Chromosomal aberrations in UVB-induced tumors of immunosuppressed mice

Abstract

In immunocompromised individuals, such as organ transplant recipients, the risk of cutaneous squamous cell carcinoma (SCC) is increased 60-250 fold, and there is an increased likelihood to develop aggressive, metastatic SCC. An understanding of the genes involved in SCC tumorigenesis is critical to prevent SCC-associated morbidity and mortality. Mouse models show that different immunosuppressive drugs lead to SCCs varying in size, number, and malignant potential. In this study, we used mouse models that mimic adult transplant recipients to study the effect of immunosuppressive drugs and UV light on SCC development. UV-induced tumors from six treatment groups, control, tacrolimus (Tac), rapamycin (Rap), cyclosporin (CsA), mycophenolate mofetil (MMF), and Rap plus CsA, were evaluated by array comparative genomic hybridization. Mouse SCCs appear to show similar genomic aberrations as those reported in human SCCs and offer the ability to identify genomic changes associated with specific and combinatorial effects of drugs. Fewer aberrations were seen in tumors of mice treated with MMF or Rap. Tumors from Tac-treated animals showed the highest number of changes. Calcineurin inhibitors (Tac and CsA) did not cluster together by their genomic aberrations, indicating their contribution to UV mediated carcinogenesis may be through different pathways. The combination treatment (Rap plus CsA) did not cluster with either treatment individually, suggesting it may influence SCC tumorigenesis via a different mechanism. Future studies will identify specific genes mapping to regions of aberration that are different between treatment groups to identify target pathways that may be affected by these drugs.

Figure 1

Percentage of BACs showing gains or losses in each treatment group. A. Percentage of BACs showing loss by treatment. B. Percentage of BACs showing gains by treatment. Small tumors (<2 mm) are shown in red squares; medium tumors (between >2 mm and <10 mm) are shown in blue circles; large tumors (>10 mm) are shown in green triangles; averages for each treatment are represented by the bolded line.

Figure 2

Copy number aberrations in control and MMF treated tumors. Unsupervised hierarchical cluster analysis using 2352 BACs was performed on seven PBS-treated tumors (control) and five MMF treated tumors. A representation of the cluster plot is shown. Gains are shown in red and losses in green. Both the MMF and control treated tumors show few copy number changes and are not able to be separated by unsupervised cluster analysis, suggesting that many of the changes occurring in these two groups are similar.

Figure 3

Copy number aberrations in calcineurin treated tumors. Unsupervised hierarchical cluster analysis using 130 BACs was performed on eight CsA-treated tumors and eight Tac treated tumors. Gains are shown in red and losses in green. A. The complete cluster analysis is shown with the boxed region indicating the cluster highlighted in B. B. A close up view of a portion of the cluster analysis is shown. CsA and Tac segregate on cluster analysis. CsA tumors are underlined in orange and Tac clusters are underlined in blue.

Figure 4

Copy number aberrations in CsA, Rap, and Rap plus CsA combination treated tumors. Unsupervised hierarchical cluster analysis using 61 BACs was performed on eight CsA, eight Rap, and seven Rap plus CsA combination treated tumors. Gains are shown in red and losses in green. Tumors from the Rap plus CsA combination clusters independently of tumors from CsA and Rap treated animals and show fewer genomic alterations. Using these 61 BACs, tumors from CsA and Rap treated animals cluster near each other, suggesting that they share many genomic changes. Rap plus CsA tumors are indicated by a purple line, CsA tumors by an orange line, and Rap tumors by an aqua line.