Clinical testing for the nevoid basal cell carcinoma syndrome in a DNA diagnostic laboratory

Abstract

Purpose: This study determines which clinical features predict positive test results among samples submitted for DNA-based diagnostic nevoid basal cell carcinoma syndrome (NBCCS) testing, and further defines the mutational spectrum of the PTCH gene. Methods: DNA was extracted from peripheral blood leukocytes, and polymerase chain reaction products from exons 1 to 23 of the PTCH gene were directly sequenced. Pedigree phenotypic information was obtained by written questionnaire. Results: Among 106 presumably unrelated pedigrees, 44 independent mutations were found in 47 families. There were 11 nonsense mutations; 1 in-frame deletion; 17 deletions, 6insertions, and 1 deletion-insertion that generated frameshifts; 5 splice-site mutations; 1 in-frame duplication; and 2 presumptive missense mutations. Twenty-seven of 46 pedigrees (58.7%) with two or more typical radiographic or pathologic features of NBCCS tested positive for PTCH mutations. Of these, 26 had jaw cysts in combination with other characteristics or neoplasms including basal cell carcinomas, palmar pits, skeletal abnormalities, ocular abnormalities, medulloblastomas, cardiac or ovarian fibromas, calcification of the falx cerebri, polydactyly, cleft lip and/or palate, and agenesis of the corpus callosum or other central nervous system malformations. None of the

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)

“…While many cases of NBCCS are inherited, sporadic occurrences are thought to account for up to 50 % of cases [7]. Although the disease is characterized by high penetrance, individuals display varying levels of expressivity even within families, sometimes making diagnosis challenging [5].…”

“…Under pathogenic circumstances, constitutive activation of the hedgehog signaling pathway due to mutation of critical regulatory proteins leads to tumor cell proliferation. Loss of function mutations in PTCH1, which occur by a variety of mechanisms such as deletions, insertions, and nonsense and missense mutations [7], are thought to occur in *70 % of patients who fulfill diagnostic criteria for NBCCS [15,16]. In addition, loss of function SUFU germline mutations have also been recently associated with NBCCS in a subset of cases [16].…”

Clinical and radiological features in young individuals with nevoid basal cell carcinoma syndrome

“…Although PTCH has been identified as the gene causing NBCCS and mutations in PTCH can confirm a clinical diagnosis, molecular genetic testing has not been able to detect mutations in all affected individuals. [17][18][19][20][21] Bale et al 17,22 found that families with a history of multiple NBCCS features were more likely to have a detectable mutation; nevertheless, mutations were detected in only 40% of families tested in the study. 22 This failure to detect a mutation is likely due to the limitations of available technology, as well as the high rate of somatic mutations, rather than the presence of other causative genes.…”

“…[17][18][19][20][21] Bale et al 17,22 found that families with a history of multiple NBCCS features were more likely to have a detectable mutation; nevertheless, mutations were detected in only 40% of families tested in the study. 22 This failure to detect a mutation is likely due to the limitations of available technology, as well as the high rate of somatic mutations, rather than the presence of other causative genes. More recent use of technologies such as multiplex ligation-dependent probe amplification and competitive genomic hybridization array help identify single or multiple exon deletions in PTCH that were previously undetectable by direct sequencing of exons and splice junctions.…”

The anaplastic lymphoma kinase as an oncogene in solid tumors

“…PTCH1 gene is located on chromosome 9, in the chromosome region 9q22.32, with 24 exons streching through 70 kb (14). PTCH1 gene has one polymorphic CGG repeat marker located directly upstream of the first ATG codon of exon 1b (rs71366293) (15), and at least 48 single nucleotide polymorphisms (SNP) throughout the gene (16), 7 of them common (17).…”