Clinical characteristics.

CDKN2A cancer predisposition is characterized by an increased risk of developing multiple cutaneous melanomas, pancreatic cancer, and other tumors including gliomas and astrocytomas. Some affected individuals have a high total nevus count (often >50 nevi) and atypical-appearing nevi, although the number and extent of atypical nevi can vary significantly.

Diagnosis/testing.

The diagnosis of CDKN2A cancer predisposition is established in a proband by identification of a heterozygous germline pathogenic variant in CDKN2A by molecular genetic testing.

Management.

Treatment of manifestations: Standard treatment for melanoma, pancreatic cancer, and other cancers.

Surveillance: Dermatologic examination for melanoma every six months; monthly self-skin examinations; annual alternating magnetic resonance cholangiopancreatography and endoscopic ultrasound starting at age 40 years or 10 years younger than the earliest exocrine pancreatic cancer diagnosis in the family, whichever is earlier; full-body and brain MRI in those with a CDKN2A pathogenic variant affecting the p14^ARF isoform in the setting of a family history of nervous system tumors.

Agents/circumstances to avoid: Ultraviolet light exposure, particularly sunburns and tanning booths; tobacco use.

Evaluation of relatives at risk: Molecular genetic testing for the familial CDKN2A pathogenic variant is recommended for at-risk relatives of an affected individual. Family members who have a CDKN2A pathogenic variant should be offered regular lifelong surveillance. At-risk family members whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.

Genetic counseling.

CDKN2A cancer predisposition is inherited in an autosomal dominant manner. The majority of individuals diagnosed with CDKN2A cancer predisposition inherited the CDKN2A germline pathogenic variant from a parent. A parent with a CDKN2A pathogenic variant may or may not have had a cancer diagnosis. Each child of an individual with CDKN2A cancer predisposition has a 50% chance of inheriting the pathogenic variant. Once the CDKN2A pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Suggestive Findings

CDKN2A cancer predisposition should be suspected in probands with the following clinical findings and family history.

Clinical findings [Hampel et al 2015, Soura et al 2016]

• ≥3 cutaneous melanomas at any age
• Pancreatic cancer and melanoma at any age
• ≥1 melanoma AND multiple melanocytic nevi (>50)
• Astrocytoma and melanoma in the same individual at any age
• Astrocytoma and family history of melanoma in two first-degree relatives at any age

Family history of ≥2 first- or second-degree relatives with melanoma and/or pancreatic cancer at any age

Establishing the Diagnosis

The diagnosis of CDKN2A cancer predisposition is established in a proband by identification of a heterozygous germline pathogenic (or likely pathogenic) variant in CDKN2A by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision-making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous CDKN2A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

CDKN2A cancer predisposition is characterized by an increased risk of developing multiple cutaneous melanomas, pancreatic cancer, and other tumors including gliomas and astrocytomas. Some affected individuals have a high total nevus count (often >50 nevi) and atypical-appearing nevi, although the number and extent of atypical nevi can vary significantly [Ipenburg et al 2016, Soura et al 2016]. Affected individuals from more than 300 families have been identified with a pathogenic variant in CDKN2A [Berwick et al 2006, Soura et al 2016, Kimura et al 2021, Overbeek et al 2021, Ibrahim et al 2023]. The following description of the phenotypic features associated with this condition is based on these reports.

Cutaneous melanoma is the most commonly associated malignancy in individuals with CDKN2A cancer predisposition. Individuals often develop multiple cutaneous melanomas in their lifetime. Studies have shown a lower median age of onset (around age 40 years) of cutaneous melanoma in individuals with CDKN2A cancer predisposition as compared to those with sporadic cutaneous melanoma, in whom the median age of diagnosis is the mid-60s [van der Rhee et al 2011, Soura et al 2016]. The age of onset of the first cutaneous melanoma is quite variable and has been reported as young as age nine years [Goldstein et al 2018]. These reports may be subject to ascertainment bias; in some individuals age of onset of melanoma may be at older ages, and penetrance is not 100%. Individuals often have multiple nevi, some of which may have atypical features. However, these are not considered precursors of melanoma but rather potential risk factors for melanoma. Melanoma most commonly develops on normal skin in individuals with and without CDKN2A cancer predisposition [Soura et al 2016]. Superficial spreading and nodular melanoma may be more prevalent in individuals with CDKN2A cancer predisposition than in those with sporadic melanoma. There does not appear to be a difference in risk for metastasis between individuals with CDKN2A cancer predisposition and sporadic cutaneous melanoma [Hornbuckle et al 2003, Soura et al 2016].

Pancreatic cancer is the second most common malignancy reported in individuals with CDKN2A cancer predisposition. The suggested risk is widely accepted as approximately 12-fold that of the general population (15%-20% lifetime risk) [Kimura et al 2021, Klatte et al 2022] (see also NCCN Guidelines, Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate Version 2.2025 [login required; accessed 1-8-25]). Meta-analysis of published studies suggests risk for pancreatic ductal adenocarcinoma is increased 12- to 47-fold for individuals with CDKN2A pathogenic germline variants [Pantaleo et al 2023]. This larger range includes some cohorts subject to ascertainment bias and/or population-specific data. The mean age of onset for pancreatic cancer in individuals with CDKN2A pathogenic variants ranges from age 65 to 71 years [Goldstein et al 2000, Lynch et al 2002]. It is unknown if the mean age of onset for pancreatic cancer is meaningfully lower for individuals with CDKN2A pathogenic variants compared to sporadic pancreatic cancer.

Nervous system tumors. Germline CDKN2A variants that disrupt p14^ARF are associated with an increased risk for glioma, glioblastoma multiforme, astrocytoma, neurilemmoma, neuroma, schwannoma, and meningioma, although reports of this are relatively rare [Toussi et al 2020, Chan et al 2021].

Other cancers have been reported in individuals with germline CDKN2A variants including head and neck squamous cell, sarcoma, esophageal, lung, breast, and non-melanoma skin cancers (particularly in individuals with a CDKN2A pathogenic variant affecting p14^ARF) [Chan et al 2021]. However, data are too limited to determine if the CDKN2A variant is causative or if these were sporadic cancers.

Genotype-Phenotype Correlations

Pathogenic variants in CDKN2A can affect p16^INK4, p14^ARF, or both proteins (see Molecular Pathogenesis). The spectrum of cancers reported in individuals with pathogenic variants affecting p14^ARF is broader than in individuals with pathogenic variants affecting p16^INK4A [Chan et al 2021].

• p14^ARF. Large deletions including CDKN2A or loss of intact p14^ARF have been associated with tumors including astrocytoma [Bahuau et al 1998, Randerson-Moor et al 2001, Sargen et al 2016, Chan et al 2017].
• p16^INK4. Pancreatic adenocarcinoma is seen more frequently in those with pathogenic variants affecting p16^INK4.

CDKN2A pathogenic variant p.Arg112dup is associated with higher risk for pancreatic, lung, head/neck, and gastroesophageal cancers with risk modified by smoking history [Goldstein et al 2007, Helgadottir et al 2014].

Biallelic CDKN2A pathogenic variants. Only two individuals with biallelic CDKN2A pathogenic variants have been reported in the literature; one developed adenocarcinoma at age 54 and reportedly had no history of atypical nevi or melanoma, while the other had many atypical nevi and seven melanomas [Pavel et al 2003].

Penetrance

The penetrance for CDKN2A cancer predisposition is less than 100%, with a lifetime risk of 28%-76% for melanoma and 10%-15% for pancreatic cancer (see Table 2).

Prevalence

The true prevalence of CDKN2A cancer predisposition is currently unknown. Of individuals with multiple primary melanomas, approximately 5% of individuals without a family history of melanoma and approximately 10% of individuals with at least three family members affected with melanoma have a germline CDKN2A pathogenic variant [Bruno et al 2022]. Pathogenic variants in CDKN2A have been identified in 0.1%-2.5% of unselected individuals with pancreatic ductal adenocarcinoma and 2.2%-3.3% of individuals with familial pancreatic cancer (two first-degree relatives with pancreatic cancer) [Paranal et al 2024].

The prevalence of CDKN2A cancer predisposition may be increased in certain populations due to founder variants (see Table 7).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CDKN2A cancer predisposition, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

The treatments for CDKN2A cancer predisposition cancers are those used in standard practice, similar to sporadic melanoma, pancreatic cancer, and other cancers.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended. To date, specific surveillance guidelines for those with a CDKN2A pathogenic variant that affects p14 ^ARF or p16^INK have not been published, although annual full-body and brain MRI can be considered for individuals with pathogenic variants disrupting p14^ARF (see NCCN Guidelines, Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate Version 2.2025 [login required; accessed 1-8-25]).

Agents/Circumstances to Avoid

Avoid the following:

• Ultraviolet light exposure, particularly sunburns and tanning booths
• Tobacco use

Evaluation of Relatives at Risk

Molecular genetic testing for the familial CDKN2A pathogenic variant is recommended for at-risk relatives of an affected individual. Family members who have a CDKN2A pathogenic variant should be offered regular lifelong surveillance. Family members who have not inherited the pathogenic variant and their subsequent offspring have cancer risks similar to the general population.

In general, genetic testing for CDKN2A cancer predisposition is not indicated for at-risk family members younger than age 18 years. However, predictive testing should be considered if there is a history of early-onset melanoma in the family (melanoma has been reported as young as age nine years [Goldstein et al 2018]) or a strong individual/familial preference for testing. At-risk family members whose genetic status is unknown should undergo skin exams at their well child / health maintenance visits.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Cancer of the Pancreas Screening-5 Study (CAPS5; NCT02000089). This study is open to individuals with germline pathogenic variants in CDKN2A age 40 years or older. It includes pancreatic imaging by magnetic resonance cholangiopancreatography and/or endoscopic ultrasound, measurement of CA19-9, and/or assessment of pancreatic digestive fluid for biomarkers. The study measures presence of early cancer markers in pancreatic digestive fluid, comparison of pancreatic digestive fluid and pancreas cyst fluid, disease progression and prevalence, and diagnostic performance of CA19-9 concentration as a tumor marker [Abe et al 2020, Canto et al 2020, Kumar et al 2021, Kohi et al 2022].

Other clinical trials available for individuals with CDKN2A cancer predisposition may include personalized cancer therapies for individuals with a cancer diagnosis and a known germline CDKN2A pathogenic variant. CDKN2A usually inhibits p16^INK4 and p14^ARF signaling [Danishevich et al 2023]. Loss of CDKN2A leads to uninhibited p16^INK4 and p14^ARF, signaling and several pharmacologic inhibitors for p16^INK4 and p14^ARF are being explored for CDKN2A-related cancers. Current or recent drug trials may be limited to specific tumor types (and may have additional eligibility criteria) and include:

• Ilorasertib (NCT02478320, NCT02540876)
• Milademetan in combination with atezolizumab (NCT06090318)
• Abemaciclib when administered with bevacizumab (NCT04074785)
• AZD1775 monotherapy (NCT02688907)
• Palbociclib and cetuximab in comparison with cetuximab monotherapy (NCT04966481)

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

CDKN2A cancer predisposition is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of individuals diagnosed with CDKN2A cancer predisposition inherited the CDKN2A germline pathogenic variant from a parent. A parent with a CDKN2A pathogenic variant may or may not have had a cancer diagnosis. An affected parent with a history of cancer may have had a CDKN2A-related or unrelated cancer that differs from the proband [Chan et al 2021].
• Individuals with CDKN2A cancer predisposition may have the diagnosis as the result of a de novo pathogenic variant. The proportion of individuals diagnosed with CDKN2A cancer predisposition caused by a de novo pathogenic variant is unknown. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of symptoms, or differences in exposure to environmental modifiers of cancer risk (geographical location, sun exposure, tobacco use) [Soura et al 2016]. Therefore, de novo occurrence of a CDKN2A pathogenic variant in the proband cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has the CDKN2A pathogenic variant.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for CDKN2A-related cancer surveillance.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the gonadal cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the CDKN2A pathogenic variant is 50%.
• The risk of developing cancer in a sib who inherits the familial CDKN2A pathogenic variant depends on the penetrance of the specific pathogenic variant and is not dependent on the age or sex of the heterozygous sib.
• If the CDKN2A pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [Rahbari et al 2016].
• If the proband is the only family member known to have CDKN2A cancer predisposition and the parents have not been tested for the CDKN2A pathogenic variant and are clinically unaffected, sibs of a proband are still considered to be at increased risk for CDKN2A cancer predisposition because of the possibility of reduced penetrance in a heterozygous parent and the possibility of parental gonadal mosaicism. Therefore, sibs should be offered molecular genetic testing regardless of the clinical status of parents.

Offspring of a proband. Each child of an individual with CDKN2A cancer predisposition has a 50% chance of inheriting the CDKN2A pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the CDKN2A pathogenic variant, the parent's family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the CDKN2A pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years). In general, genetic testing for CDKN2A cancer predisposition is not recommended for at-risk individuals younger than age 18 years. However, there are no current published guidelines regarding the age to initiate melanoma surveillance in individuals with CDKN2A cancer predisposition. Therefore, it is appropriate to consider predictive genetic testing if there is history of early-onset melanoma in the family or if there is a strong individual/familial preference for testing.

In a family with an established diagnosis of CDKN2A cancer predisposition, it is appropriate to consider testing of symptomatic individuals regardless of age.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ®, National Cancer Institute).

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the CDKN2A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CDKN2A is a tumor suppressor gene that encodes two major proteins, cyclin-dependent kinase inhibitor 2A (also called p16^INK4) and tumor suppressor ARF (also called p14^ARF), which function as cell cycle regulators. P16^INK4 inhibits cyclin-dependent kinases, ultimately resulting in increased RB tumor suppression function, while p14^ARF inhibits MDM2 function, resulting in increased TP53 activation. On a cellular level, activation of CDKN2A products lead to tumor-suppressive effects, such as cell cycle arrest or cellular senescence.

Mechanism of disease causation. Loss of function

CDKN2A-specific laboratory technical considerations. CDKN2A encodes p16^INK4 and p14^ARF, which utilize different first exons but the same second exon resulting in a different open reading frame. While p14^ARF terminates in the second exon, p16^INK4 continues in the second exon and also consists of a third exon.

Revision History

• 17 July 2025 (sw) Review posted live
• 1 November 2024 (te) Original submission

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