Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers.

Ziegler, Annemarie; Leffell, David J.; Subrahmanyam, K; Sharma, Harsh W.; Gailani, Mae R.; Simon, John; Halperin, Alan J.; Baden, Howard P.; Shapiro, P.; Bale, Allen E.; Brash, Douglas E.

doi:10.1073/pnas.90.9.4216

Cited by 657 publications

(434 citation statements)

References 32 publications

(35 reference statements)

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“…Of equal interest is the potential involvement of other, well-characterized pathways, implicated in other human cancers, that cooperate with the breakdown in Shh signalling. A significant player appears to be the tumor suppressor gene p53, which is mutated in approximately 50% of sporadic BCC (Ziegler et al, 1993). Our data show that, in line with previous studies, b-catenin is targeted to the nucleus in some BCC samples.…”

supporting

confidence: 89%

RUNX3 protein is overexpressed in human basal cell carcinomas

et al. 2006

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Basal cell carcinomas (BCC), which are the most common form of skin malignancy, are invariably associated with the deregulation of the Sonic Hedgehog (Shh) signalling pathway. As such, BCC represent a unique model for the study of interactions of the Shh pathway with other genes and pathways. We constructed a tissue microarray (TMA) of 75 paired BCC and normal skin and analysed the expression of b-catenin and RUNX3, nuclear effectors of the wingless-Int (Wnt) and bone morphogenetic protein/ transforming growth factor-b pathways, respectively. In line with previous reports, we observed varying subcellular expression pattern of b-catenin in BCC, with 31 cases (41%) showing nuclear accumulation. In contrast, all the BCC cases tested by the TMA showed RUNX3 protein uniformly overexpressed in the nuclei of the cancer cells. Analysis by Western blotting and DNA sequencing indicates that the overexpressed protein is normal and full-length, containing no mutation in the coding region, implicating RUNX3 as an oncogene in certain human cancers. Our results indicate that although the deregulation of Wnt signalling could contribute to the pathogenesis of a subset of BCC, RUNX3 appears to be a universal downstream mediator of a constitutively active Shh pathway in BCC.

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supporting

confidence: 89%

RUNX3 protein is overexpressed in human basal cell carcinomas

et al. 2006

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“…Many of the mutations were found in the conserved II region of the core domain (127 ± 158), an area of the gene which has not been reported as a hot spot (Figure 1). In addition, mutations clustered around codons 173 ± 179 and 235 ± 250, previously described as hot spots (Ziegler et al, 1993). 70% of the mutations were C to T transitions at dipyrimidine sites, including two CC to TT transitions, compatible with u.v.…”

Section: Resultsmentioning

confidence: 90%

Molecular pathology in basal cell cancer with p53 as a genetic marker

et al. 1997

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Human basal cell cancer (BCC) has unique growth characteristics with virtual inability to metastasize. We investigated clonality and genetic progression using p53 mutations as marker. Sampling was done through microdissection of frozen immunohistochemically stained 16 mm slices of tumors. From 11 BCC tumors 78 samples were analysed. Direct DNA sequencing of exons 5 ± 8 was performed, haplotypes were determined after cloning of p53 exons and loss of heterozygosity (LOH) ascertained by microsatellite analysis. All tumors had p53 mutations and in a majority both p53 alleles were a ected, commonly through missense mutations. Microdissection of small parts (50 ± 100 cells) of individual tumors showed BCC to be composed of a dominant cell clone and prone to genetic progression with appearance of subclones with a second and even third p53 mutation. Samples from normal immunohistochemically negative epidermis always showed wild type sequence, except for a case of previously unknown germline p53 mutation. Our analysis also included p53 immunoreactive patches i.e. morphologically normal epidermis with a compact pattern of p53 immunoreactivity. Mutations within those were never the same as in the adjacent BCC. This detailed study of only one gene thus uncovered a remarkable heterogeneity within a tumor category famous for its benign clinical behavior.

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“…The loss of a nuclear tumor suppressor gene is an early event in the elaborate sequence that leads to tumorigenesis. There are, however, several examples of poorly angiogenic precursor lesions, including those of early squamous cell carcinomas of the skin, cutaneous melanomas, and cervical intraepithelial neoplasia/carcinoma (27,28).…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine Lung Tumors: Grade Correlates with Proliferation but not Angiogenesis

Arbiser

Cohen

et al. 2001

Modern Pathology

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Angiogenesis has been implicated in the progression of human neoplasia from benign precursor to invasive and metastatic phenotypes. The acquisition of dominant oncogenes in preneoplastic cells in vitro and in vivo has been associated with the increased ability of tumor cells to secrete angiogenic mediators and recruit blood vessels. However, in a subset of benign lesions, high levels of angiogenesis have been found before the conversion to invasive and metastatic phenotypes. In many of these benign lesions, dominant oncogenic pathways are activated first; then as malignant potential is acquired, there is a loss of nuclear tumor suppressor genes, such as p53 and p16. We studied neuroendocrine lung tumors (NLT) ranging from typical and atypical carcinoid tumors to large cell neuroendocrine and small cell carcinomas in order to determine whether angiogenesis (as assessed by mean vessel density) and proliferation rates (as assessed by MIB-1 nuclear immunohistochemical staining) correlate with tumor type. We found that increased rates of proliferation, but not angiogenesis, correlate with tumor type. The association of increased proliferation and tumor type may prove to be clinically useful and shed light on the role of sequential oncogenic alterations in NLT.

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Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers.

Cited by 657 publications

References 32 publications

RUNX3 protein is overexpressed in human basal cell carcinomas

RUNX3 protein is overexpressed in human basal cell carcinomas

Molecular pathology in basal cell cancer with p53 as a genetic marker

Neuroendocrine Lung Tumors: Grade Correlates with Proliferation but not Angiogenesis

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