Somatic mutations in thePTCH,SMOH,SUFUHandTP53genes in sporadic basal cell carcinomas

Reifenberger, Julia; Wolter, Marietta; Knobbe, Christiane B.; Köhler, Benjamin; Schönicke, Alexandra; Scharwächter, C.; Kumar, Krishan; Blaschke, Britta; Ruzicka, Thomas; Reifenberger, Guido

doi:10.1111/j.1365-2133.2005.06353.x

Cited by 365 publications

(212 citation statements)

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“…BCC, the most common human cancer consistently has abnormalities of the hedgehog pathway with PTCH1 mutations in 50% human sporadic BCCs, suggesting alteration of additional genes in the hedgehog pathway in this type of skin cancer. Indeed, mutations of SMO are found in about 10% of sporadic BCCs (Reifenberger et al, 1998(Reifenberger et al, , 2005Xie et al, 1998;Lam et al, 1999;Couve-Privat et al, 2002). Unlike wildtype SMO, expression of activated SMO molecules in mouse skin results in formation of BCC-like tumors (Xie et al, 1998).…”

Section: Activation Of the Hedgehog Pathway In Human Cancermentioning

confidence: 99%

“…Unlike wildtype SMO, expression of activated SMO molecules in mouse skin results in formation of BCC-like tumors (Xie et al, 1998). It is also reported that SU(FU) is mutated in a small number of BCCs (Reifenberger et al, 2005). Taking all the mutation data into account, there are still about 30% of BCCs without the underlying molecular basis for the activated hedgehog signaling.…”

Section: Activation Of the Hedgehog Pathway In Human Cancermentioning

confidence: 99%

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Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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Section: Activation Of the Hedgehog Pathway In Human Cancermentioning

confidence: 99%

Section: Activation Of the Hedgehog Pathway In Human Cancermentioning

confidence: 99%

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

et al. 2009

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“…Surgery, the primary course of treatment for most BCCs, and radiotherapy are often not viable options in advanced BCC 1, 2, 3. In recent years, hedgehog (Hh) pathway inhibitors (HPIs) were developed to block aberrant Hh signalling that is found in most sporadic BCCs; HPIs have demonstrated efficacy in patients with laBCC and those with mBCC 4, 5, 6, 7, 8, 9, 10, 11, 12, 13…”

Section: Introductionmentioning

confidence: 99%

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Lear

Migden

Lewis

et al. 2017

Acad Dermatol Venereol

172

183

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BackgroundPatients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult‐to‐treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial.ObjectiveTo evaluate long‐term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18‐ and 30‐month analyses.MethodsBOLT (NCT01327053, ClinicalTrials.gov), a double‐blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI‐treatment–naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review.ResultsWith 30 months of follow‐up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200‐mg arm died. Median overall survival was not reached in either population; 2‐year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non‐aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%).ConclusionSonidegib continued to demonstrate long‐term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

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“…Mice with haploinsufficieny of Ptch1 [71,72], or those with haploinsufficiency of SuFu when combined with p53 haploinsufficiency [73], develop a common spectrum of cutaneous, brain and cartilaginous tumors that corresponds to the specific types of gene anomalies found in basal cell (skin) carcinoma (BCC), medulloblastomas or rhabdomyosarcomas in humans [74]. These types of tumors often have reduced Ptch1 expression associated with loss of heterozygosity at 9q22 (the Ptch1 locus), which may or may not be associated with a mutation in the remaining Ptch allele [75]. Likewise, inactivating mutations in Ptch or SuFu underlie the Gorlin syndrome that predisposes to the development of BCC and/or medulloblastoma [76,77].…”

Section: Hedgehog and Human Cancersmentioning

confidence: 99%

Targeting the CB2 cannabinoid receptor in osteoporosis

Chen

Carkner

Buttyan

2011

Expert Review of Endocrinology & Metabolism

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Hedgehog is a ligand-activated signaling pathway that regulates Gli-mediated transcription. Although most noted for its role as an embryonic morphogen, hyperactive hedgehog also causes human skin and brain malignancies. The hedgehog-related gene anomalies found in these tumors are rarely found in prostate cancer. Yet surveys of human prostate tumors show concordance of high expression of hedgehog ligands and Gli2 that correlate with the potential for metastasis and therapy-resistant behavior. Likewise, prostate cancer cell lines express hedgehog target genes, and their growth and survival is affected by hedgehog/Gli inhibitors. To date, the preponderance of data supports the idea that prostate tumors benefit from a paracrine hedgehog microenvironment similar to the developing prostate. Uncertainty remains as to whether hedgehog’s influence in prostate cancer also includes aspects of tumor cell autocrine-like signaling. The recent findings that Gli proteins interact with the androgen receptor and affect its transcriptional output have helped to identify a novel pathway through which hedgehog/Gli might affect prostate tumor behavior and raises questions as to whether hedgehog signaling in prostate cancer cells is suitably measured by the expression of Gli target genes alone.

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Somatic mutations in thePTCH,SMOH,SUFUHandTP53genes in sporadic basal cell carcinomas

Abstract: Our data confirm the importance of PTCH, SMOH and TP53 mutations in the pathogenesis of sporadic BCCs. SUFUH alterations are restricted to individual cases while the other investigated genes do not appear to be important targets for mutations in BCCs.

Cited by 365 publications

References 46 publications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Long‐term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30‐month analysis of the randomized phase 2 BOLT study

Targeting the CB2 cannabinoid receptor in osteoporosis

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