Genetics of cutaneous malignant melanoma

Lang, Julie M.S (2004) Genetics of cutaneous malignant melanoma. PhD thesis, University of Glasgow.

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Cutaneous malignant melanoma has doubled in incidence in many countries over the past 20 years. The majority of melanomas are sporadic, but up to 5% of melanoma patients have one or more first-degree relatives also affected, and genetic analysis of these families shows germline mutations of CDKN2A in 20-30% of patients. This thesis has investigated 48 Scottish families with cutaneous malignant melanoma and also 28 patients with sporadic melanoma for mutations in the CDKN2A, MCIR and BRAF genes using molecular genetic techniques. The work presented in this thesis adds 32 new melanoma families to the 16 already reported from Scotland (MacKie et al. 1998). In total, 13/48 (27%) Scottish families have detectable CDKN2A mutations. One of the mutations detected (H83N) has not previously been reported in melanoma, and molecular modelling suggests the likely functional result of this mutation. in the course of studying the CDKN2A gene the M531 mutation was identified in six Scottish families making it the most common CDKN2A mutation identified in this thesis from the Scottish melanoma families studied. Haplotype analysis surrounding CDKN2A was therefore performed on the six Scottish families and also examined in 12 M53I carrying families from around the world. This study provides further evidence that the M53I mutation appears to have originated from a common founder and provides further evidence demonstrating common founders for most of the recurrent mutations in the CDKN2A gene. The aim of the analysis of the MCIR gene was to investigate any underlying genetic relationship between MCIR variants and CDKN2A mutations. In total, 13 MCIR variants leading to an amino acid substitution were detected, three of which have not been described elsewhere (L44I, M128K, A171G) and appear to be very rare. Collectively, both familial and sporadic melanoma patients are more likely to carry a MCIR variant than normal control subjects (P = 0.006; OR = 4.485; CI 1.492-12.883) and melanoma patients carry significantly more MCIR variants than control subjects (P = 0.003; OR = 2.696; CI 1.384-5.253). Familial melanoma patients are more likely to carry the R151C variant than normal control subjects (P = 0.043; OR = 2.406; CI 1.062-5.452). CDKN2A positive familial melanoma patients are more likely to carry the V60L and R151C variants than CDKN2A negative familial melanoma patients (P = 0.017; OR = 3.818; CI 1.315-11.084 and P = 0.029; OR = 3.515; CI 1.160-10.650, respectively). Conversely, CDKN2A negative familial melanoma patients are more likely to carry the V92M variant than CDKN2A positive familial melanoma patients (P = 0.021; OR = 9.308; CI 1.112-77.888). The variant R160W is significantly correlated with skin type 1 (P < 0.001) and variants R142H (P = 0.019) and R160W (P = 0.018) are significantly correlated with red hair, although this significance is lost after the Bonferroni correction. During the time of this study Davies et al. (2002) reported that the most frequently targeted gene in melanoma is BRAF. All mutations were within the kinase domain, with a single substitution in exon 15 (V599E) accounting for 80% of mutations. BRAF mutations in germline DNA from familial melanoma patients had not been investigated, and the number of melanoma tissue samples investigated for BRAF mutations was low. One of the aims of this thesis therefore was to screen exon 15 of BRAF to determine if the V599E mutation would contribute to melanoma predisposition in familial melanoma as a germline mutation. The study of this thesis also investigated primary and secondary melanomas for exon 15 BRAF mutations. DNA from the peripheral blood of 42 familial melanoma cases contained no exon 15 BRAF mutations. DNA from two samples of secondary melanoma from two individuals with a family history of melanoma also failed to show exon 15 BRAF mutations. These results therefore suggest that exon 15 BRAF mutations are not causative germline mutations in melanoma. The V599E substitution was however detected in formalin fixed paraffin embedded primary tumour DNA from 13/52 sporadic cases (25%). The V599E substitution was also detected in secondary tumour DNA from 6/22 sporadic cases (27%) of frozen secondary melanoma.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Rona Mackie
Keywords: Genetics, Oncology
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-74060
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33

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