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Author: Cathy Yunjia Zhao, Dermatology Registrar, Westmead Hospital, Sydney, New South Wales, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof. Amanda Oakley, Dermatologist, Hamilton, New Zealand. October 2019.
Genes carry information in the form of DNA and control how cells function. A germline mutation affects all the cells in the body. A somatic mutation is restricted to a tumour cell, such as a melanoma cell.
Germline genetic testing for melanoma provides information on whether the patient has a mutation predisposing him/her to develop melanoma.
If the patient carries a germline gene mutation for melanoma, they may have an increased risk of developing a melanoma. They may have a positive family history for melanoma, and the onset of melanoma may be at a younger age compared to sporadic melanoma.
A biopsy sample of melanoma can be tested in the laboratory for somatic mutations to give information on treatment options or prognosis.
Some of the germline gene mutations involved in cutaneous melanoma include, but are not limited to :
Features of cutaneous melanoma tumour syndromes may include:
CDKN2A mutation has been found in 1.2% of patients with a single primary melanoma and in 2.9% of patients with multiple primary melanomas. Carriers of CDKN2A mutation often develop cutaneous melanoma at a young age, have a positive family history of melanoma, and may also be predisposed to pancreatic cancer .
The American Academy of Dermatology’s guideline published in 2019 recommends that the following patients may warrant CDKN2A genetic testing where available :
BAP1 mutation has been recognised as a rare cause of hereditary melanoma. Germline mutations of BAP1 are associated with:
Approximately 13% of carriers of a germline BAP1 mutation will develop a cutaneous melanoma, and a higher percentage of carriers will develop uveal melanoma [2,4].
The American Academy of Dermatology’s guideline published in 2019 recommends that the following history may warrant BAP1 genetic testing :
Genetic counsellors and medical geneticists may arrange germline genetic testing for melanoma. During an initial genetic counselling appointment, the patient’s personal and family history will be thoroughly reviewed to estimate their inherited cancer risks. The patient will then be counselled regarding the benefits and disadvantages of performing the genetic test. The ultimate decision to pursue genetic testing for germline mutations is a complex decision based on family history, cancer patterns, patient wishes, and perceived risks versus benefits .
Oncogenic somatic mutations such as BRAF, NRAS, c-KIT or PTEN can be tested by immunohistochemistry or genomic techniques. Of these mutations, BRAF is the most common, observed in 50–70% of cutaneous melanomas. Information about an oncogenic mutation may help the clinician choose the best treatment for advanced melanoma, as there are targeted therapies such as BRAF-inhibitors for tumours harbouring certain BRAF mutations. Oncogenic mutation testing is recommended in patients with metastatic disease or if there is potential for enrolment into a relevant clinical trial .
Somatic genetic testing on a tumour may also provide prognostic information. Prognostic tests are mostly still undergoing investigation.
Benefits to an individual include knowing their predisposition to melanoma, or to another type of cancer, depending on the gene tested .
A positive test can increase patient concern about their personal and family's risk of developing cancer, and it may also lead to concern about obtaining health insurance or life insurance.
A negative test may give the patient a false sense of security, leading to reduced melanoma vigilance and sun protection. Therefore, it is important to inform the patient that approximately 90% of cutaneous melanoma are sporadic and unrelated to gene mutations.
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