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Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome.

ABSTRACT: AIM:To search for patched homologue 1 (PTCH1) mutations in four families with basal cell nevus syndrome (BCNS). METHODS:Mutation analysis of PTCH1 in unrelated Japanese families affected with BCNS was carried out by direct sequencing. RESULTS:Six novel PTCH1 mutations, 833G-->A in exon 6, 1415C-->A and 1451G-->T in exon 10, 2798delC in exon 17, 2918-2925dupAGTTCCCT in exon 18 and 3956C-->A in exon 23, were identified. CONCLUSIONS:Among the six PTCH1 mutations, two frameshift mutations (2798delC and 2918-2925dupAGTTCCCT) and one nonsense mutation (833G-->A) are predicted to lead to premature termination of PTCH1 protein translation. Three simultaneous mutations, 1415C-->A (A472D) and 1451G-->T (G484V) in exon 10, and 3956G-->A (R1319H) in exon 23, were found on one allele in only affected members in one family and none of them were found among 90 unrelated healthy Japanese. The three mutations on one chromosome may have resulted from errors in the recombinational repair process and this is the first report on the PTCH1 mutations due to such a mechanism.

SUBMITTER: Matsuzawa N

PROVIDER: S-EPMC1861741 | biostudies-literature | 2006 Oct

REPOSITORIES: biostudies-literature

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Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome.

Matsuzawa N N Nagao T T Shimozato K K Niikawa N N Yoshiura K-I KI

Journal of clinical pathology 20061001 10

<h4>Aim</h4>To search for patched homologue 1 (PTCH1) mutations in four families with basal cell nevus syndrome (BCNS).<h4>Methods</h4>Mutation analysis of PTCH1 in unrelated Japanese families affected with BCNS was carried out by direct sequencing.<h4>Results</h4>Six novel PTCH1 mutations, 833G-->A in exon 6, 1415C-->A and 1451G-->T in exon 10, 2798delC in exon 17, 2918-2925dupAGTTCCCT in exon 18 and 3956C-->A in exon 23, were identified.<h4>Conclusions</h4>Among the six PTCH1 mutations, two fr ...[more]

PMID: 17021131

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Project description:BackgroundDysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas.MethodsWe tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas.ResultsIn 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas.ConclusionsVismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

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Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome.

Publications

Patched homologue 1 mutations in four Japanese families with basal cell nevus syndrome.

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