AbstractsBiology & Animal Science


Cutaneous melanoma is a cancer of melanocytes, the pigment-producing cells in our skin. It is one of the most aggressive human malignancies, constituting only about 2% of all dermatological cancers but being responsible for over 75% of all deaths from skin cancer. It has recently become a major public health problem, as it is now the fifth most common cancer in the United Kingdom after its incidence more than quadrupled in the last three decades. For these reasons, understanding the biological processes that are involved in its development is of great importance for devising novel treatments and for the management of patients in the clinic. The study of the genetic factors that influence melanoma risk can uncover mechanisms that are relevant in the transition from a benign melanocyte to a malignant melanoma. Approximately 10% of all melanoma cases are familial, and about half of these familial cases can be explained by pathogenetic variants in genes such as cyclin-dependent kinase inhibitor 2A (CDKN2A), cyclin-dependent kinase 4 (CDK4), breast cancer 2 (BRCA2), BRCA1-associated protein-1 (BAP1) and in the promoter of the telomerase reverse transcriptase (TERT). However, about 50% of all familial melanoma cannot be explained by mutations in known genes. In this dissertation, I detail the methodology I followed in an effort to uncover additional high-penetrance melanoma susceptibility genes. I analysed exome and genome sequence data from a total of 184 individuals that belong to 105 melanoma-prone families from the United Kingdom, The Netherlands and Australia that did not have any pathogenetic variants in known susceptibility genes. I applied different gene prioritisation strategies and developed novel software tools in order to devise a list of plausible melanoma susceptibility candidate genes; these analyses suggested that genes regulating telomere function could be influencing melanoma risk. After performing functional experimental analyses, our research team was able to determine that carriers of rare variants in the protection of telomeres (POT1) gene, a member of the shelterin complex that safeguards telomere integrity, are at high risk for developing melanoma. We successfully described the mechanism by which this happens, showing that the variants identified either disrupt POT1 mRNA splicing or abolish the ability of POT1 to bind to telomeres, and lead to increased telomere length in carriers when compared to melanoma cases with wild-type POT1. The main finding of the work described in this dissertation is the identification of telomere dysfunction as an important contributor to the risk of developing melanoma, and possibly other cancers. Our analyses suggest that POT1 is the second most commonly mutated high-penetrance melanoma susceptibility gene reported thus far, and moreover, that rare variants in this gene constitute the first hereditary mechanism for telomere lengthening in humans.