Identification of Mutations in the Human PATCHED Gene in Sporadic Basal Cell Carcinomas and in Patients with the Basal Cell Nevus Syndrome

Aszterbaum, Michelle; Rothman, Alana; Johnson, Ronald L.; Fisher, Monte; Xie, Jingwu; Bonifas, Jeannette M.; Zhang, Xioli; Scott, Mathew P; Epstein, Ervin

doi:10.1046/j.1523-1747.1998.00222.x

Cited by 285 publications

(180 citation statements)

References 23 publications

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“…Most BCC tumors have PTCH1 gene inactivating mutations that cause Shh signaling to be activated constitutively (Aszterbaum et al, 1998;Johnson et al, 1996;Ling et al, 2001;Xie et al, 1998). In general, more than 70% of sporadic BCCs have detectable genetic mutations in components of the Shh signaling pathway that lead to elevated levels of the Gli1 transcription factor (Dahmane et al, 1997;Ling et al, 2001).…”

Section: Basal Cell Nevus Syndrome and Ptch1 Heterozygous (+/−) Micementioning

confidence: 99%

Novel Hedgehog pathway targets against basal cell carcinoma

Tang

Epstein

2007

Toxicology and Applied Pharmacology

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The Hedgehog signaling pathway plays a key role in directing growth and patterning during embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin, and hair. Aberrant activation of the Hedgehog (Hh) pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and a subset of pancreatic, gastro-intestinal, and other cancers. This review will provide an overview of what is known about the mechanisms by which activation of Hedgehog signaling leads to the development of BCCs and will review two recent papers suggesting that agents that modulate sterol levels might influence the Hh pathway. Thus, sterols may be a new therapeutic target for the treatment of BCCs, and readily available agents such as statins (HMG-CoA reductase inhibitors) or vitamin D might be helpful in reducing BCC incidence. Epidemiology of Basal cell carcinoma (BCC)Basal cell carcinoma (BCC), the most common of all human cancers, affects close to 1 million Americans a year. Over the past 40 years there has been a dramatic increase in the incidence of BCC, and it is estimated that nearly 30% of Caucasians living in areas of high ambient sun exposure will develop a BCC (Miller and Weinstock, 1994). Furthermore, the incidence of BCC is rising in younger populations, especially among women (Christenson et al., 2005). Although the case fatality rate of BCCs is low, the high incidence and frequent occurrence of multiple primary tumors in affected individuals leads to significant morbidity. BCCs characteristically arise in sun-exposed body areas, most commonly on the head and neck, but also occur on the trunk and extremities. There are three accepted environmental insults for BCC development: ultraviolet radiation (UV), ionizing radiation (IR), and arsenic. Interindividual differences in the susceptibility to BCC development have been recognized for many years. Epidemiologic studies have identified phenotypic features such as fair skin and freckling tendency that are associated with an increased susceptibility to BCCs (Rubin et al., 2005).It is generally accepted that BCC can be caused by UV exposure from the sun. While the risk of squamous cell carcinoma is strongly related to cumulative sun exposure, sunlight's exact role in BCC development remains less clear (Armstrong and Kricker, 2001). Thus, epidemiologic studies have shown that BCC risk correlates better with intermittent sun exposure (i.e. childhood sunburns, weekend sun exposure) than with cumulative lifetime sun exposure (Corona et al., 2001). Hence, the timing, dose, and duration of UV exposure are critical to carcinogenesis, but UV seems to have a different role in SCC versus BCC carcinogenesis development. Consistent with this, a randomized clinical trial of daily sunscreen use showed that sunscreen reduced the incidence of SCC but not BCC. The daily application of an SPF 15 sunscreen to the head, neck, arms, and hands over a 4-5 year period had no e...

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Section: Basal Cell Nevus Syndrome and Ptch1 Heterozygous (+/−) Micementioning

confidence: 99%

Novel Hedgehog pathway targets against basal cell carcinoma

Tang

Epstein

2007

Toxicology and Applied Pharmacology

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“…49,58 The gene, Patched, which modifies the Hedgehog signaling pathway, is mutated not only in the syndrome but in ordinary isolated basal cell carcinomas. 59,60 Patched, in the absence of its ligand, Sonic Hedgehog, acts a cell-cycle regulator, normally inhibiting expression of downstream genes (Smoothened, among others), which control cell fate, patterning, and growth 61 (Fig. 8).…”

Section: Geneticsmentioning

confidence: 99%

Nevoid basal cell carcinoma (Gorlin) syndrome

Gorlin

2004

Genetics in Medicine

317

189

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“…The estimated frequency of PTCH mutations in sporadic BCCs ranges from 12 ± 38%, although in all cases this may represent an underestimate based on the mutation detection procedures employed (Aszterbaum et al, 1998b;Unden et al, 1997;Wolter et al, 1997). In addition to mutations in the PTCH gene, loss of heterozygosity of markers on the region of chromosome 9q encompassing PTCH is observed in upwards of 50% of BCCs (Gailani et al, 1992).…”

Section: Patched and Bccsmentioning

confidence: 99%