Human papillomavirus DNA in cutaneous primary and metastasized squamous cell carcinomas from patients with epidermodysplasia verruciformis.

Ostrow, Ronald S.; Bender, Mitchell E.; Niimura, Michihito; Seki, Toshihito; Kawashima, Makoto; Pass, Franklin; Faras, Anthony J.

doi:10.1073/pnas.79.5.1634

Cited by 178 publications

(98 citation statements)

References 20 publications

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“…Ostrow et al reported the presence of HPV Type 5 in both a primary CSCC and its metastasis in 2 epidermodysplasia-verruciformis patients. 21 Nindl et al reported the presence of cutaneous HPV DNA in a primary CSCC and its metastasis in an immunocompetent and immunocompromised patient. 20 In our study however, we could not detect any persistent HPV infection.…”

Section: Discussionmentioning

confidence: 99%

“…The PM-PCR RHA method has previously been described in detail. 24,26 The method was designed for the identification of 25 established beta-PV types, namely genotypes 5,8,9,12,14,15,17,19,20,21,22,23,24,25,36,37,38,47,49,75,76,80,92,93 and 96.…”

Section: Dna Isolation and Pcr Reactions For Mutation Analysesmentioning

confidence: 99%

“…[17][18][19] Up to now, only few studies included HPV testing in skin tumors and their metastasis. 20,21 Comparison of the prevalence of HPV in both metastasis and primary tumor might lead to the detection of HPV types that are persistently present, possibly indicating a more oncogenic role for these HPV types.…”

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confidence: 99%

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CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Küsters‐Vandevelde

Leeuwen

Verdijk

et al. 2009

Intl Journal of Cancer

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Genetic alterations in metastatic cutaneous squamous cell carcinoma (CSCC) which might serve as prognostic biomarkers are not well investigated. We investigated the mutation status and protein expression of the CDKN2A (INK4a-ARF) and TP53 genes in metastatic CSCCs and correlated this with clinicopathological variables, HPV presence, and survival data. Sequence analysis was performed on formalin-fixed and paraffin-embedded tissue of 35 metastases and their primary tumors, and was correlated with immunohistochemical stainings for p53, p16 and p14. Beta-PV and alpha-PV DNA was detected using PCRbased assays. Kaplan-Meier and Cox regression methods were used for survival assessment. CDKN2A was mutated in 31% of the metastases and their primary tumors, while the TP53 gene was mutated in 51% of the metastases. P53 protein expression was significantly associated with missense type of mutations (p 5 0.002). No persistent HPV types were detected. CDKN2A mutations were significantly associated with disease-specific death (p 5 0.001). A significant difference was observed in disease-specific survival between patients with or without a CDKN2A mutation (p 5 0.010), while this was not the case for TP53. At univariate Cox's regression analysis tumor size (p 5 0.010), invasion depth (p 5 0.030) and CDKN2A mutations (p 5 0.040) were significantly related to shorter disease-specific survival. At multivariate Cox's regression only tumor size had an adverse effect on survival (p 5 0.002). In conclusion, our study indicates that the CDKN2A mutation status might be of prognostic value in metastatic CSCCs. In most cases, CDKN2A and TP53 mutations are early genetic events in CSCC tumorigenesis. The possible role of HPV in metastatic CSCC needs further exploration.Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy in Caucasians, after basal cell carcinoma, and its incidence is still rising. 1 Generally the risk of metastasis is reported up to 5%, while immunocompromised patients have a larger tendency to metastasize (5-10%). 1,2 The outcome of these patients once metastasized is poor, with a 5-year survival rate between 25 and 50%. 3,4 Genetic alterations in CSCCs which might serve as prognostic biomarkers are not well investigated.TP53 mutations are the most frequent genetic alterations in CSCC with incidences of up to 50%. 5,6 TP53 mutations are early events in skin carcinogenesis, with a similar mutation frequency of 50% in actinic keratosis, a precancerous skin lesion that potentially can progress to CSCC. 7 Mutations in the CDKN2A (INK4a-ARF) locus are reported in CSCC with frequencies ranging up to 24% in sporadic CSCC. [8][9][10] This gene maps to chromosome 9p21, which by alternative transcripts encodes for 2 cell cycle regulatory proteins, p16 INK4a (Exons 1a, 2 and 3) and p14 ARF (Exons 1b, 2 and 3). 10,11 The exact role of the CDKN2A gene in skin carcinogenesis is not well understood. Especially in metastatic CSCCs alterations in the CDKN2A gene have not been investigated. In a small previous stud...

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Section: Discussionmentioning

confidence: 99%

Section: Dna Isolation and Pcr Reactions For Mutation Analysesmentioning

confidence: 99%

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CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Küsters‐Vandevelde

Leeuwen

Verdijk

et al. 2009

Intl Journal of Cancer

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“…Cases positive for HPV by this intial screen were further analysed by Southern hybridisation using the restriction enzyme PstI. Filters containing 50 pg of purified HPV plasmid DNA of types 1, 2, 3, 4, 5, 8, 10, 12, 13, 14, 17, 19 and 20 (Heilman et al, 1980;Ostrow et al, 1982Ostrow et al, , 1983Kremsdorf et al, 1983Kremsdorf et al, , 1984Pfister et al, 1983a, b;Gassenmaier et al, 1984) mixed with 10 gAg of genomic DNA were also made for use in initial optimisation experiments. The sensitivity of this technique was investigated by performing Southern hybridisation analyses on serially diluted HPV 16 plasmid DNA mixed with a known concentration of genomic DNA.…”

Section: Histopathologymentioning

confidence: 99%

Prevalence of human papillomavirus DNA in cutaneous neoplasms from renal allograft recipients supports a possible viral role in tumour promotion

Stark

Arends²,

McLaren³

et al. 1994

Br J Cancer

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Summary It is well established that renal allograpft recipients (RARs) have an increased incidence of viral warts and premalignant and malignant cutaneous lesions, and the risk of their development increases in proportion to duration of graft survival. It has been postulated that, in addition to the effects of prolonged immunosuppression and previous sun exposure, human papillomaviruses (HPV) may also contribute to the carcinogenic process. In this study, the prevalence of HPV DNA was examined in a range of premalignant and malignant cutaneous tumours from 50 immunosuppressed patients (47 renal allograft recipients plus three cardiac allograft recipients) and 56 immunocompetent patients using Southern hybridisation as a lowstringency screening method and type-specific polymerase chain reaction (PCR) assays for eight HPV types. The combined results for renal allograft recipients show that HPV DNA was detectable in 79% of viral warts, 42% of premalignant keratoses, 33% of intraepidermal carcinomas, 43% of invasive squamous cell carcinomas and 16% of uninvolved skin specimens (squamous cell carcinomas/renal allograft recipients significantly different at P <0.05 from uninvolved skin specimens/renal allograft recipients). In immunocompetent patients the pattern of HPV DNA prevalence was 100% for viral warts; 25% for keratoses, 23% for intraepidermal carcinomas, 22% for squamous cell carcinomas and 8% for uninvolved skin. No single HPV type predominated in tumour specimens from either group. More tumours were found to contain HPV DNA by Southern hybridisation analysis than PCR, indicating the presence of HPV types other than HPV 1, 2, 5, 6, 8, 11, 16 and 18 in some tumours. However, 'low cancer risk' HPV types 1, 2 and 6 as well as 'high cancer risk' HPV types 5 and 16 were specifically detected by PCR in a small number of neoplasms. These data suggest that multiple HPV types may contribute to cutaneous neoplasia in RARs and that they appear to act early in the process of carcinogenesis, perhaps by functioning as tumour promoters via stimulation of cell proliferation.

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“…The HPV DNAs isolated from flat warts or macular lesions of EV patients have been analysed using restriction endonucleases, and several types of HPV, including 3, 5, 8, and 9, have been found in EV lesions (Orth et al, 1978;Pfister et al, 1981;Green et al, 1982;Kremsdorf et al, 1982). HPV-5 DNA has been reported to exist in carcinoma cells as unintegrated, free viral DNA (Orth et al, 1980;Ostrow et al, 1982). Although HPV is strongly suspected of being involved in carcinogenesis, little is known about this virus in comparison with other papovaviruses such as polyoma virus and SV40.…”

mentioning

confidence: 99%

Molecular Cloning of a New Human Papilloma Virus Isolated from Epidermodysplasia Verruciformis Lesions

Tsumori

Yutsudo

Nakano

et al. 1983

Journal of General Virology

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SUMMARYWe have recently reported isolation of a new human papilloma virus (HPVNF) from red plaques of a patient (NF) with epidermodysplasia verruciformis. The HPV DNA was molecularly cloned in Escherichia coli X1776 using plasmid pBR325. We have constructed a detailed physical map of the cloned DNA, which should be useful for examining the relationship of HPV and skin carcinoma.Epidermodysplasia Verruciformis (EV) is a chronic skin disease caused by human papilloma virus (HPV) (Lewandowsky & Lutz, 1922;Orth et al., 1978). EV converts to squamous cell carcinoma in 30 % of the cases (Jablonska et al., 1972;zur Hausen, 1977;Lutzner, 1978;Orth et al., 1979). The HPV DNAs isolated from flat warts or macular lesions of EV patients have been analysed using restriction endonucleases, and several types of HPV, including 3, 5, 8, and 9, have been found in EV lesions (Orth et al., 1978;Pfister et al., 1981;Green et al., 1982;Kremsdorf et al., 1982). HPV-5 DNA has been reported to exist in carcinoma cells as unintegrated, free viral DNA (Orth et al., 1980;Ostrow et al., 1982). Although HPV is strongly suspected of being involved in carcinogenesis, little is known about this virus in comparison with other papovaviruses such as polyoma virus and SV40. This is due in part to the narrow host range of HPV and absence of a system for virus propagation in cultured cells.Recently, we isolated a new HPV from an EV patient (NF), a 24 year-old man (Yutsudo et al., 1982). The cutaneous lesions of NF were red plaques with pityroid scales on the surface. The molecular weight of isolated HPV DNA was 5.0 x 106. The DNA was cleaved at one site with EcoRI or BglI, two sites with HindlII, three sites with BamHI or XbaI, and at more than five sites with HindlI. This cleavage pattern differs from those of other types of HPV reported so far. To elucidate the functions of HPV genes and their role in carcinogenesis, a means of efficiently preparing large amounts of DNA is necessary. Unfortunately, the new virus, like other HPVs, does not replicate in cultured cells. We therefore carried out experiments to clone the DNA of this HPV.HPV DNA used for cloning was extracted from red plaques of patient NF. Form I DNA was purified by caesium chloride-ethidium bromide density gradient centrifugation as described previously (Yutsudo et al., 1982). HPV DNA was cut with EcoRI, producing linear DNA which was then ligated into the EcoRI site of plasmid pBR325 (3.6 x 106 daltons). The single EcoRI site in pBR325 lies within the gene coding for chloramphenicol resistance. After digestion with EcoRI, pBR325 DNA was treated with bacterial alkaline phosphatase. The cleaved HPV and plasmid pBR325 DNAs were mixed at a ratio of 2 : 1 (i.e. 0.2 p.g of HPV DNA and 0.1 lag of pBR325 DNA) in a ligation mixture (20 ~tl) containing 50 mM-Tris-HC1 pH 7.8, 10 mM-MgCI2, 20 mM-dithiothreitol, 1 mM-ATP, 50 ~tg/ml bovine serum albumin, and 3 units ofT4 DNA ligase (New England Biolabs, Beverly, Mass., U.S.A.). After incubation for 15 h at 4 °C, the DNA was precipitated, resuspende...

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Human papillomavirus DNA in cutaneous primary and metastasized squamous cell carcinomas from patients with epidermodysplasia verruciformis.

Cited by 178 publications

References 20 publications

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

CDKN2A but not TP53 mutations nor HPV presence predict poor outcome in metastatic squamous cell carcinoma of the skin

Prevalence of human papillomavirus DNA in cutaneous neoplasms from renal allograft recipients supports a possible viral role in tumour promotion

Molecular Cloning of a New Human Papilloma Virus Isolated from Epidermodysplasia Verruciformis Lesions

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