Jane M. McGregor

A common polymorphism acts as an intragenic modifier of mutant p53 behaviour.

The p73 protein, a homologue of the tumour-suppressor protein p53, can activate p53-responsive promoters and induce apoptosis in p53-deficient cells. Here we report that some tumour-derived p53 mutants can bind to and inactivate p73. The binding of such mutants is influenced by whether TP53 (encoding p53) codon 72, by virtue of a common polymorphism in the human population, encodes Arg or Pro. The ability of mutant p53 to bind p73, neutralize p73-induced apoptosis and transform cells in cooperation with EJ-Ras was enhanced when codon 72 encoded Arg. We found that the Arg-containing allele was preferentially mutated and retained in squamous cell tumours arising in Arg/Pro germline heterozygotes. Thus, inactivation of p53 family members may contribute to the biological properties of a subset of p53 mutants, and a polymorphic residue within p53 affects mutant behaviour.

Human papillomavirus infection and non‐melanoma skin cancer in immunosuppressed and immunocompetent individuals

The role of human papillomavirus (HPV) in anogenital carcinogenesis is established firmly, but a similar role in non‐melanoma skin cancer remains speculative. Certain immunosuppressed individuals have an increased incidence of both viral warts and non‐melanoma skin cancer, that has prompted the suggestion that HPV may play a pathogenic role. Differences in the techniques used to detect HPV DNA in skin, however, have led to discrepancies in the prevalence and spectrum of HPV types reported in these malignancies. This study describes the use of a comprehensive degenerate PCR technique to compare the HPV status of 148 Non‐melanoma skin cancers from immunosuppressed and immunocompetent individuals. HPV DNA was detected in 37/44 (84.1%) squamous cell carcinomas, 18/24 (75%) basal cell carcinomas and 15/17 (88.2%) premalignant skin lesions from the immunosuppressed group compared with 6/22 (27.2%) squamous cell carcinomas, 11/30 (36.7%) basal cell carcinomas and 6/11 (54.4%) premalignancies in the immunocompetent group. Epidermodysplasia verruciformis HPV types prevailed in all lesion types from both groups of patients. In immunosuppressed individuals, cutaneous HPV types were also identified at high frequency, and co‐detection of multiple HPV types within single tumours was commonly observed. This study represents the largest and most comprehensive analysis of the HPV status of non‐melanoma skin cancers yet undertaken; whereas there are clearly significant differences in non‐melanoma skin cancers from immunosuppressed and immunocompetent populations, we provide evidence that the prevalence and spectrum of HPV types does not differ in squamous cell carcinomas, basal cell carcinomas or premalignancies within the two populations. These data have important implications for future investigation of the role of HPV in cutaneous carcinogenesis at a functional level. J. Med. Virol. 61:289–297, 2000.

Guidelines for the management of actinic keratoses

These guidelines stemmed from a consensus meeting held by the British Photobiology Group (BPG) in 1999. Following this meeting one of the authors (J.M.M.) was invited to draw up guidelines for the management of actinic keratoses by the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee. Relevant evidence was sought using the search terms ‘solar keratosis’ and ‘actinic keratosis’ in Medline from 1966 onwards. Additional and earlier literature was reviewed on the basis of references within post‐1966 publications. All articles of apparent relevance were reviewed independently of the nature of the publication. The quality of the evidence elicited has been indicated. The National Ambulatory Medical Care Survey (U.S.A.) was used for further data on topical chemotherapy. Papers were reviewed and discussed by the contributors to the BPG Workshop (see Acknowledgments ). Recommendations are evidence based where possible. Strength of recommendation is coupled with quality of evidence. Strength of recommendation includes consideration of apparent cost‐benefit and practical considerations. Quality of evidence reflects the nature of the trial structure that provides data of efficacy.

Increased risk of skin cancer associated with the presence of epidermodysplasia verruciformis human papillomavirus types in normal skin.

Background  Human papillomaviruses (HPVs) are found in normal skin and in benign and malignant skin conditions. Epidermodysplasia verruciformis (EV) HPV types are those most plausibly linked to the development of squamous cell carcinomas of the skin.

Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy.

Background  Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowens disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments.

Azathioprine treatment photosensitizes human skin to ultraviolet A radiation

Background  Azathioprine is used to treat a variety of conditions and to prevent graft rejection in organ transplant recipients (OTRs).

Guidelines for topical PUVA: a report of a workshop of the British Photodermatology Group

Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] plays an important part in dermatological therapeutics, being an effective and generally safe treatment for psoriasis and other dermatoses. In order to maintain optimal efficacy and safety, guidelines concerning best practice should be available to operators and supervisors. The British Photodermatology Group (BPG) have previously published recommendations on PUVA, including UVA dosimetry and calibration, patient pretreatment assessment, indications and contraindications, and the management of adverse reactions .1 While most current knowledge relates to oral PUVA, the use of topical PUVA regimens is also popular and presents a number of questions peculiar to this modality, including the choice of psoralen, formulation, method of application, optimal timing of treatment, UVA regimens and relative benefits or risks as compared with oral PUVA. Bath PUVA, i.e. generalized immersion, is the most frequently used modality of topical treatment, practised by about 100 centres in the U.K., while other topical preparations tend to be used for localized diseases such as those affecting the hands and feet. This paper is the product of a recent workshop of the BPG and includes guidelines for bath, local immersion and other topical PUVA. These recommendations are based, where possible, on the results of controlled studies, or otherwise on the consensus view on current practice.

p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status

Mutations in p53 were detected in 11/23 (48%) of non melanoma skin cancers in renal allograft recipients and in 5/8 (63%) of sporadic tumours from immune competent patients. 9/12 (75%) of mutations in transplant patients and all 5 mutations in non transplant tumours were consistent with damage caused by ultraviolet (u.v.) irradiation. DNA sequences, predominantly of the epidermodysplasia verruciformis (EV) subgroup, were detected in 9/23 (39%) of transplant tumours and in 2/8 (25%) of eight non-transplant tumours. There was no relationship between HPV status and p53 mutation, HPV DNA being present in 5/16 (31%) of tumours with p53 mutation and 6/15 (40%) of tumours lacking p53 mutation. These data are consistent with an important role for sunlight in the development of post-transplant skin cancer, and with limited functional data suggesting that E6 proteins of the cutaneous and EV-related papillomaviruses do not target p53 for ubiquitin-mediated degradation.

A Surveillance Model for Skin Cancer in Organ Transplant Recipients: A 22‐Year Prospective Study in an Ethnically Diverse Population

Skin cancer is a frequent complication of organ transplantation. Current guidelines advise specialist skin surveillance but there are limited data on how these should be implemented. This study determines overall burden of cancer and relevant intervals for strategic surveillance in an ethnically diverse transplant population. Prospective data on time to first and subsequent cancers and cumulative burden with respect to defined risk factors were analyzed in a cohort of 1010 patients in a UK center over 22 years. Among 931 individuals transplanted >6 months (mean 10.3 years), 1820 skin cancers occurred in 267 (29%) individuals and were multiple in 66%. Cumulative incidence at 5, 10, 20 and 30 years was 11%, 25%, 54% and 74%, with median time to second, third and fourth cancers of 24, 14.7 and 8.4 months, respectively. Tumors were overwhelmingly squamous and basal cell carcinomas (73% and 24%, respectively). Skin phototype, ultraviolet radiation exposure, age at transplant and duration of transplant were significant risk predictors and were used to construct clinically relevant surveillance intervals. This study provides a comprehensive, prospective analysis of skin cancer morbidity and risk in an ethnically diverse transplant population from which we derive an evidence‐based skin cancer surveillance program.

Human papillomavirus and the development of non-melanoma skin cancer.

Human papillomaviruses (HPV) are increasingly recognised as important human carcinogens. The best established association with human malignancy is that of high-risk mucosal HPV types and anogenital cancer. HPV-induced transformation of anogenital epithelia has been the subject of intense research which has identified the cellular tumour suppressor gene products, p53 and pRB, as important targets for the viral oncoproteins E6 and E7 respectively. Certain HPV types are also strongly associated with the development of non-melanoma skin cancer in the inherited disorder epidermodysplasia verruciformis (EV). However, in contrast with anogenital malignancy the oncogenic mechanisms of EV-HPV types remain uncertain, and there appears to be a crucial additional requirement for ultraviolet radiation. Cutaneous HPV types in the general population are predominantly associated with benign viral warts, but a role in non-melanoma skin cancer has recently been postulated. Polymerase chain reaction based HPV detection techniques have shown a high prevalence of HPV DNA, particularly in skin cancers from immunosuppressed patients and to a lesser extent in malignancies from otherwise immunocompetent individuals. No particular HPV type has yet emerged as predominant, and the role of HPV in cutaneous malignancy is unclear at present. It remains to be established whether HPV plays an active or purely a passenger role in the evolution of non-melanoma skin cancer.