Polubothu, Satyamaanasa;
(2020)
Genetic studies in Congenital Melanocytic Naavi.
Doctoral thesis (Ph.D), UCL (University College London).
Abstract
Background: Congenital melanocytic naevi (CMN) are moles present at birth, can be associated with extracutaneous features and the most severely affected children have a 10-15% risk of development of fatal melanoma. The cause of multiple CMN was previously identified as somatic mosaicism for NRAS in 70% of cases. Although a somatic mosaic condition, up to 1/3 of patients have a family history of CMN, implying a role for Mendelian genetics in disease onset or presentation. Identification of novel somatic and germline variants in CMN will enable us to understand which effector pathways are important in pathogenesis, with a view to identifying novel therapeutic targets. Aims: To establish genotype-phenotype associations in CMN, to look for novel somatic genetic causes of CMN, to characterise the role and pathogenetic mechanism of novel germline duplications affecting the gene PPP2R3B in CMN and melanoma and to establish the natural colour history of CMN. Methods: Next generation sequencing (NGS) was used to identify novel somatic variants and copy number variants in a population of CMN and adult melanoma. Cellular modelling of PPP2R3B duplications was undertaken using stable, inducible PPP2R3B cell lines and proliferation and migration studies. A standardised measurement of colour of CMN was devised and lightening measured over time. Results: NRAS is the commonest cause of multiple CMN found in 68%. BRAF was identified as a new, rare cause of multiple CMN, affecting 7%. No novel somatic variants were identified following whole exome sequencing or targeted next generation sequencing. PPP2R3B duplications were identified in an adult melanoma cohort and overexpression of PPP2R3B leads to increased proliferation and decreased migration of melanoma cell lines via C21orf91. Final CMN colour is genetically-determined, related to inherited pigmentary phenotype, not related to colour in the first three months of life, and not affected by superficial removal techniques.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Genetic studies in Congenital Melanocytic Naavi |
| Event: | UCL |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10091983 |
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