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What is BioGenoMEL?

BioGenoMEL is a consortium for the pooling of data and samples to identify genes and environmental exposures that predict risk of relapse from melanoma. Our hypothesis is that survival is determined by an interaction between the tumour, the host, and the host's environment. To achieve sufficient statistical power we are integrating the resources of groups from across the world.

The consortium will build on the highly successful work of GenoMEL www.genomel.eu in identifying susceptibility genes.

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Familial melanoma

Melanoma sometimes occurs in families, indicative of genetic susceptibility. Around 1% of melanoma patients report a family history in the UK[1], 7% of Canadian patients[2] and 11% in an Australian study[3]. The reason for the observation of different rates of family clustering in countries at different latitudes is uncertain. One explanation however, may be that it indicates an effect both of shared genes and environment (sun exposure).

Genetic susceptibility to anything may be variably potent. For example, there are predisposing genes with near 100% penetrance such as Huntington’s Chorea (everyone with the predisposition will manifest the syndrome if they live long enough), while there are many other genes, which have a low penetrance. The majority of people who carry these low penetrance genes will not develop the disease. Further, whether they do develop the disease or not may depend on their lifestyle or other genes. For melanoma it is easiest to group susceptibility genes into rare high penetrance genes and more common lower penetrance genes but the truth is that this distinction is not absolute. There is likely to be a continuous range of genes with variable penetrance all of which probably interact with other genes and with the environment.

Rare high penetrance genes for melanoma

By definition these genes have a high penetrance and therefore there are usually multiple cases of cancer in the family.

In some families there appears to be a pre-disposition to a variety of different cancers. For example melanoma may occur as a second tumour in familial retinoblastoma[4], [5]. There is also a possible association with the Li-Fraumeni syndrome[6] in which the predisposition is predominantly to brain tumours, sarcomas and breast cancer and in which inherited mutations in the p53 gene occur[7], [8]. Melanoma is a major risk factor for patients with xeroderma pigmentosum. Thus melanoma occurs as a part of family cancer syndromes where the susceptibility is to a variety of different cancers. In practice, then, taking a good family history, looking for recognisable patterns of cancers and seeking the opinion of Clinical Geneticists if in doubt, is the key approach.

There are in addition reports in the literature of clustering of melanoma in families and individuals with a variety of other cancers such as testicular tumours, lymphoma and brain tumours, the significance of which remains to be established [9-11] but which probably represents shared genetic and environmental aetiology.

In the majority of families with high penetrance melanoma susceptibility genes however the family history will reveal melanoma predominantly. To date there are probably at least 4 genes which underlie predisposition to melanoma in these families. The commonest is a gene on chromosome 9, called CDKN2A, which codes for a cell cycle control protein called p16. Families carrying mutations in this gene have been reported from Europe, the US and Australia. In UK studies, the likelihood of finding a mutation in this gene in melanoma families is much greater in families with larger numbers of affected family members. 50% of English families with 3 or more melanoma cases have CDKN2A mutations but only 12% of families with 2 or 3 cases[12-15]. In most CDKN2A families in the UK, the predisposition appears to be to melanoma alone. In other series however, particularly from the Netherlands and the US, there also appears to be an increased risk of pancreatic cancer[16], [17]. Valid estimates of risk of non-melanoma cancer in CDKN2A families are not yet available.

The second is the CDK4 gene[18], which codes for the protein to which p16 binds. Families with mutations in this gene are very rare indeed.

The third is p14ARF, which is adjacent to and continuous with CDKN2A on chromosome 9 and is coded by exon 1ß, alternately spliced with CDKN2A exon 2. p14ARF is therefore a second product of the same CDKN2A locus. Deletions of this gene have been shown to underlie susceptibility to melanoma and neural tumours[19]. These deletions appear to be very rare. More recently mutations in exon 1ß have been reported.

Low penetrance susceptibility genes.

The commonest gene yet identified, which predisposes to melanoma is the gene which underlies most if not all red hair[20] and freckles[21], known as MC1R. Variation in this gene has been shown to be associated with melanoma risk even in patients without red hair[22], [23]. The gene codes for the receptor for Melanocyte Stimulating Hormone, through which signaling for melanin production occurs. Variants in the gene appear to result in differing proportions of the black pigment eumelanin, and the redder pigment phaeomelanin, being produced. Some variants appear then to result in the production of phaeomelanin predominantly, with resultant red hair, freckles and sun sensitivity. The precise molecular determinants and biology of the susceptibility to melanoma remain to be elucidated but there appears to be no doubt that MC1R underlies weak susceptibility to melanoma in white populations.

There are other possible low penetrance genes promoting susceptibility to melanoma which Melanoma Genetics Consortium and others are exploring.

The hypothesis then, is that inheritance of these putative low penetrance genes predisposes white skinned peoples to melanoma but that as this predisposition is weak, there may be only one or occasionally two cases in the family. It is possible that the co-inheritance of more than one such low penetrance gene may result in more marked clustering of melanoma in some families. It is also possible that families carrying these low penetrance genes may have more cases of melanoma if they live in areas of the world where the environmental exposures are more extreme such as Queensland: that is, as a result of gene/environment interaction. This may at least in part explain why a family history of melanoma is more common in melanoma patients in hot climates.

In counselling patients as to what is the perceived risk of melanoma these considerations are taken into account and this is discussed below.

Assessing the significance of a family history of melanoma in the clinic

These are the questions to ask

  • Is all the melanoma on the same side of the family?
  • Does there seem to be an excess of other cancers as well as melanoma such as sarcoma, early onset of breast cancer, brain tumours or pancreatic cancer? If so referral to clinical genetics will be appropriate.
  • How many cases of melanoma are there? The more cases there are then the more likely it is that there is a high penetrance susceptibility gene in the family as described above.

The families who require specialist counselling about risk then are those

  • With 2 first degree relatives with melanoma.
  • With 2 cases (even if more distant relatives) if one or more have had multiple primaries or the cases have the atypical mole syndrome (dysplastic nevi) as self examination is then rather more difficult.
  • With 3 or more cases of melanoma.

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Glossary

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Associated
When two things are associated they are connected or joined in some way. It may be that one thing causes the other but they could be linked in some other way. For instance, if both things were caused by a separate, third thing.
Clinical geneticist
A doctor concerned with the care of people with genetic conditions.
Dermatologist
A specialist 'skin' doctor.
Freckle
A small brown patch on the skin that becomes darker following exposure to sunlight. Freckles can vary from light brown to dark brown, and are often found on the cheeks and across the bridge of the nose.
Genes
Genes are pieces of genetic 'code': they are the instructions or recipes that our bodies use for growth and repair.
GenoMEL
The Melanoma Genetics Consortium: an international, collaborative organisation researching the genetics of melanoma.
High-risk genes
Particular genes can make us more susceptible to diseases. If we have changes in them called mutations, and if the mutation significantly increase the risk of a disease (as compared to someone who does not have a mutation in the gene), it is called a high-risk gene.
IU
International Units
Melanoma
Melanoma is a form of cancer that develops from the pigment producing cells of the skin. If untreated it can spread through the body and is potentially fatal.
Microgram
A microgram (mcg) is a millionth of a gram.
Mutations
Mutations are changes or faults in our genes. Sometimes mutations can increase our chances of developing a disease.
nmol/L
nmol/L stands for nanomoles per litre. A nanomole is an extremely small unit of measurement.
Nervous system tumours
The nervous system consists of the brain, spinal cord, nerves and other structures that control our bodies. A tumour is an abnormal growth, which can be cancerous (having the potential to spread around the body) or benign (the growth remains in a single spot but may continue to grow in size).
Pancreas
The pancreas is a gland that lies behind the stomach. It produces digestive juices and controls blood sugar levels.
Risk
We are using the word risk to mean the chances of something happening. For example, if something is more likely to happen to John than to Peter then John is at greater risk than Peter.
SPF
Sun Protection Factor
UVA
UVA is a form of ultraviolet radiation. It is sometimes called long wave UV or black light.
Uveal melanoma
Uveal melanoma is a melanoma that occurs either in the coloured part of the eye (the iris) or other tissues nearby. It is a rare type of cancer.
UV Index
The UV index is a measurement of how much ultraviolet radiation is reaching a particular place at a given time. UV index forecasts are sometimes given as part of weather reports.

References

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Physician Information References
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How common is the atypical mole syndrome phenotype in apparently sporadic melanoma?
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2. Cutler, C., W. Foulkes, J.-S. Brunet, et al.,
Cutaneous malignant melanoma in women is uncommonly associated with a family history of melanoma in first-degree relatives: a case control study.
Melanoma Research, 1996. 6: p. 435-440.
http://www.ncbi.nlm.nih.gov/pubmed/9013481?dopt=Abstract
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Heterogeneity of melanoma risk in families of melanoma patients.
American Journal of Epidemiology, 1994. 140(11): p. 961-973.
http://www.ncbi.nlm.nih.gov/pubmed/7985658?dopt=Abstract
4. Bataille, V., R. Hiles, and J. Newton Bishop,
Retinoblastoma, melanoma and the atypical mole syndrome.
British Journal of Dermatology, 1995. 60: p. 622-626.
http://www.ncbi.nlm.nih.gov/pubmed/7756125?dopt=Abstract
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Cutaneous Malignant Melanoma in Survivors of Heritable Retinoblastoma.
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Solid tumors after chronic lymphocytic leukemia.
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Germline mutations of the CDKN2 gene in UK melanoma families, in Human Molecular Genetics.
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http://www.ncbi.nlm.nih.gov/pubmed/9328469?dopt=Abstract
13. Harland, M., E.A. Holland, P. Ghiorzo, et al.,
Mutation screening of the CDKN2A promoter in melanoma families.
Genes Chromosomes Cancer, 2000. 28(1): p. 45-57.
http://www.ncbi.nlm.nih.gov/pubmed/10738302?dopt=Abstract
14. Harland, M., S. Mistry, D.T. Bishop, et al.,
A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees.
Hum Mol Genet, 2001. 10(23): p. 2679-86.
http://www.ncbi.nlm.nih.gov/pubmed/11726555?dopt=Abstract
15. Newton Bishop, J.A., M. Harland, D.C. Bennett, et al.,
Mutation testing in melanoma families: INK4A, CDK4 and INK4D.
Br J Cancer, 1999. 80(1-2): p. 295-300.
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16. Bergman, W., P. Watson, J. de Jong, et al.,
Systemic cancer and the FAMMM syndrome.
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17. Lynch, H.T. and R.M. Fusaro,
Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome.
Pancreas, 1991. 6(2): p. 127-131.
http://www.ncbi.nlm.nih.gov/pubmed/1886881?dopt=Abstract
18. Zuo, L., J. Weger, Q. Yang, et al.,
Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma.
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http://www.ncbi.nlm.nih.gov/pubmed/8528263?dopt=Abstract
19. Randerson-Moor, J.A., M. Harland, S. Williams, et al.,
A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.
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http://www.ncbi.nlm.nih.gov/pubmed/11136714
20. Valverde, P., E. Healy, I. Jackson, et al.,
Variants of the melanocyte stimulating hormone receptor gene are associated with red hair and fair skin in humans.
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The melanocortin-1-receptor gene is the major freckle gene.
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23. Palmer, J.S., D.L. Duffy, N.F. Box, et al.,
Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?
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Consortium Information References
1. Harland, M., et al.,
Mutation screening of the CDKN2A promoter in melanoma families.
Genes Chromosomes Cancer, 2000. 28(1): p. 45-57.
2. Pollock PM, et al.,
Mutation analysis of the CDKN2A promoter in Australian melanoma families.
Genes Chromosomes Cancer. 2001 32(1):p 89-94.
3. Liu, L., et al.,
Mutation of the CDKN2A5'UTR creates an aberrant initiation codon and predisposes to melanoma.
Nature Genetics, 1999. 21: p. 1-5.
4. Harland, M., et al.,
A deep intronic mutation in CDKN2A is associated with disease in a subset of melanoma pedigrees.
Hum Mol Genet, 2001. 10(23): p. 2679-86.
5. Randerson-Moor, J.A., et al.,
A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family.
Hum Mol Genet, 2001. 10(1): p. 55-62.
6. Rizos, H., et al.,
A melanoma-associated germline mutation in exon 1beta inactivates p14ARF.
Oncogene, 2001. 20(39): p. 5543-7.
7. Gillanders, E., et al.,
Localization of a novel melanoma susceptibility locus to 1p22.
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8. Bishop, D.T., et al.,
Geographical variation in the penetrance of CDKN2A mutations for melanoma.
J Natl Cancer Inst, 2002. 94(12): p. 894-903.
9. Wachsmuth, R.C., et al.,
Heritability and gene-environment interactions for melanocytic nevus density examined in a U.K. adolescent twin study.
J Invest Dermatol, 2001. 117(2): p. 348-52.
10. Newton Bishop, J., et al.,
Genotype/phenotype and penetrance studies in melanoma families with germline CDKN2A mutations.
J Invest Dermatol, 2000. 114: p. 28-33.