Association of gene expression with sequential proliferation, differentiation and tumor formation in murine skin.

Differential gene expression in two established initiation and promotion skin carcinogenesis models during promo-tion and tumor formation was determined by microarray technology with the purpose of distinguishing the genes more associated with neoplastic transformation from those linked with proliferation and differentiation. The first model utilized dimethylbenz[a]anthracene initiation and 12-O-tetradecanoylphorbol 13-acetate (TPA) promotion in the FVB/N mouse, and the second TPA promotion of the Tg.Ac mouse, which is endogenously initiated by virtue of an activated Ha-ras transgene. Comparison of gene expression profiles across the two models identified genes whose altered expression was associated with papilloma formation rather than TPA-induced proliferation and differentiation. DMBA suppressed TPA-induced dif-ferentiation which allowed identification of those genes associated more specifically with differentiation rather than proliferation. EASE (Expression Analysis Systemic Explorer) indicated a correlation between muscle-associated genes and skin differentiation, whereas genes involved with protein biosynthesis were strongly correlated with proliferation. For verification the altered expression of selected genes were confirmed by RT–PCR; Carbonic anhydrase 2, Thioredoxin 1 and Glutathione S-transferase omega 1 associated with papilloma formation and Enolase 3, Cystatin b and Filaggrin associated with TPA-induced proliferation and differentiation. In situ analysis located the papillomas Glutathione S-transferase omega 1 expres-sion to the proliferating areas of the papillomas. Thus we have identified profiles of differential gene expression associated with the tumorigenesis and promotion stages for skin carcinogenesis in the mouse

Loss of the p53/p63 Regulated Desmosomal Protein Perp Promotes Tumorigenesis

Dysregulated cell–cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell–cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell–cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer

Germline Variation Controls the Architecture of Somatic Alterations in Tumors

Studies have suggested that somatic events in tumors can depend on an individual's constitutional genotype. We used squamous cell carcinomas (SCC) of the skin, which arise in high multiplicity in organ transplant recipients, as a model to compare the pattern of somatic alterations within and across individuals. Specifically, we performed array comparative genomic hybridization on 104 tumors from 25 unrelated individuals who each had three or more independently arisen SCCs and compared the profiles occurring within patients to profiles of tumors across a larger set of 135 patients. In general, chromosomal aberrations in SCCs were more similar within than across individuals (two-sided exact-test p-value ), consistent with the notion that the genetic background was affecting the pattern of somatic changes. To further test this possibility, we performed allele-specific imbalance studies using microsatellite markers mapping to 14 frequently aberrant regions of multiple independent tumors from 65 patients. We identified nine loci which show evidence of preferential allelic imbalance. One of these loci, 8q24, corresponded to a region in which multiple single nucleotide polymorphisms have been associated with increased cancer risk in genome-wide association studies (GWAS). We tested three implicated variants and identified one, rs13281615, with evidence of allele-specific imbalance (p-value = 0.012). The finding of an independently identified cancer susceptibility allele with allele-specific imbalance in a genomic region affected by recurrent DNA copy number changes suggest that it may also harbor risk alleles for SCC. Together these data provide strong evidence that the genetic background is a key driver of somatic events in cancer, opening an opportunity to expand this approach to identify cancer risk alleles

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications

Loss of the p53/p63 regulated desmosomal protein Perp promotes tumorigenesis.

Dysregulated cell-cell adhesion plays a critical role in epithelial cancer development. Studies of human and mouse cancers have indicated that loss of adhesion complexes known as adherens junctions contributes to tumor progression and metastasis. In contrast, little is known regarding the role of the related cell-cell adhesion junction, the desmosome, during cancer development. Studies analyzing expression of desmosome components during human cancer progression have yielded conflicting results, and therefore genetic studies using knockout mice to examine the functional consequence of desmosome inactivation for tumorigenesis are essential for elucidating the role of desmosomes in cancer development. Here, we investigate the consequences of desmosome loss for carcinogenesis by analyzing conditional knockout mice lacking Perp, a p53/p63 regulated gene that encodes an important component of desmosomes. Analysis of Perp-deficient mice in a UVB-induced squamous cell skin carcinoma model reveals that Perp ablation promotes both tumor initiation and progression. Tumor development is associated with inactivation of both of Perp's known functions, in apoptosis and cell-cell adhesion. Interestingly, Perp-deficient tumors exhibit widespread downregulation of desmosomal constituents while adherens junctions remain intact, suggesting that desmosome loss is a specific event important for tumorigenesis rather than a reflection of a general change in differentiation status. Similarly, human squamous cell carcinomas display loss of PERP expression with retention of adherens junctions components, indicating that this is a relevant stage of human cancer development. Using gene expression profiling, we show further that Perp loss induces a set of inflammation-related genes that could stimulate tumorigenesis. Together, these studies suggest that Perp-deficiency promotes cancer by enhancing cell survival, desmosome loss, and inflammation, and they highlight a fundamental role for Perp and desmosomes in tumor suppression. An understanding of the factors affecting cancer progression is important for ultimately improving the diagnosis, prognostication, and treatment of cancer

Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-beta1 (TGF-beta1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. This study investigates whether TGF-beta signaling is elevated in transplant patients.Journal ArticleResearch Support, N.I.H. Extramuralinfo:eu-repo/semantics/publishe