Mechanisms of inactivation of PTCH1 gene in nevoid basal cell carcinoma syndrome: modification of the two-hit hypothesis.
OBJECTIVE
PTCH1 has been identified as the gene responsible for nevoid basal cell carcinoma syndrome (NBCCS). Keratocystic odontogenic tumors (KCOT) are aggressive jaw lesions that may occur in isolation or in association with NBCCS. The aim of this study was to investigate the genetic and/or epigenetic mechanisms of inactivation of the PTCH1 gene in patients with NBCCS and related sporadic KCOTs.


METHODS
Loss of heterozygosity was analyzed in 44 patients (15 NBCCS-related and 29 sporadic KCOTs), all of whom were previously analyzed for PTCH1 mutations. Allelic location was established in tumors carrying two coincident mutations. PTCH1 mRNA expression and promoter methylation status were analyzed in a panel of KCOTs to define the possible role of epigenetic effects on PTCH1 inactivation.


RESULTS
Although mutations and loss of heterozygosity of PTCH1 were frequently detected in both syndromic and nonsyndromic cases, hypermethylation of the PTCH1 promoter was not identified in the present series. Of all the 44 cases examined, 13 were identified to fit the two-hit model, 14 to conform to a one-hit model, and the remaining 17 cases showing no alteration in PTCH1. The distribution of two-hit, one-hit, and non-hit cases was significantly different between syndrome and nonsyndrome patients (P < 0.02).


CONCLUSIONS
This study indicates that PTCH1 gene alternation may play a significant role in the pathogenesis of NBCCS and the related sporadic tumors. Not only the standard two-hit model, but also haploinsufficiency or dominant-negative isoforms may be implicated in the inactivation of the PTCH1 gene.
Pan
Shuang
S
Department of Oral Pathology, Peking University School and Hospital of Stomatology, Beijing, China.
Dong
Qing
Q
Sun
Li-Sha
LS
Li
Tie-Jun
TJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001478:Basal Cell Nevus Syndrome / Q000235:genetics* / Q000473:pathology; D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D020022:Genetic Predisposition to Disease; D005887:Gingival Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation / Q000502:physiology; D009808:Odontogenic Tumors / Q000235:genetics / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D055815:Young Adult
C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface