Low Frequency of Genetic Change in p53 Immunopositive Clones in Human Epidermis

Tabata, Hideyuki

doi:10.1046/j.1523-1747.1999.00810.x

Cited by 20 publications

(25 citation statements)

References 8 publications

(14 reference statements)

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“…6,10,36,37 Confocal microscopy revealed that epidermal p53 clones originated from putative stem cell compartments, and it was hypothesized that these mutated keratinocytes were awaiting further genetic change before developing a malignant phenotype. 7 Although one study suggests a role for p53 clones as early precursors for BCC, 38 no genetic link has been detected between p53 clones and skin cancer. In addition, experimental studies have shown the early onset of epidermal p53 clones after chronic UV irradiation in histologically normal appearing mouse skin.…”

Section: Discussionmentioning

confidence: 99%

Persistent p53 Mutations in Single Cells from Normal Human Skin

Gao

Persson

Berne

et al. 2001

The American Journal of Pathology

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Epidermal clones of p53-mutated keratinocytes are abundant in chronically sun-exposed skin and may play an important role in early development of skin cancer. Advanced laser capture microdissection enables genetic analysis of targeted cells from tissue sections without contamination from neighboring cells. In this study p53 gene mutations were characterized in single cells from normal, chronically sunexposed skin. Biopsies were obtained from skin subjected to daily summer sun and skin totally protected from the sun by blue denim fabric. Using laser capture microdissection, 172 single-cell samples were retrieved from four biopsies and analyzed using single-cell polymerase chain reaction and direct DNA sequencing. A total of 14 different mutations were identified in 26 of 99 keratinocytes from which the p53 gene could be amplified. Mutations displayed a typical UV signature and were detected in both scattered keratinocytes and in a small cluster of p53-immunoreactive keratinocytes. This minute epidermal p53 clone had a diameter of 10 to 15 basal cells. Two missense mutations were found in all layers of epidermis within the p53 clone. The presented data show that p53 mutations are common in normal skin and that a clone of keratinocytes with a mutated p53 gene prevailed despite 2 months of total protection from ultraviolet light. 1 Ultraviolet (UV) radiation from the sun is accepted as a major risk factor and tumor cells exhibit mutations with typical UV signature in cancerrelated genes.2 Skin carcinogenesis is a multistep process, in which the early clandestine events, preceding malignant transformation are primarily unknown. In chronically sun-damaged skin SCC develops through stages of actinic keratosis and SCC in situ, whereas no such precursor lesions are known for BCC. Although several genes and pathways are important for development of skin cancer, the genetic events underlying the different steps from a normal cell to SCC or BCC are virtually unknown. Mutation of the p53 gene is one frequent, known genetic alteration found in SCC and BCC. In addition, activation of the sonic hedgehog/patched signaling pathway seems essential for development of BCC. 4,5 In human skin there exists a multitude of p53-immunoreactive clusters of morphologically normal epidermal keratinocytes.6 -8 These p53 clones are predominantly found in chronically sun-exposed skin. Microdissection followed by polymerase chain reaction (PCR) and direct DNA sequencing has shown an underlying p53 mutation in at least 70% of analyzed cases. Epidermal p53 clones and adjacent cancers have never been shown to share the same p53 mutation and thus there is no solid evidence of a genetic link between p53 clones and any specific type of skin cancer.9,10 However, the incidence and location of p53 clones suggest a role for p53 mutations in skin cancer. Mutations in the p53 gene have also been detected in UV-irradiated mouse skin months before the gross appearance of skin tumors, suggesting that p53 mutations are an early event for the development of skin ...

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Section: Discussionmentioning

confidence: 99%

Persistent p53 Mutations in Single Cells from Normal Human Skin

Gao

Persson

Berne

et al. 2001

The American Journal of Pathology

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“…As is commonly encountered in NMSC (shared with AKs and cSCCs), the other frequent molecular alteration occurring in BCCs is the presence of the so-called "UV-signature" TP53 gene mutations that result from UVB damage from chronic sun exposure. [72][73][74][75][76] . Genetic alterations of these two important pathways, HH and p53, appear to interact and be necessary for tumor survival 77,78 .…”

Section: Pathogenesis and Basic Science Review Of Bccmentioning

confidence: 99%

Basal cell carcinoma: Epidemiology, clinical and histologic features, and basic science overview

Prieto-Granada¹,

Rodriguez‐Waitkus²

2015

Current Problems in Cancer

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“…34 Instead, clonal expansion requires continuous UV exposure. In the absence of UV, their growth is halted and the clones regress.…”

Section: Molecular Pathways To Early Melanoma Developmentmentioning

confidence: 99%

Early cancers of the skin: clinical, histopathological, and molecular characteristics

Takata

Saida

2005

Int J Clin Oncol

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Because skin lesions are visible and easily accessible, skin cancers provide us with an excellent in vivo model to study the development of cancers. Cutaneous malignant melanoma and squamous cell carcinoma (SCC) both arise from the epidermis and have an initial progression stage in which proliferation of the neoplastic cells is confined to the epidermis. This stage is called melanoma in situ or SCC in situ. Molecular analyses of melanoma in situ and of solar keratosis, a prototype of early SCC in situ, show that loss of p16(INK4a)/p14(ARF) and dysfunction of p53 play a critical role, respectively. Furthermore, there seems to be potential precursor cells to these in situ lesions, which are not discernible with conventional hematoxylin and eosin-stained sections. The precursor cells have minimal but critical genetic alterations, such as cyclin D1 amplification and p53 mutation, and can be identified using fluorescent in situ hybridization and immunostaining with p53 antibodies, respectively. These precursor cells may be defective in repair response to DNA damage, and would have proliferative or survival advantages over their normal neighboring counterparts in the presence of growth factor stimulation or genotoxic events, such as ultraviolet irradiation. Such precursor clones may be induced at a rather young age, and their number and size increase with accumulating carcinogenic stimuli. If these lesions acquire additional mutations, they could progress to clinically visible lesions of in situ carcinoma. Precise molecular analyses of early stages of skin cancers may have a strong impact on our understanding of in vivo development of cancers in other human organs.

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Low Frequency of Genetic Change in p53 Immunopositive Clones in Human Epidermis

Cited by 20 publications

References 8 publications

Persistent p53 Mutations in Single Cells from Normal Human Skin

Persistent p53 Mutations in Single Cells from Normal Human Skin

Basal cell carcinoma: Epidemiology, clinical and histologic features, and basic science overview

Early cancers of the skin: clinical, histopathological, and molecular characteristics

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