- Group summary: The Melanoma Research Group uses genetic epidemiology to understand why people get melanoma and what determines survival after diagnosis.
- Website: www.genomel.org
What we do
Genetic epidemiology describes research using genetics and assessed measures of exposure allowing an examination of how genes interact with the environment. The research group, for example, considers the role of genetic variation associated with melanoma risk and patterns of sun exposure in susceptibility. It also looks at exposures after a diagnosis of melanoma eg vitamin D deficiency, and how those exposures interact with genetic profile both inherited and in the tumour.
The work designed to better understand what causes melanoma has been taking place for many years both within the UK and internationally. The Leeds group has chaired the international melanoma genetics consortium GenoMEL since 1997, and this collaborative effort has led the work on melanoma genetics since then. We have carried out studies which have defined the skin type at risk (skin which burns and freckles in the sun) and the presence of increased numbers of melanocytic naevi (moles). We have used genetics (the inheritance of small variations in inherited genes which increase the risk of melanoma each to a small degree, but when combined may be associated with a significantly increased risk) to understand the biology behind these skin factors. We have shown (in collaboration with research groups worldwide) that genetic changes in genes coding for pigmentation play a critical role in determining risk as does genetic variation for naevus susceptibility but that there is also a substantial contribution for genes involved in telomere function. Thus, these studies have identified a crucial role for genes controlling telomere function in melanoma initiation.
The identification of high risk inherited genes is an important aim because their identification tells us something important about the biology of melanoma. It is important to families at risk of melanoma in order that counselling about risk is accurate and that appropriate screening be put in place. The first identified high risk gene was CDKN2A which codes for two proteins p16 and p14ARF;mutations in this gene are found in around 2% of melanoma patients worldwide. This is the most common of the genes identified so far. Inherited mutations in the gene CDK4 produce risks very similar to those associated with CDKN2A, predominantly melanoma risk with a risk of pancreatic cancer in some families worldwide. The risk of other cancers is still a subject of investigation although in some founder mutations there appears to be an increased risk of smoking related cancers. Inherited mutations in BAP1, POT1, TERT and a group of genes coding for the shelterin complex, are very rare and cancer risks for each are the focus of research in our group and internationally.
In terms of sun exposure and risk, we have carried out case-control studies in the UK and a meta-analysis of studies performed world wide. The clearest message from these studies is that melanoma is caused by sunburn. There is evidence that sunbathing is associated with risk probably via sunburn but perhaps surprisingly little evidence that chronic sun exposure is associated with risk. Melanoma is not a disease of outdoor workers. It may be that repeated mild sunburn in the pale skinned increases the risk of melanoma on often sun exposed skin, e.g. head and neck but this is difficult to prove. A unifying conclusion from the work performed is that sunburn should be avoided.
The group has been carrying out research into environmental factors modifying the chance of survival from melanoma. We have asked many patients to take part in studies to understand these factors since then, enabling us to build sufficiently large and complex data sets to explore this. The largest is the Leeds Melanoma Cohort. Data from this cohort formed the basis of a paper in JCO in 2009, in which lower vitamin D levels in the blood at melanoma diagnosis were reported to be associated with thicker primary tumours and poorer survival independent of thickness. 4 subsequent studies from around the world reported similar observations and since then we have reported a series of studies which were designed to understand whether there was a biological explanation for these observations (ie was this a causal relationship?). We have reported some evidence that higher vitamin D levels are associated with less microscopic ulceration of primary tumours (a marker of a poor prognostic tumour), and a paper under review Nov 2018 reports a role for vitamin D/VDR signalling in the control of melanoma cell proliferation and the promotion of immune responses.
We have also reported that smoking has an independent adverse effect on survival and we are investigating the mechanism currently in the lab.
Most recently we have been using transcriptomic data from a data set of 703 primary melanomas to understand host tumour interaction. We have published evidence that beta catenin signalling and MYC both play significant roles in the failure to mount an immune response to melanoma.
It is our hypothesis that host and tumour factors control survival from melanoma and response to therapies. Moreover that measures of both will prove better prognostic and predictive biomarkers and we are working currently to explore this.
Cancer Research UK, MRC, NIH, Melanoma focus, WCRF.
1. Nsengimana J, Laye J, Filia A, O'Shea S, Muralidhar S, Pozniak J, et al. beta-Catenin-mediated immune evasion pathway frequently operates in primary cutaneous melanomas. J Clin Invest. 2018;128(5):2048-63.
2. Muinonen-Martin AJ, O'Shea SJ, Newton-Bishop J. Amelanotic melanoma. BMJ. 2018;360:k826.
3. Lipplaa A, Fernandes R, Marshall A, Lorigan P, Dunn J, Myers KA, et al. 25-hydroxyvitamin D serum levels in patients with high risk resected melanoma treated in an adjuvant bevacizumab trial. Br J Cancer. 2018.
4. Lindsay CR, Shaw EC, Blackhall F, Blyth KG, Brenton JD, Chaturvedi A, et al. Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme. ESMO Open. 2018;3(6):e000408.
5. Del Castillo Velasco-Herrera M, van der Weyden L, Nsengimana J, Speak AO, Sjoberg MK, Bishop DT, et al. Comparative genomics reveals that loss of lunatic fringe (LFNG) promotes melanoma metastasis. Mol Oncol. 2018;12(2):239-55.
6. Cust AE, Drummond M, Kanetsky PA, Australian Melanoma Family Study I, Leeds Case-Control Study I, Goldstein AM, et al. Assessing the Incremental Contribution of Common Genomic Variants to Melanoma Risk Prediction in Two Population-Based Studies. J Invest Dermatol. 2018.
7. O'Shea SJ, Robles-Espinoza CD, McLellan L, Harrigan J, Jacq X, Hewinson J, et al. A population-based analysis of germline BAP1 mutations in melanoma. Hum Mol Genet. 2017.
8. Rogers Z, Elliott F, Kasparian NA, Bishop DT, Barrett JH, Newton-Bishop J. Psychosocial, clinical and demographic features related to worry in patients with melanoma. Melanoma Res. 2016;26(5):497-504.
9. O'Shea SJ, Mitra A, Graham JL, Charlton R, Adlard J, Merchant W, et al. Histopathology of melanocytic lesions in a family with an inherited BAP1 mutation. J Cutan Pathol. 2016;43(3):287-9.
10. O'Shea SJ, Davies JR, Newton-Bishop JA. Vitamin D, vitamin A, the primary melanoma transcriptome and survival. Br J Dermatol. 2016;175 Suppl 2:30-4.
11. Lauss M, Nsengimana J, Staaf J, Newton-Bishop J, Jonsson G. Consensus of Melanoma Gene Expression Subtypes Converges on Biological Entities. J Invest Dermatol. 2016.
12. Hayes AJ, Maynard L, Coombes G, Newton-Bishop J, Timmons M, Cook M, et al. Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol. 2016;17(2):184-92.
13. Harland M, Petljak M, Robles-Espinoza CD, Ding Z, Gruis NA, van Doorn R, et al. Germline TERT promoter mutations are rare in familial melanoma. Fam Cancer. 2016;15(1):139-44.
14. Tagliabue E, Fargnoli MC, Gandini S, Maisonneuve P, Liu F, Kayser M, et al. MC1R gene variants and non-melanoma skin cancer: a pooled-analysis from the M-SKIP project. Br J Cancer. 2015;113(2):354-63.
15. Stamataki Z, Brunton L, Lorigan P, Green AC, Newton-Bishop J, Molassiotis A. Assessing the impact of diagnosis and the related supportive care needs in patients with cutaneous melanoma. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2015;23(3):779-89.
16. Sargen MR, Kanetsky PA, Newton-Bishop J, Hayward NK, Mann GJ, Gruis NA, et al. Histologic features of melanoma associated with CDKN2A genotype. J Am Acad Dermatol. 2015;72(3):496-507 e7.
17. Nsengimana J, Laye J, Filia A, Walker C, Jewell R, Van den Oord JJ, et al. Independent replication of a melanoma subtype gene signature and evaluation of its prognostic value and biological correlates in a population cohort. Oncotarget. 2015;6(13):11683-93.
18. Newton-Bishop JA, Davies JR, Latheef F, Randerson-Moor J, Chan M, Gascoyne J, et al. 25-Hydroxyvitamin D2 /D3 levels and factors associated with systemic inflammation and melanoma survival in the Leeds Melanoma Cohort. Int J Cancer. 2015;136(12):2890-9.
19. Macbeth F, Newton-Bishop J, O'Connell S, Hawkins JE, Guideline Development G. Melanoma: summary of NICE guidance. BMJ. 2015;351:h3708.
20. Jewell R, Elliott F, Laye J, Nsengimana J, Davies J, Walker C, et al. The clinicopathological and gene expression patterns associated with ulceration of primary melanoma. Pigment Cell Melanoma Res. 2015;28(1):94-104.
21. Davies JR, Chang YM, Bishop DT, Armstrong BK, Bataille V, Bergman W, et al. Development and validation of a melanoma risk score based on pooled data from 16 case-control studies. Cancer Epidemiol Biomarkers Prev. 2015;24(5):817-24.
22. Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, et al. Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma. J Natl Cancer Inst. 2015;107(2).
23. Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478-81.
24. Field S, Elliott F, Randerson-Moor J, Kukalizch K, Barrett JH, Bishop DT, et al. Do vitamin A serum levels moderate outcome or the protective effect of vitamin D on outcome from malignant melanoma? Clin Nutr. 2013;32(6):1012-6.
25. Davies JR, Field S, Randerson-Moor J, Harland M, Kumar R, Anic GM, et al. An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study. Pigment Cell Melanoma Res. 2013.
26. Storr SJ, Safuan S, Mitra A, Elliott F, Walker C, Vasko MJ, et al. Objective assessment of blood and lymphatic vessel invasion and association with macrophage infiltration in cutaneous melanoma. Mod Pathol. 2012;25(4):493-504.
27. Jewell R, Mitra A, Conway C, Iremonger J, Walker C, de Kort F, et al. Identification of differentially expressed genes in matched formalin-fixed paraffin-embedded primary and metastatic melanoma tumor pairs. Pigment cell & melanoma research. 2012;25(2):284-6.
28. Macgregor S, Montgomery GW, Liu JZ, Zhao ZZ, Henders AK, Stark M, et al. Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3. Nature genetics. 2011.
29. Davies JR, Chang YM, Snowden H, Chan M, Leake S, Karpavicius B, et al. The determinants of serum vitamin D levels in participants in a melanoma case-control study living in a temperate climate. Cancer causes & control : CCC. 2011.
30. Mitra A, Conway C, Walker C, Cook M, Powell B, Lobo S, et al. Melanoma sentinel node biopsy and prediction models for relapse and overall survival. Br J Cancer. 2010;103(8):1229-36.
31. Conway C, Beswick S, Elliott F, Chang YM, Randerson-Moor J, Harland M, et al. Deletion at chromosome arm 9p in relation to BRAF/NRAS mutations and prognostic significance for primary melanoma. Genes Chromosomes Cancer. 2010;49(5):425-38.
32. Newton-Bishop JA, Beswick S, Randerson-Moor J, Chang YM, Affleck P, Elliott F, et al. Serum 25-Hydroxyvitamin D-3 Levels Are Associated With Breslow Thickness at Presentation and Survival From Melanoma. Journal of Clinical Oncology. 2009;27(32):5439-44.
33. Lens M, Rosdahl I, Newton-Bishop J. Cutaneous melanoma during pregnancy: is the controversy over? J Clin Oncol. 2009;27(19):e11-2; author reply e3-4.
34. Chang YM, Newton-Bishop JA, Bishop DT, Armstrong BK, Bataille V, Bergman W, et al. A pooled analysis of melanocytic nevus phenotype and the risk of cutaneous melanoma at different latitudes. Int J Cancer. 2009;124(2):420-8.
35. Chang YM, Barrett JH, Bishop DT, Armstrong BK, Bataille V, Bergman W, et al. Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009;38(3):814-30.
36. Duffy DL, Zhu G, Li X, Sanna M, Iles MM, Jacobs LC, et al. Novel pleiotropic risk loci for melanoma and nevus density implicate multiple biological pathways. Nat Commun. 2018;9(1):4774.
37. Robles-Espinoza CD, Roberts ND, Chen S, Leacy FP, Alexandrov LB, Pornputtapong N, et al. Germline MC1R status influences somatic mutation burden in melanoma. Nat Commun. 2016;7:12064.
38. Law MH, Bishop DT, Lee JE, Brossard M, Martin NG, Moses EK, et al. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat Genet. 2015;47(9):987-95.
39. Barrett JH, Taylor JC, Bright C, Harland M, Dunning AM, Akslen LA, et al. Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions. Int J Cancer. 2015;136(6):1351-60.
40. Barrett JH, Iles MM, Harland M, Taylor JC, Aitken JF, Andresen PA, et al. Genome-wide association study identifies three new melanoma susceptibility loci. Nature genetics. 2011;43(11):1108-13.
41. Brown KM, Macgregor S, Montgomery GW, Craig DW, Zhao ZZ, Iyadurai K, et al. Common sequence variants on 20q11.22 confer melanoma susceptibility. Nat Genet. 2008;40(7):838-40.
42. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94(12):894-903.
Who we are
Professor Julia Newton-Bishop