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Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand, 2011.
Basal cell carcinoma (BCC) is the most common malignancy in people of European descent and is particularly prevalent in Australia and New Zealand. The exact cause of BCC is unknown, but environmental and genetic factors predispose patients to BCC.
Recently, there have been advances in the understanding of the molecular genetics of inherited and sporadic BCC. Malfunctioning of the hedgehog (HH) signalling pathway and gene mutations increase the risk of BCC.
The hedgehog signalling pathway (HH pathway) influences the differentiation of various tissues during fetal development.
In adults, it continues to function in the regulation of cell growth and differentiation.
Malfunctioning of this pathway is associated with human malignancy, including BCC.
The hedgehog gene in the HH pathway codes for an extracellular protein, the sonic hedgehog (SHH) protein. SSH binds to the cell membrane receptor complex to start a cascade of cellular events leading to cell proliferation.
The cell membrane receptor complex consists of two proteins:
In the resting state, PTCH1 holds SMO in an inactive state, thus inhibiting signalling to downstream genes.
In the active state:
Malfunctioning of the HH pathway is associated with human malignancy, including BCC.
The normal functioning of the HH pathway can be disrupted because of mutations in the genes coding for the PTCH1, PTCH2, SMO or SUFU proteins.
PTCH1 gene mutations prevent PTCH1 protein from binding to SMO.
Unbound SMO allows unregulated cell growth through activation of the following:
Mutations in the PTCH1, PTCH2, SMO and SUFU genes predispose patients to BCC.
Patients with basal cell naevus syndrome (Gorlin syndrome) are born with an inherited mutation of one allele of the PTCH1 gene. The mutation leads to an autosomal dominant syndrome of cancer predisposition. The remaining good allele can undergo mutation through UV radiation exposure in one lifetime, such that these patients can develop BCC tumours at an earlier age than the general population.
Mutations in the tumour suppressor gene P53 and the melanocortin-1 receptor (MCR1) gene may be involved in the development of sporadic BCC.
Mutations/variants of the following genes may predispose patients to sporadic BCC:
Vismodegib (trade name Erivedge™) is a hedgehog pathway inhibitor that was approved in 2012 for the treatment of advanced and metastatic BCC. In 2015, sonidegib was also approved for the treatment for advanced basal cell carcinoma.
Other therapies targeting molecules of the HH signalling pathway are under development.
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