How family history affects melanoma risk, which inherited genes are known, who is offered genetic counseling, and what a test result changes.
About 1 in 10 people diagnosed with melanoma has a close relative who also had it, according to the American Cancer Society. Shared genes explain part of that. Families also share fair skin, freckling, many moles, and habits such as beach vacations, so a family history does not by itself mean that a single faulty gene is being passed down.
Having a first-degree relative (a parent, brother, sister, or child) with melanoma raises a person's own risk to more than 2 times the average. Risk is higher still when several relatives are affected, when a relative was diagnosed young, or when 1 relative has had more than 1 melanoma.
Doctors use the term familial melanoma when the disease clusters in a family. Roughly 5% to 10% of melanomas occur in that setting. In fewer than half of those families can a specific high-risk gene be found with current tests. The rest are thought to result from combinations of lower-risk gene variants and shared sun exposure.
CDKN2A carries the instructions for 2 proteins, p16 and p14ARF, that act as brakes on cell division. A person who inherits 1 faulty copy has cells with weaker brakes. Harmful CDKN2A variants turn up in about 20% to 40% of large, high-risk melanoma families and account for about 2% of all melanomas.
Carriers tend to develop melanoma earlier than average, often in their 30s or 40s, and may develop several over a lifetime. Many, though not all, have large numbers of atypical moles, which are moles that are bigger than usual with irregular borders or mixed color.
That combination of many atypical moles plus melanoma in the family has a long name: familial atypical multiple mole melanoma (FAMMM) syndrome. In families with a CDKN2A variant, the syndrome also brings a higher risk of pancreatic cancer, and some families show a raised risk of a type of brain tumor called astrocytoma. For that reason a genetic counselor asks about pancreatic cancer on both sides of the family.
MC1R differs from the genes above. Variants are common, and their effect is modest. The gene controls which pigment the skin makes: brown-black eumelanin, which shields against UV, or red-yellow pheomelanin, which shields poorly. Certain MC1R variants produce red hair, freckles, and skin that burns easily.
People with these variants have a higher melanoma risk, and research suggests the increase is partly independent of sun exposure. Someone can carry 1 red hair variant and have brown hair. In families with CDKN2A variants, carrying an MC1R variant as well roughly doubles the risk again. Doctors do not usually test for MC1R in the clinic, because hair color, skin type, and freckling already give the same information.
Testing helps most when the chance of finding something is reasonably high. A widely used guide comes from Leachman and colleagues (Journal of the American Academy of Dermatology, 2009), who set criteria meant to identify people with at least a 10% chance of carrying a CDKN2A variant. For countries with moderate to high melanoma rates, such as the United States, it became known as the rule of 3s. Referral is suggested for:
In countries where melanoma is uncommon, such as Italy or Spain, 2 such cancers are enough. A 2017 update from the same group adapted the rule for multi-gene panels and gave credit for related cancers, including uveal melanoma, mesothelioma, kidney cancer, and early breast cancer. Clinicians also consider referral for melanoma at an unusually young age. These are guides, and judgment still applies.
Counselors prefer to test a family member who has had melanoma first. A normal result in an unaffected relative is hard to interpret unless the family's variant is already known.
A positive result mostly changes surveillance. Experts recommend that carriers have full skin exams by a dermatologist every 3 to 12 months, depending on mole pattern and history, and that they check their own skin monthly. Many clinics add total body photography and digital dermoscopy so that a changing mole can be caught early. Children in these families are taught sun protection early, and clinician skin exams typically begin around puberty.
For CDKN2A carriers, many centers also offer pancreatic screening with MRI or endoscopic ultrasound, particularly when a close relative has had pancreatic cancer. This is best done at a high-volume center, often within a research program. BAP1 carriers are usually advised to have yearly eye exams and to avoid asbestos.
A negative result is less clear-cut. If a known family variant was tested and not found, that person's risk falls toward what their skin type and sun history predict. If no variant was ever identified in the family, a negative panel leaves the family history in place, and doctors continue to recommend regular skin exams.
