CDK4-associated hereditary cancer

What Does It Mean to Test Positive for a CDK4 Mutation?

CDK4 mutations are a rare cause of hereditary melanoma. Individuals who test positive for a CDK4 mutation are at increased risk of developing melanoma over their lifetime. However, it is important to understand that the risk for cancer is not 100%, which means that not everyone with a CDK4 mutation will develop melanoma.  

What Are the Cancer Risks Associated with a CDK4 Mutation?

Since CDK4 mutations are rare, the cancer risks are not completely understood. Estimates of the lifetime risk for melanoma are believed to be similar to those associated with mutations in CDKN2A, another gene associated with hereditary melanoma, and are provided below.  

In general, the risk of melanoma associated with a CDK4 mutation is 58 to 92% by age 80, compared to approximately 2% in the general population. This risk depends on many factors, including a person's skin tone and where they live (sun exposure). For example, individuals living in Australia or those with fair skin tone are at higher risk for melanoma than someone living in the U.S. or Europe or those with darker skin tone. Individuals with CDK4 mutations may be diagnosed with melanoma at younger ages (33 to 45 years of age) than individuals without a CDK4 mutation (55 to 61 years of age). Additionally, individuals with CDK4 mutations are more likely to have multiple melanoma diagnoses within their lifetime.

Cancer Type Cancer Risk Average Age of Onset General Population Risk
Melanoma 58 to 92% 33 to 45 years 2.2%

Mutations in CDK4 have been reported in individuals with other types of cancer; however, more research is needed to determine the exact associated cancer types and possible risks. While screening and management guidelines for melanoma exist for those who test positive for a CDK4 mutation, there are currently no screening or management recommendations for other possible types of cancers.

What Cancer Screening or Risk-Reducing Options Are Available?

The most important aspect of management of an individual with a CDK4 mutation is increased cancer screening, to allow the earliest possible detection of cancer.

Several screening and risk-reducing options exist for individuals with CDK4 mutations, including more-frequent and more-specialized screenings. Management should be based on multiple factors, including family history, skin tone, hair color, and lifetime sun exposure. A thorough review of personal and family history with a healthcare provider will assist in the development of an individualized cancer-screening plan.

Screening Options

Individuals with a CDK4 mutation should consider increased screening for melanoma. This screening may include the following:

  • Beginning at age 10, a baseline total-body-skin examination should be performed. Repeat examinations should occur every 6 to 12 months, depending on the stability of nevi (moles), and suspicious skin lesions may require biopsy. Increased screening may be necessary during puberty or pregnancy to ensure that there are no changes in nevi.
    • The use of screening tools such as dermatoscopy (a lighted magnifying tool), total body photography, and digital dermoscopy (computer-image analysis) may help identify melanoma in the early stages.
  • Monthly self-examinations of skin should be performed. Beginning at age 10, education regarding self-examination should be provided. Self-examination is ideally performed in a well-lit room in front of a full-length mirror. A hand-held mirror may be used to examine areas that are hard to see, such as the back of the thighs. Alternatively, a spouse, close friend, or family member can help with the examinations, especially for hard-to-see areas like the back or scalp.
    • Nevi (moles) should be evaluated using the “ABCDE” rules. If a mole has any of the following features, follow-up with a dermatologist is appropriate:
      • Asymmetric Shape
      • Border irregularity
      • Color variability
      • Diameter greater than 6 mm
      • Elevation or Evolution

Risk-Reducing Options

While it is important for everyone, including children, to practice sun protection in order to avoid UV radiation exposure, it is especially important for individuals with CDK4 mutations. Risk-reducing steps include the following:   

  • Wear sunscreen or protective clothing, such as sunglasses and a hat
  • Stay in the shade
  • Avoid sun exposure between 10:00 a.m. and 4:00 p.m.  

What Is the Chance That Family Members of CDK4 Mutation Carriers Have the Same Mutation?

CDK4 mutations are passed down in a family. This means that family members of CDK4 mutation carriers may have the same mutation and may also be at increased risk to develop cancer. For this reason, it is important for CDK4 mutation carriers to discuss genetic test results with family members.

  • Close blood relatives of CDK4 mutation carriers, such as parents, siblings, and children, have a 50% chance of having the same mutation.
  • Distant relatives, such as aunts, uncles, grandparents, and cousins, also have a chance of having the same CDK4 mutation.
  • A physician or a genetic counselor can help mutation carriers determine whether the mutation was more likely to have been inherited from the maternal or paternal side of the family. In general, the mutation will only be found on one side of the family, and it is more likely to be on the side of the family that has a history of melanoma.

Genetic testing of family members can help determine those members with increased risk for cancer who may benefit from screening and/or risk-reduction options discussed above. As melanoma risk can depend on additional genetic factors such as skin and hair coloration, family members testing negative for a known familial CDK4 mutation may still be at increased risk for cancer and may still need additional screening for melanoma. All family members should speak with a healthcare professional for a personalized risk assessment.

What Else Should CDK4 Mutation Carriers Know?

Mutation carriers who are interested in options to prevent passing their mutation to future children may wish to consider preimplantation genetic diagnosis (PGD). PGD is a procedure that involves in vitro fertilization (IVF) and can determine if an embryo carries the genetic mutation present in a family. Determining which embryos carry the family mutation may allow a mutation carrier to prevent the condition from being passed to future children. The decision to undergo PGD is personal. Mutation carriers and their family members can talk with a healthcare provider to learn more about their reproductive options.