.All the genes with statistically (p<10−5) different mRNA level between any NBCCS pool and the control pool are plotted. In abscissa: the logarithm of the ratio of the intensities in the missense and the control pools. In ordinate: the logarithm of the ratio of the intensities in the nonsense and the control pools. Note the correlation between the missense (MS) signature and the nonsense (NS) signature revealed by the linear shape of the common signature (correlation coefficient of 0.929).
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pone-0004818-g001: Comparison plot of the missense and the nonsense signatures revealed by the microarray analysis.All the genes with statistically (p<10−5) different mRNA level between any NBCCS pool and the control pool are plotted. In abscissa: the logarithm of the ratio of the intensities in the missense and the control pools. In ordinate: the logarithm of the ratio of the intensities in the nonsense and the control pools. Note the correlation between the missense (MS) signature and the nonsense (NS) signature revealed by the linear shape of the common signature (correlation coefficient of 0.929).

Mentions: Results of this genomic screen are available in the database ArrayExpress (accession number: E-TABM-549). To select the genes with a high probability to be differentially expressed in the NBCCS pools, the threshold for the p-value was set to 10−5. 182 genes were found up-regulated and 126 down-regulated (p-value<10−5) in both the missense and the nonsense pools (Table S1). These 308 genes of the common signature displayed a high correlation between the two NBCCS pools (correlation coefficient of 0.929) (Figure 1). Only 6 probes corresponding to 5 genes were anti-correlated, i.e. up-regulated in one NBCCS pool and down-regulated in the other one (CILP, LY6K, CLEC3B, CYP1B1 and LEPROT; Table S2). For all the primary sequences, an analysis of variance (ANOVA) of the logarithm of the ratio of the intensities in each NBCCS pool to the WT pool was performed. Cluster analysis was done on the ANOVA results. 38 genes, including the 5 anti-correlated genes, with different levels of expression in the two NBCCS pools are listed and clustered in Figure S1 and Table S3. These data indicate for the first time that missense or nonsense mutations of PTCH1 have overall very similar consequences on the transcriptome of dermal fibroblasts.


PTCH1 +/- dermal fibroblasts isolated from healthy skin of Gorlin syndrome patients exhibit features of carcinoma associated fibroblasts.

Valin A, Barnay-Verdier S, Robert T, Ripoche H, Brellier F, Chevallier-Lagente O, Avril MF, Magnaldo T - PLoS ONE (2009)

Comparison plot of the missense and the nonsense signatures revealed by the microarray analysis.All the genes with statistically (p<10−5) different mRNA level between any NBCCS pool and the control pool are plotted. In abscissa: the logarithm of the ratio of the intensities in the missense and the control pools. In ordinate: the logarithm of the ratio of the intensities in the nonsense and the control pools. Note the correlation between the missense (MS) signature and the nonsense (NS) signature revealed by the linear shape of the common signature (correlation coefficient of 0.929).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654107&req=5

pone-0004818-g001: Comparison plot of the missense and the nonsense signatures revealed by the microarray analysis.All the genes with statistically (p<10−5) different mRNA level between any NBCCS pool and the control pool are plotted. In abscissa: the logarithm of the ratio of the intensities in the missense and the control pools. In ordinate: the logarithm of the ratio of the intensities in the nonsense and the control pools. Note the correlation between the missense (MS) signature and the nonsense (NS) signature revealed by the linear shape of the common signature (correlation coefficient of 0.929).
Mentions: Results of this genomic screen are available in the database ArrayExpress (accession number: E-TABM-549). To select the genes with a high probability to be differentially expressed in the NBCCS pools, the threshold for the p-value was set to 10−5. 182 genes were found up-regulated and 126 down-regulated (p-value<10−5) in both the missense and the nonsense pools (Table S1). These 308 genes of the common signature displayed a high correlation between the two NBCCS pools (correlation coefficient of 0.929) (Figure 1). Only 6 probes corresponding to 5 genes were anti-correlated, i.e. up-regulated in one NBCCS pool and down-regulated in the other one (CILP, LY6K, CLEC3B, CYP1B1 and LEPROT; Table S2). For all the primary sequences, an analysis of variance (ANOVA) of the logarithm of the ratio of the intensities in each NBCCS pool to the WT pool was performed. Cluster analysis was done on the ANOVA results. 38 genes, including the 5 anti-correlated genes, with different levels of expression in the two NBCCS pools are listed and clustered in Figure S1 and Table S3. These data indicate for the first time that missense or nonsense mutations of PTCH1 have overall very similar consequences on the transcriptome of dermal fibroblasts.

Bottom Line: Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome.They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts.These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

View Article: PubMed Central - PubMed

Affiliation: CNRS FRE2939, Université Paris Sud-Institut Gustave Roussy, Villejuif, France.

ABSTRACT
Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1(+/-) genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients.

Show MeSH
Related in: MedlinePlus