Melanoma incidence has markedly increased in recent decades. It represents 3–5% of skin cancers, but it is responsible for 75% of all skin cancer deaths1. Approximately 10% of melanoma cases report a relative affected with melanoma, and a positive family history is associated with an increased risk of developing melanoma. The heritable (germ line) variants which contribute to melanoma susceptibility vary in terms of risk from common relatively low penetrance genes to rare high penetrance genes1. This project relates to families with rare high penetrance susceptibility genes. Low penetrance susceptibility genes are associated with three main “phenotypes”: pigmentation characteristics associated with a tendency to burn in the sun, increased numbers of melanocytic naevi (moles) or a genotype associated with predicted long telomeres.
The most extensively studied gene related to familial melanoma is cyclin-dependent …show more content…
Through structural modelling, it was predicted that the missense mutations could prevent the binding of the OB domains with telomeric DNA, which was confirmed by an electrophoretic mobility shift assay3. The disruption of POT1 binding to telomeric DNA is believed to cause POT1 mutation carriers to have longer telomeres, probably through the abolition of the ability of shelterin to protect the telomeric ssDNA repeats, allowing access by components of the DNA damage response pathway and/or the telomerase complex. One study described a founder mutation (p.S270N) in POT1 in Italian melanoma families, with mutation carriers having longer telomeres than non-carriers. In the absence of shelterin , telomeres resemble unstable genomic DNA, known as fragile sites, which lead to the formation of aberrant DNA structures; these were found in mutation carriers, reinforcing the hypothesis that these mutations alter the function of the shelterin
The most extensively studied gene related to familial melanoma is cyclin-dependent …show more content…
Through structural modelling, it was predicted that the missense mutations could prevent the binding of the OB domains with telomeric DNA, which was confirmed by an electrophoretic mobility shift assay3. The disruption of POT1 binding to telomeric DNA is believed to cause POT1 mutation carriers to have longer telomeres, probably through the abolition of the ability of shelterin to protect the telomeric ssDNA repeats, allowing access by components of the DNA damage response pathway and/or the telomerase complex. One study described a founder mutation (p.S270N) in POT1 in Italian melanoma families, with mutation carriers having longer telomeres than non-carriers. In the absence of shelterin , telomeres resemble unstable genomic DNA, known as fragile sites, which lead to the formation of aberrant DNA structures; these were found in mutation carriers, reinforcing the hypothesis that these mutations alter the function of the shelterin