Demonstration of allelic loss on chromosome 9q22 in both sporadic and familial BCCs suggested the potential presence of an associated tumor suppressor gene.[47,48] Further investigation identified a mutation in PTCH that localized to the area of allelic loss. Up to 30% of sporadic BCCs demonstrate PTCH mutations. In addition to BCC, medulloblastoma and rhabdomyosarcoma, along with other human tumors, have been associated with PTCH mutations. All three malignancies are associated with BCNS, and most people with clinical features of BCNS demonstrate PTCH mutations, predominantly truncation in type.
Truncating mutations in PTCH2, a homolog of PTCH1 mapping to chromosome 1p32.1-32.3, has been demonstrated in both BCC and medulloblastoma.[52,53]PTCH2 displays 57% homology to PTCH1, differing in the conformation of the hydrophilic region between transmembrane portions 6 and 7, and the absence of C-terminal extension. While the exact role of PTCH2 remains unclear, there is evidence to support its involvement in the hedgehog signaling pathway.[52,55]
Syndromes Associated with a Predisposition to Basal Cell Cancer
Basal cell nevus syndrome
BCNS, also known as Gorlin Syndrome, Gorlin-Goltz syndrome, and nevoid basal cell carcinoma syndrome, is an autosomal dominant disorder with an estimated prevalence of 1 in 57,000 individuals. The syndrome is notable for complete penetrance and extremely variable expressivity, as evidenced by evaluation of individuals with identical genotypes but widely varying phenotypes.[51,57] The clinical features of BCNS differ more among families than within families.
As detailed above, PTCH provides both developmental and regulatory guidance; spontaneous or inherited germline mutations of PTCH in BCNS may result in a wide spectrum of potentially diagnostic physical findings. The BCNS mutation has been localized to chromosome 9q22.3-q31, with a maximum logarithm of the odd (LOD) score of 3.597 and 6.457 at markers D9S12 and D9S53. The resulting haploinsufficiency of PTCH in BCNS has been associated with structural anomalies such as odontogenic keratocysts, with evaluation of the cyst lining revealing heterozygosity for PTCH. The development of BCC and other BCNS-associated malignancies is thought to arise from the classic two-hit suppressor gene model: baseline heterozygosity secondary to germline PTCH mutation as the first hit, with the second hit due to mutagen exposure such as UV or ionizing radiation.[60,61,62,63,64] However, haploinsufficiency or dominant negative isoforms have also been implicated for the inactivation of PTCH1.
The diagnosis of BCNS is typically based upon characteristic clinical and radiologic examination findings. Several sets of clinical diagnostic criteria for BCNS are in use (Refer to Table 1 for a comparison of these criteria).[66,67,68] Although each set of criteria has advantages and disadvantages, none of the sets have a clearly superior balance of sensitivity and specificity for identifying mutation carriers. PTCH1 mutations are found in 60% to 85% of patients who meet clinical criteria.[69,70] Most notably, BCNS is associated with the formation of both benign and malignant neoplasms. The strongest benign neoplasm association is with ovarian fibromas, diagnosed in 14% to 24% of females affected by BCNS.[63,67,71] BCNS-associated ovarian fibromas are more likely to be bilateral and calcified than sporadic ovarian fibromas.