Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The p53 gene is involved in the control of cell-cycle arrest and apoptosis. The germline Arg72Pro polymorphism alters the protein's biochemical functions, and may confer individual susceptibility to skin cancer. We evaluated the association of the Arg72Pro polymorphism with skin cancer risk among Caucasians in a nested case-control study within the Nurses' Health Study (NHS) (219 melanoma, 286 squamous cell carcinoma (SCC), and 300 basal cell carcinoma (BCC) and 874 controls). Compared to the Arg/Arg genotype, the Pro/Pro genotype had an OR of 1.57 (95%CI, 0.81-3.06) for melanoma risk, and an OR of 1.79 (95%CI, 1.01-3.17) for BCC risk. The positive association of the Pro allele with BCC risk was only limited to women with two or fewer lifetime sunburns (P, trend, 0.002; P, interaction, 0.02). No association was observed between the polymorphism and SCC risk. We also observed that the Pro allele was inversely associated with the risk of childhood sunburn among Caucasian participants pooled from four nested case-control studies within the NHS. This study suggests that the Arg72Pro polymorphism may play a role in skin carcinogenesis.
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PMID:The p53 codon 72 polymorphism, sunburns, and risk of skin cancer in US Caucasian women. 1673 24

Epidemiological studies suggest that UV exposure from sunlight is the major etiology for skin cancers, both melanocytic and non-melanocytic. However, the radiation-related risk for skin cancer among atomic bomb survivors of Hiroshima and Nagasaki is primarily derived from the excess risk of basal cell carcinoma (BCC), with no demonstrable excess in squamous cell carcinoma or melanoma. The BCCs in this cohort are therefore unusual in being potentially attributable to two types of radiation-UV and ionizing (IR). BCCs have been associated with PTCH and/or p53 tumor suppressor gene alterations. To investigate the roles of these genes in relation to IR and UV exposures, we analyzed both genes in BCC samples from atomic bomb survivors. We examined 47 tumors, of which 70% had non-silent base-substitution p53 mutations independent of IR or UV exposure. However, the distribution of mutation type depends on UV and/or IR exposure. For example, C-to-T transitions at CpG sites adjacent to pyrimidine-pyrimidine (PyPy) sequences were more prevalent in tumors from UV-exposed than UV-shielded body areas and CpG-mutations at non-PyPy sequences were more prevalent in tumors from UV-shielded body areas with high-IR (>or=1 Gy) than low-IR (<0.2 Gy) exposure. And notably, although p53 deletion-frequencies demonstrated no IR-dose associations, deletions at the PTCH locus were more frequent (79% versus 44%) in tumors with high-IR than low-IR exposure. Moreover, 60% of high-IR tumors harbored both p53 and PTCH abnormalities compared with 23% of low-IR tumors. Therefore, alteration of both genes is likely to play a role in radiation-induced basal cell carcinogenesis.
Carcinogenesis 2006 Nov
PMID:Molecular basis of basal cell carcinogenesis in the atomic-bomb survivor population: p53 and PTCH gene alterations. 1677 89

Chronic arsenic poisoning is a world public health issue. Long-term exposure to inorganic arsenic (As) from drinking water has been documented to induce cancers in lung, urinary bladder, kidney, liver and skin in a dose-response relationship. Oxidative stress, chromosomal abnormality and altered growth factors are possible modes of action in arsenic carcinogenesis. Arsenic tends to accumulate in the skin. Skin hyperpigmentation and hyperkeratosis have long been known to be the hallmark signs of chronic As exposure. There are significant associations between these dermatological lesions and risk of skin cancer. The most common arsenic-induced skin cancers are Bowen's disease (carcinoma in situ), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Arsenic-induced Bowen's disease (As-BD) is able to transform into invasive BCC and SCC. Individuals with As-BD are considered for more aggressive cancer screening in the lung and urinary bladder. As-BD provides an excellent model for studying the early stages of chemical carcinogenesis in human beings. Arsenic exposure is associated with G2/M cell cycle arrest and DNA aneuploidy in both cultured keratinocytes and As-BD lesions. These cellular abnormalities relate to the p53 dysfunction induced by arsenic. The characteristic clinical figures of arsenic-induced skin cancer are: (i) occurrence on sun-protected areas of the body; (ii) multiple and recrudescent lesions. Both As and UVB are able to induce skin cancer. Arsenic treatment enhances the cytotoxicity, mutagenicity and clastogenicity of UV in mammalian cells. Both As and UVB induce apoptosis in keratinocytes by caspase-9 and caspase-8 signaling, respectively. Combined UVB and As treatments resulted in the antiproliferative and proapoptotic effects by stimulating both caspase pathways in the keratinocytes. UVB irradiation inhibited mutant p53 and ki-67 expression, as well as increased in the number of apoptotic cells in As-BD lesions which resulted in an inhibitory effect on proliferation. As-UVB interaction provides a reasonable explanation for the rare occurrences of arsenical cancer in the sun-exposed skin. The multiple and recurrent skin lesions are associated with cellular immune dysfunction in chronic arsenism. A decrease in peripheral CD4+ cells was noticed in the inhabitants of arsenic exposure areas. There was a decrease in the number of Langerhans cells in As-BD lesion which results in an impaired immune function on the lesional sites. Since CD4+ cells are the target cell affected by As, the interaction between CD4+ cells and epidermal keratinocytes under As affection might be closely linked to the pathogenesis of multiple occurrence of arsenic-induced skin cancer. In this review, we provide and discuss the pathomechanisms of arsenic skin cancer and the relationship to its characteristic figures. Such information is critical for understanding the molecular mechanism for arsenic carcinogenesis in other internal organs.
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PMID:Arsenic carcinogenesis in the skin. 1680 64

Basal cell carcinoma (BCC) is the most common human malignancy, affecting 750,000 Americans each year. The understanding of mutations that are known to activate hedgehog (Hh) signalling pathway genes, including PATCHED (PTCH), sonic hedgehog (Shh) and smoothened (Smo), has substantially expanded our current understanding of the genetic basis of BCC development. The Hh signalling pathway is one of the most fundamental signal transduction pathways in embryonic development. In skin, the Shh pathway is crucial for maintaining stem cell population, and for regulating hair follicle and sebaceous gland development. This pathway plays a minimal role in adult tissues, but is known to be activated in many neoplasms, including those arising in the skin. In this review, we attempt to summarize the results of published studies on some important aspects of the Shh pathway and its involvement in skin development and carcinogenesis. We also provide a description of various animal models that have been developed, based on our knowledge of the Shh pathway in human skin cancers. Additionally, we include a brief description of studies conducted in our laboratory and by others on the chemoprevention of BCCs. This review therefore provides a current understanding of the role of the Shh pathway in skin development and neoplasia. It also provides a basis for the molecular target-based chemoprevention and therapeutic management of skin cancer.
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PMID:Hedgehog signalling in skin development and cancer. 1688 63

Folate and vitamin D have been shown to be influenced by ultraviolet (UV) radiation. UVA radiation can break down plasma folate, whereas vitamin D can be synthesized in UVB-exposed skin. Folate metabolism is involved in DNA synthesis and repair, and vitamin D processes anti-proliferative effects. The functions of both nutrients are implicated in skin carcinogenesis. We evaluated genetic polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene (C677T and A1298C) and the vitamin D receptor (VDR) gene (Fok1, Bsm1 and Cdx2) with skin cancer risk in a nested case-control study within the Nurses' Health Study [219 melanoma, 286 squamous cell carcinoma (SCC), 300 basal cell carcinoma (BCC) and 873 controls]. No significant associations were observed for the two MTHFR polymorphisms on skin cancer risk. We observed an interaction between the C677T polymorphism and total folate intake on SCC risk (P, interaction=0.04); the highest risk was observed among women with TT genotype and low folate intake (OR=2.14; 95% CI=1.01-4.50). The VDR Bsm1 BB genotype was significantly associated with an increased SCC risk (OR=1.51; 95% CI=1.00-2.28). An interaction between the Bsm1 polymorphism and total vitamin D intake on SCC was observed, with the highest risk seen in women with the BB genotype and high vitamin D intake (OR=2.38; 95% CI=1.22-4.62) (P, interaction=0.08). This study suggests a possible role of the polymorphisms in MTHFR and VDR interacting with dietary intakes of folate and vitamin D in skin cancer development, especially for SCC. Due to a large number of comparisons and tests, the possible associations should be interpreted with caution and confirmed by other studies.
Carcinogenesis 2007 Feb
PMID:Polymorphisms in the MTHFR and VDR genes and skin cancer risk. 1695 Aug

Tumors of the nervous system most often occur in both children and adults as sporadic events with no family history of the disease, but they are also among the clinical manifestations of a significant number of familial cancer syndromes, including familial retinoblastoma, neurofibromatosis 1 and 2, tuberous sclerosis, and Cowden, Turcot, Li-Fraumeni and nevoid basal cell carcinoma (Gorlin) syndromes. All of these syndromes involve transmissible genetic risk resulting from loss of a functional allele, or inheritance of a structurally defective allele, of a specific gene. These genes include RB1, NF1, NF2, TSC1, TSC2, TP53, PTEN, APC, hMLH1, hPSM2, and PTCH, most of which function as tumor suppressor genes. The same genes are also observed in mutated and inactive forms, or are deleted, in tumor cells in sporadic cases of the same tumors. The nature of the mutational events that give rise to these inactivated alleles suggests a possible role of environmental mutagens in their causation. However, only external ionizing radiation at high doses is clearly established as an environmental cause of brain, nerve and meningeal tumors in humans. Transplacental carcinogenesis studies in rodents and other species emphasize the extraordinary susceptibility of the developing mammalian nervous system to carcinogenesis, but the inverse relationship of latency to dose suggests that low transplacental exposures to genotoxicants are more likely to result in brain tumors late in life, rather than in childhood. While not all neurogenic tumor-related genes in humans have similar effects in experimental rodents, genetically engineered mice (GEM) increasingly provide useful insights into the combined effects of multiple tumor suppressor genes and of gene-environment interactions in the genesis of brain tumors, especially pediatric brain tumors such as medulloblastoma.
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PMID:Inducible and transmissible genetic events and pediatric tumors of the nervous system. 1701 46

Immunosuppressed renal transplant recipients (RTRs) are predisposed to non-melanoma skin cancers (NMSCs), predominantly squamous cell carcinomas (SCCs). We have analyzed skin lesions from RTRs with aggressive tumors for p53 gene modifications, the presence of Human Papillomas Virus (HPV) DNA in relation to the p53 codon 72 genotype and polymorphisms of the XPD repair gene. We detected 24 p53 mutations in 15/25 (60%) NMSCs, 1 deletion and 23 base substitutions, the majority (78%) being UV-specific C to T transitions at bipyrimidine sites. Importantly, 35% (6/17) are tandem mutations, including 4 UV signature CC to TT transitions possibly linked to modulated DNA repair caused by the immunosuppressive drug cyclosporin A (CsA). We found 8 p53 mutations in 7/17 (41%) precancerous actinic keratosis (AK), suggesting that p53 mutations are early events in RTR skin carcinogenesis. Immunohistochemical analysis shows a good correlation between p53 accumulation and mutations. HPV DNA was detected in 78% of skin lesions (60% Basal Cell Carcinomas, 82%AK and 79% SCCs). Thus, immunosuppression has increased the risk of infections by HPVs, predominantly epidermodysplasia verruciformis, speculated to play a role in skin cancer development. No association is found between HPV status and p53 mutation. Moreover, p53 codon 72 or frequencies of three XPD genotypes of RTRs are comparable with control populations. The p53 mutation spectrum, presenting a high level of CC to TT mutations, shows that the UV component of sunlight is the major risk factor and modulated DNA repair by immunosuppressive drug treatment may be significant in the skin carcinogenesis of RTRs.
Carcinogenesis 2007 Mar
PMID:Analysis of skin cancer risk factors in immunosuppressed renal transplant patients shows high levels of UV-specific tandem CC to TT mutations of the p53 gene. 1706 98

Tumors arising from the skin are of multiple phenotypes, with differing degrees of malignant potential. In mouse models of skin carcinogenesis, tumors of squamous phenotype are the most common; however, human disease indicates that multiple phenotypes may arise from a common pool of stem cells that are then influenced by epigenetic factors. The use of transgenic and knockout gene technologies with mice is unraveling some of the specific genes regulating fate determination in stem cells other than squamous lineage, including basal cell carcinoma and sebaceous adenomas. The following review examines the evidence for the stem cell origin of epidermal tumors and the contribution of some specific gene families toward stem cell fate decisions during epidermal tumor progression.
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PMID:The contribution of epidermal stem cells to skin cancer. 1714 59

The class III histone deacetylase (HDAC), SIRT1, is a mammalian homologue of the Saccharomyces cerevisiae chromatin-silencing factor Sir2 that regulates longevity. SIRT1 regulates cell survival via deacetylation of p53 and forkhead transcription factors, and overexpression of SIRT1 is reported to be essential for cell growth and survival in some kinds of cancer. To elucidate the role of SIRT1 in human skin carcinogenesis, we have examined SIRT1 protein expression in 20 cases each of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Bowen's disease (BD), and actinic keratosis (AK) by immunohistochemical analysis. Overexpression of SIRT1 is frequently observed in all kinds of non-melanoma skin cancers included in this study. In particular, strong expression was observed in all cases of BD. In addition, no obvious difference between AK and SCC was observed in the expression of SIRT1, suggesting that overexpression of SIRT1 may have some relevance to the early stage of skin carcinogenesis. We suppose that SIRT1 could be one of the critical targets for future therapy with the aim of inhibiting cell proliferation and promoting apoptosis in non-melanoma skin cancers.
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PMID:Strong expression of a longevity-related protein, SIRT1, in Bowen's disease. 1718 Jun 56

Skin cancer, the most common cancer in the general population, is strongly associated with exposure to the ultraviolet component of sunlight. To investigate the relationship between DNA damage processing and skin tumour development, we determined the POLH status of a cohort of skin cancer patients. The human POLH gene encodes DNA polymerase eta (poleta), which normally carries out accurate translesion synthesis past the major UV-induced photoproduct, the dithymine cyclobutane dimer. In the absence of active poleta in xeroderma pigmentosum variant (XPV) patients, mutations accumulate at sites of UV-induced DNA damage, providing the initiating step in skin carcinogenesis. Forty patients diagnosed with skin cancer were genotyped for polymorphisms in the POLH protein-coding sequence, using glycosylase-mediated polymorphism detection (GMPD) and direct DNA sequencing of POLH PCR products derived from white blood cell genomic DNA. All individuals carried the wild-type POLH sequence. No POLH mutations were identified in genomic DNA from skin tumours derived from 15 of these patients. As determined by RT-PCR, POLH mRNA was expressed in all normal and skin tumour tissue examined. Poleta protein was also detectable by Western blotting, in two matched normal and skin tumour extracts. An alternatively spliced form of POLH mRNA, lacking exon 2, was more readily detected in skin tissue than in white blood cells from the same patient. Real-time PCR was used to quantify POLH expression in matched normal and skin tumour-derived mRNA from a series of patients diagnosed with either basal or squamous cell carcinoma. Compared to matched normal skin tissue from the same patient, 1 of 7 SCC, and 4 of 10 BCC tumours examined showed at least a 2-fold reduction in POLH expression, while 1 of 7 SCC, and 3 of 10 BCC tumours showed at least a 2-fold increase in POLH expression. Differences in gene expression, rather than sequence changes may be the main mechanism by which POLH status varies between normal and skin tumours in the population under investigation. Knowledge of the POLH status in skin tumours could contribute to an understanding of the role of this gene in the development of the most common cancer in the general population.
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PMID:The human POLH gene is not mutated, and is expressed in a cohort of patients with basal or squamous cell carcinoma of the skin. 1733 34


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