Genetics of basal cell carcinoma

Author: Anoma Ranaweera B.V.Sc; PhD (Clinical Biochemistry, University of Liverpool, UK), 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 are believed to predispose patients to BCC.

Recently, there have been advances in the understanding of the molecular genetics of sporadic BCC.

There is evidence that malfunctioning of the hedgehog (HH) signalling pathway and gene mutations increase the risk BCC development.

What is the hedgehog signalling pathway?

The hedgehog signalling pathway (HH pathway) influences differentiation of various tissues during fetal development.

In adults, it continues to function in regulation of cell growth and differentiation.

Malfunctioning of this pathway is associated with human malignancy, including BCC.

How does the HH signalling pathway work?

The hedgehog gene in the HH pathway, codes for an extracellular protein, the sonic hedgehog (SHH) protein that 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:

What happens when the HH pathway malfunctions?

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 (changes in the genomic sequence i.e. the DNA sequence of the cell's genome) 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:

Major genes increasing BCC risk

There is evidence that mutations in the PTCH1, PTCH2, SMO and SUFU genes predispose patients to BCC.

Other genes of importance in BCC risk

There is evidence that mutations in the tumour suppressor gene P53 and the melanocortin-1 receptor gene may be involved in the development of sporadic BCC.

P53 gene

Melanocortin-1 receptor gene

Miscellaneous genes

Mutations/variants of the following genes may predispose patients to sporadic BCC:

Hedgehog antagonist for advanced BCC

Vismodegib (trade name Erivedge™) is a hedgehog pathway inhibitor that was approved in 2012 for the treatment of advanced and metastatic BCC.

A number of other experimental therapies targeting molecules of the HH signalling pathway are in early stages of investigation and development.

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