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Title: The Genetic and Environmental Determinants of Benign Melanocytic Naevi
Author: Wachsmuth, Rachel Caroline
ISNI:       0000 0001 3549 4926
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2006
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Abstract for thesis entitled 'The genetic and environmental determinants ofbenign melanocytic naevi' submitted by Dr Rachel Caroline Wachsmuth for the degree of Doctor of Medicine 2006. The work covered in this thesis contributes to our understanding ofthe relationships between genes, sun exposure, benign melanocytic naevi and melanoma. Rare families with multiple cases of melanoma have been found to possess mutations in a limited number of genes, the first of which to be identified being CDKN2A (on chromosome 9p) that codes for the cell cycle regulating protein: p16. Epidemiological studies have shown that melanoma is a disease primarily of Caucasians who are at even greater risk with increased sun exposure. Furthermore, individuals with numerous benign melanocytic naevi are at increased risk ofmelanoma both in melanoma families and the general population. A combination of sun exposure and genes defining general and naevus phenotype is therefore key to the development of melanoma. In the first part of this thesis I examine the relationships between CDKN2A mutation status, --- --- ---:-----nae\ilisphe-riotype -ana presence of melanom-a,-inastuCly of 5-UK-iriehirioma-families. -I----- demonstrate a naevogenic role for CDKN2A, but a lack of absolute correlation between general naevus phenotype and CDKN2A genotype. I also estimate the penetrance ofCDKN2A mutation for melanoma within these families. I conClude that the practice oftargeting individuals with many naevi as potential gene carriers is untenable for melanoma screening purposes. In the second and main part of this thesis I examine the role ofgenes and sun exposure on the development of benign naevi in a twin study of221 UK twin pairs. In agreement with published literature, naevi were more common in males, persons with fairer skintypes or blue eyes, and in continuously sun exposed body sites compared to intermittently or non-exposed sites. Heritability analysis assessed genetic and environmental effects on naevus development and estimated that 26% of the variation in naevus counts between individuals was due to environmental effects (one third of which is hot holiday sun exposure), 3% to age and sex, 6% to measurement error and 65% due to genetic effects. Variation in naevus number is thus predominantly genetically inherited with a further breakdown ofthis 65% into 7% associated with eye colour, 6% with hair colour, I% with skintype and 51% with as yet unidentified 'naevus genes'. Such naevus genes may represent more common but lower penetrant melanoma genes than those identified to date. The previously mentioned CDKN2A gene was studied as a possible naevus gene by linkage analysis, but found not to associate with naevus counts. Further gene studies are therefore required to identify these naevus genes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available