Familial Melanoma
Familial melanoma (ORPHA:618) is a term referring to families in which two first-degree relatives or more have developed histologically confirmed melanoma, a type of skin cancer. The definition, however, varies across countries. In regions with a high prevalence of melanoma, it is typically defined as the presence of three first- or second-degree relatives diagnosed with melanoma.
Overall, about 8% of people newly diagnosed with cutaneous melanoma have a first-degree relative with melanoma, and about 1% has two or more close relatives with melanoma.
Melanoma and neural system tumour syndrome (orpha:252206) is a rare clinical phenotype characterized by the co-occurrence of melanoma and neural system tumours in an individual or a family.
FAMMM (ORPHA:404560) is an inherited condition characterized by the development of more than 50 atypical moles (e.g. >0.6 cm in diameters, asymmetric shape, coloured) associated with personal and/or family history of melanoma. A subset of patients with FAMMM also have an increased risk of pancreatic cancer. FAMMM has been associated with pathogenic variants in the high-penetrance gene CDKN2A, but more than 50% of patients with FAMMM do not have a CDKN2A pathogenic variant.
FAMMM is primarily a clinical diagnosis and is less commonly used.
There are several risk factors for melanoma, including genetic background, skin phenotype (pigmentation, freckles, number of moles) and UV exposure.
Genetic factors include alterations in low, medium, and high penetrance genes. Most low and medium penetrance genes are involved in determining phenotypic traits such as pigmentation of skin, hair and eyes, or number of moles on the body.
The best-known high penetrance gene involved in melanoma predisposition is CDKN2A, where pathogenic variants are found in 20-40% of melanoma families with three or more individuals with the disease.
Other rare high penetrance genes are CDK4, BAP1, and POT1; the latter two are responsible of predisposition to various types of neoplasia beyond melanoma (BAP1 and POT1 tumour predisposition syndromes).
In families without pathogenic variants in high-penetrance genes, the inheritance is complex and usually involves low-medium-penetrance gene variants combined with environmental exposures such as UV-radiation.
Familial melanoma caused by pathogenic variants in known high-penetrance genes is inherited in an autosomal dominant manner. This means that the presence of a heterozygous pathogenic variant is sufficient to significantly increase the risk of developing melanoma, which typically occurs at an earlier age than the average age of onset of melanoma in the general population. Carriers of heterozygous pathogenic variants have a 50% risk of transmitting the variant to their children. Preimplantation and prenatal genetic testing are possible when one of the parents is a known carrier of a pathogenic variant in a high-risk gene.
In families with no pathogenic variant in high-penetrance genes, disease inheritance is likely multifactorial: it is possible to identify/evaluate some of these risk factors (such as atypical nevi, low pigmentation, prior sunburn, and sun damaged skin) through skin examination.
Individuals at increased risk of developing melanoma should be educated on the importance of melanoma prevention, by using sunscreen and sun protection clothes, and avoiding tanning beds, especially for children and young adults. Individuals should also be educated in early detection of skin alterations and undergo periodical dermatologic examination by a specialist. Families with familial melanoma due to CDKN2A pathogenic variants should discuss with their doctor whether endoscopic ultrasound or magnetic resonance cholangiopancreatography (MRCP) should be performed regularly from the age of 45 for the increased risk of pancreatic cancer with some pathogenic variants, especially if there is a positive family history for this type of tumour.
Orphanet: Familial melanoma
Orphanet: Melanoma and neural system tumor syndrome
Orphanet: Familial atypical multiple mole melanoma syndrome
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Thematic Group 4: Other rare – predominantly malignant – genturis |
ERN GENTURIS webinars - Thematic group 4: Other rare genturis
ERN GENTURIS webinars - General
A list of healthcare providers with expertise in Thematic Group 4: Other rare - predominantly malignant - genturis can be found here.
A non-exhaustive list of patient associations for genetic tumour risk syndromes in EU member states can be found here.