Clinicopathologic features of skin cancer in organ transplant recipients: A retrospective case-control series

Harwood, Catherine A.; Proby, Charlotte M.; McGregor, Jane; Sheaff, Michael; Leigh, Irene M.; Cerio, R.

doi:10.1016/j.jaad.2005.10.049

Cited by 137 publications

(126 citation statements)

References 45 publications

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“…[4][5][6][7] For tumors with a depth >6 mm, the metastatic rate rises to 16% and high-risk patients such as those on immunosuppression are at an increased risk of developing aggressive cSCC with a corresponding higher rate of metastasis. 3,7,44 For these patients in particular, a biomarker to distinguish primary tumors with an increased risk of metastasis would be a highly desirable clinical tool, enabling more efficient targeted management such as sentinel lymph node surveillance. Given that the majority of the deletions found within individual metastatic series were clonal, a cytogenetic-based approach using probes within the most frequently deleted region would detect the majority of primary cSCC with deletion.…”

Section: Discussionmentioning

confidence: 99%

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Lambert

Harwood

Purdie

et al. 2011

Intl Journal of Cancer

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Cutaneous squamous cell carcinoma (cSCC) is the second most common form of nonmelanoma skin cancer (NMSC), and its incidence is increasing rapidly. Metastatic cSCC accounts for the majority of deaths associated with NMSC, but the genetic basis for cSCC progression remains poorly understood. A previous study identified small deletions (typically <1 Mb) in the protein tyrosine phosphatase receptor Type D (PTPRD) gene that segregated with more aggressive cSCC. To investigate the apparent association between deletion within PTPRD and cSCC metastasis, a series of 74 formalin-fixed paraffin-embedded tumors from 31 patients was analyzed using a custom Illumina 384 SNP microarray. Deletions were found in 37% of patients with metastatic cSCC and were strongly associated with metastatic tumors when compared to those that had not metastasized (p 5 0.007). Subsequent mutation analysis revealed a higher mutation rate for PTPRD than has been reported in any other cancer type, with 37% of tumors harboring a somatic mutation. Conversely, bisulfite sequencing showed that methylation was not a mechanism of PTPRD disruption in cSCC. This is the first report to observe an association between deletion within PTPRD and metastatic disease and highlights the potential use of these deletions as a diagnostic biomarker for tumor progression. Combined with the high mutation rate observed in our study, PTPRD is one of the most commonly altered genes in cSCC and warrants further investigation to determine its significance for metastasis in other tumor types.Nonmelanoma skin cancer (NMSC) has a predicted prevalence equal to that of all other cancers combined and its incidence is increasing.1 There are more than 81,500 new cases of NMSC diagnosed annually in the United Kingdom alone, placing a heavy burden on both patients and healthcare resources.2 Despite accounting for only 20% of total NMSC cases, cutaneous squamous cell carcinoma (cSCC) is responsible for the majority of NMSC deaths, largely as a result of metastatic disease. A subset of immunosuppressed individuals, such as organ transplant recipients on long-term immunosuppressive drugs, develop particularly aggressive tumors with an increased risk of metastasis.3 Risk factors for metastasis include poor differentiation of the tumor cells, large tumor size, tumor depth >5 mm, immunosuppression and localization on the ear and lip. [4][5][6][7] Metastatic cSCC is currently treated by surgical intervention and/or chemotherapy or radiotherapy and is associated with a poor outcome. 8Despite the well-established role of ultraviolet radiation (UVR) in the etiology of cSCC, the molecular events underlying its development remain largely undefined. Inactivation of the tumor suppressor genes TP53 and p16INK4A is a common and early event in cSCC pathogenesis and is characteristic of all histological grades of tumor. 9,10 Recently, genotyping of 60 cSCC identified high rates of loss of heterozygosity (LOH)

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Section: Discussionmentioning

confidence: 99%

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Lambert

Harwood

Purdie

et al. 2011

Intl Journal of Cancer

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“…Ultraviolet radiation (UVR) exposure is the major risk factor for NMSe in the general population, and NMSe frequently contain UVR-type signature mutations in tumor-suppressor genes such as p53. While UVR also is likely to be critically important in the pathogenesis of transplant NMSe, other factors, including reduced immunosurveillance, specific effects of immunosuppressive drugs, and human papilloma virus (HPV) infection, also may contribute (9). The excess of skin cancer in immunosuppressed patients has been attributed to two main pathological mechanisms: firstly, a direct carcinogenic action of these agents (10), and secondly, impaired eradication of precancerous changes due to permanent immunosuppression (II).…”

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Management of Non-Melanoma Skin Cancer in Solid Organ Transplant Recipients

Specchio

Saraceno

Chimenti

et al. 2014

Int J Immunopathol Pharmacol

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Non-melanoma skin cancer (NMSC) is the most frequent cancer observed in solid organ transplant recipients (SOTR). Early diagnosis, patient education, and modification of immunosuppression are effective measures for reduction of NMSC incidence. Many risk factors have been identified, including age at transplantation, fair skin, type of immunosuppressive drugs, cumulative sun exposure, viral infections, and various genetic markers. Skin self-examination and photoprotection should be encouraged in all transplanted patients. Long-term skin surveillance, early diagnosis and aggressive treatment of any suspicious lesion, reduction of immunosuppressive therapy, and conversion to mammalian target-of-rapamycin (m-TOR) inhibitors can be also effective measures for reduction of NMSC incidence.

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“…11,12 There is increasing evidence that b-HPV types facilitate the persistence of DNA-damaged cells within the epithelium, following UVB-exposure, chiefly through interfering with DNA damage responses and inhibiting apoptotic pathways, reviewed by Akg€ ul et al…”

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confidence: 99%

“…10 Epidemiological studies also invoke a role for HPV in NMSC development in both immunocompromised organ transplant recipients and immunocompetent individuals. 11,12 There is increasing evidence that b-HPV types facilitate the persistence of DNA-damaged cells within the epithelium, following UVB-exposure, chiefly through interfering with DNA damage responses and inhibiting apoptotic pathways, reviewed by Akg€ ul et al 13 The Bak protein is a key apoptogenic factor located in the outer mitochondrial membrane.…”

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Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

Simmonds

Storey

2008

Intl Journal of Cancer

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UVB induced DNA damage is the major aetiological agent in NMSC development, but mounting evidence suggests a role for human papillomaviruses (HPV) from genus beta, including HPV 5 and HPV 8, in the development of NMSC on sun exposed body sites. We have previously shown that UVB activates Bak, an apoptogenic mitochondrial factor that, following an apoptotic stimulus, undergoes a conformational change that leads to pore formation in the mitochondrial membrane that releases apoptotic factors. The HPV E6 protein effectively inhibits UVB-induced apoptosis and targets Bak for proteolytic degradation. We have now identified the regions of the HPV5 E6 that are required to mediate Bak proteolysis and contribute toward the antiapoptotic activity of the protein. Interestingly, while wild-type HPV5 E6 does not bind or target p53 for proteolysis, we have isolated specific HPV5 E6 mutants that switch target specificity from Bak to p53 in a p53 codon 72 isoform-dependent manner. Furthermore, we demonstrate that the ability of wild-type HPV5 E6 to target Bak or specific E6 mutants to target p53 for proteolysis is not dependent on the E6-AP ubiquitin ligase. ' 2008 Wiley-Liss, Inc.Key words: skin cancer; HPV; Bak; E6; UV; light Chronic exposure to solar UV irradiation has been identified as the primary causative agent in the development of nonmelanoma skin cancer (NMSC).1 The formation of ''sunburn cells'' frequently observed in epidermis treated with UVB display apoptotic characteristic such as condensed nuclei, 2,3 and the response to UVB radiation is in part dependent upon the expression of p53. 4This p53-driven response, often termed ''cellular proofreading'', eliminates rather than repairs severely damaged cells, however p53-independent pathways have also been described. [5][6][7] However, studies indicate that Li Fraumeni patients, who have only one copy of p53, and patients with regions of mutated p53 on sunexposed sites, are not predisposed to tumour development 8,9 indicating that p53-independent mechanisms also play an important role in eliminating damaged cells.Studies on Epidermodysplasia Verruciformis (EV) patients have identified a link between extensive wart infection and the development of skin tumours on sun-exposed sites.10 Epidemiological studies also invoke a role for HPV in NMSC development in both immunocompromised organ transplant recipients and immunocompetent individuals. 11,12 There is increasing evidence that b-HPV types facilitate the persistence of DNA-damaged cells within the epithelium, following UVB-exposure, chiefly through interfering with DNA damage responses and inhibiting apoptotic pathways, reviewed by Akg€ ul et al. 13The Bak protein is a key apoptogenic factor located in the outer mitochondrial membrane.14 Following UV exposure, Bak is activated and stabilized in a p53-independent manner 7 by BH3 domain-containing proteins. 15,16 Bak activation involves a change in conformation at the N-terminus of the prote in 17 leading to Bak multimerization, [18][19][20] that is believed to form pores...

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Clinicopathologic features of skin cancer in organ transplant recipients: A retrospective case-control series

Cited by 137 publications

References 45 publications

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Metastatic cutaneous squamous cell carcinoma shows frequent deletion in the protein tyrosine phosphatase receptor Type D gene

Management of Non-Melanoma Skin Cancer in Solid Organ Transplant Recipients

Identification of the regions of the HPV 5 E6 protein involved in Bak degradation and inhibition of apoptosis

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