CDKN2A Mutation: A Patient’s and Physician’s Experience

Abstract

This article discusses both the patient’s and physician’s perspective on the CDKN2A mutation. After an intriguing interview with the patient, the author writes about the patient’s feelings, thoughts, and overall experience when he was diagnosed with the CDKN2A mutation. The patient’s story discusses what prompted the patient to get tested for the mutation and how the diagnosis later impacted his life and that of his family. The author describes the clinical relevance of the CDKN2A mutation and the current guidelines for testing. The author highlights the need to recognize patients with familial melanomas as high risk and educate the patient on the importance of routine dermatological surveillance.

Patient Experience

Mr. A’s story begins more than 20 years ago when his sister passed away from melanoma. Before her passing, Mr. A was not a frequent sunscreen user and rarely examined his skin. After her passing, his mindset regarding skin cancer protection and prevention changed. Mr. A recounts meeting with his general practitioner (GP) and telling him “I don’t know what to look for”. His GP provided him with a pamphlet of information and told him “You’re looking for things that get darker, for things that get bigger, and things that change shape.”

Fast forward years later, at his annual visit with his dermatologist, Mr. A pointed out a mole on his abdomen that he had not seen before. He noticed this mole change shape and grow in size. Something did not seem right. The lesion was biopsied, and it was indeed an invasive melanoma, with a 0.9 mm Breslow depth. He was scheduled for surgery and sentinel lymph node biopsy. It was all new and unfamiliar, but with the help of his wife, who was in the medical field, he was able to better understand the process.

Coming from a family of six siblings, four of whom had been diagnosed with melanoma, his physician recommended genetic testing, after he was diagnosed with his own melanoma. When he was told he was positive for the CDKN2A mutation he was confused, he did not know what it meant, he was the first person in his family to be tested for the mutation. That is when it all started. His physician told him he was predisposed to melanoma because of the mutation and had an increased risk for pancreatic cancer. His wife, once again, helped him understand what this meant and how this would impact his routine checkups. Not only would he have to make sure to follow up consistently with his dermatologist but he would also have routine imaging with an MRI/MRCP and/or endoscopic ultrasound to screen for pancreatic cancer. After learning about the mutation, Mr. A told his siblings they should also get tested for the mutation. They soon found out that four of the six siblings were also positive for the mutation. While his oldest sister, who passed away, had not previously been tested, two of her three children were positive for the mutation. The remaining siblings were unsure whether they wanted to get tested. Mr. A mentioned “Some of them were reluctant because once you are identified as having a marker, it’s out there in the world, and if you want a life insurance policy they can charge you more because you are at risk. So, I think initially some of them were more skeptical about doing it.”

Knowing that he had this mutation and having been diagnosed with melanoma in the past, Mr. A became more proactive in checking and protecting his skin. Mr. A began checking his skin regularly, after he showered, scanning his arms, legs, abdomen, and back, to see if he noticed anything that he had not seen before. He went from barely using sunscreen, to wearing sunscreen daily, and always carrying it with him whenever he went outside.

A few years later, when performing his routine self-skin check, something stood out to him on his forehead. He pointed out the mole to his dermatologist and, once again, he was diagnosed with another invasive melanoma. The second time around he was more familiar with the process. This melanoma was thinner, with 0.6 mm Breslow depth. While surgery was required, he did not need to have a sentinel lymph node biopsy performed. He went for surgery and then scheduled his follow-up appointments with his dermatologist every 3 months. After 2 years of close monitoring and no new melanomas, or evidence of recurrence, he would then transition to skin checks every 6 months. Although he was more familiar the second time around, he remembers feeling frustrated with the location of his second melanoma, which was on his face. Mr. A mentioned “It’s unfortunate, but it is what it is. I have this mutation. The most surprising was the size of the scar both times. The scars on my head and the scar on my stomach are 5 inches long and that is something that I would have never anticipated from something that was a little bigger than a pinpoint. I get it, but that was definitely something I wasn’t anticipating.”

When asked how this has impacted his life, Mr. A stated he believes in the idea of early detection. After having been diagnosed with two melanomas, Mr. A mentioned “I am more aware, if anything pops up or changes shape, I go in.”

Physician’s Commentary

Cutaneous melanoma incidence is increasing worldwide and around 5–10% are considered familial melanomas [1, 2]. While there are multiple risk factors affecting the development of a melanoma, such as environmental exposure, UV light, and skin type, genetics also plays a strong role [3]. Having a family history of melanoma increases an individual’s risk of developing a melanoma compared to that of the general population [3]. Familial melanoma is defined as having either two first-degree relatives with a diagnosis of melanoma or three or more relatives on the same side of the family with a melanoma [4, 5]. The CDKN2A mutation is a familial melanoma and has been found in up to 40% of hereditary melanomas [2]. The incidence of melanomas among CDKN2A carriers varies depending on geographical location with 58% in Europe, 76% in the USA, and 91% in Australia [2–4, 6]. Not only are carriers of this mutation predisposed to developing melanomas but they are also at higher risk for pancreatic cancer [4].

The CDKN2A gene is a tumor suppressor gene found on chromosome 9p21 and encodes for the p16 and p14 proteins [4, 7]. Normally, p16 suppresses the G1/S phase of the cell cycle by inhibiting the phosphorylation of retinoblastoma. Similarly, the p14 protein regulates cell proliferation by inhibiting cell growth and promoting apoptosis through the p53 pathway [4]. Therefore, the autosomal dominant CDKN2A mutation allows for rapid cell cycle progression and the proliferation of potentially malignant cells.

The detection of the CDKN2A mutation in a family with a history of melanoma has been shown to increase with the number of family members diagnosed with melanoma [4, 8]. This emphasizes the importance of documenting a thorough family history regarding melanoma during skin cancer exams. As our patient mentioned, because of his very strong family history of melanomas among his siblings and personal history of melanoma, he was recommended for genetic testing, which eventually led to the diagnosis of the CDKN2A mutation. He then encouraged his siblings to get tested, which led to the discovery of multiple affected individuals in the family across generations.

While genetic testing for hereditary cancers such as breast, ovarian, and colorectal cancer is widely accepted among health care professionals for patients with a particular risk profile, the use of genetic testing for familial melanoma is not standardized [2, 4]. Leachman et al. proposed a set of guidelines to be used when selecting patients for genetic testing. The selection criteria depends on the incidence of melanoma by geographical location, number of melanomas in the patient and/or family, and/or the presence of pancreatic cancer in the family [2, 4]. Physicians should have well-informed discussions with high-risk patients about the option of genetic testing, and ideally patients should have the opportunity to meet with a genetic counselor prior to testing to fully understand the process and potential implications. In addition to the consideration of genetic testing, physicians should discuss the importance of frequent skin cancer checks with CDKN2A carriers and educate them on the importance of early detection [4]. These individuals are also recommended for regular surveillance for pancreatic cancer with MRI/MRCP and/or endoscopic ultrasound [4].

Pissa et al. studied the difference of melanoma survival in CDKN2A carriers compared to that of non-carriers who were diagnosed with invasive melanoma before and after being included in a dermatological surveillance program, which the Swedish Melanoma Study Group began in 1987 [7]. The group identified families with melanomas and provided them with skin cancer education, total body imaging, regular skin cancer exams with careful documentation of lesions, and offered CDKN2A testing [7]. In the study, Pissa et al. noted, when the invasive melanoma was diagnosed before inclusion in the program, a significantly worse survival in the carrier group vs. the non-carrier group was identified, but this difference was not seen after inclusion [7]. Additionally, fewer advanced-staged melanomas were identified in the CDKN2A carrier group after being included in the program [7]. This study demonstrated the importance of routine dermatological surveillance for CDKN2A carriers. While our patient was not enrolled in a formal skin surveillance program, he mentioned becoming more aware of his own skin and performing regular self-skin examinations after being identified as a carrier, in addition to following up with a dermatologist regularly. Similarly to this study, his second melanoma was less invasive than his first. Encouraging both frequent self-skin examinations and good compliance with total body skin examinations by a dermatologist may reduce the number of invasive melanomas and improve the melanoma-specific survival in CDKN2A carriers.

While there have been many studies focusing on screening recommendations for CDKN2A carriers, it is also important to discuss management for suspicious lesions with patients. As Yeap et al. discuss in their review article, suspicious lesions in CDKN2A carriers should not only be monitored frequently but there should also be a lower threshold for biopsies of these lesions [9]. As our patient mentioned, he identified both melanomas by noticing a new lesion that he had not seen before. The first melanoma was monitored for a longer period before being biopsied, and the second melanoma was biopsied on the same day because of suspicious dermoscopic features seen in the small lesion. Having a lower threshold for suspicious lesions in these patients can help identify thinner melanomas and hopefully prevent more advanced disease.

The role of genetic testing in cancer prevention and management is ever evolving. Similarly to other forms of hereditary cancers, physicians should recognize patients who have familial melanomas as high risk and recommend the proper workup and management to improve early detection of melanomas.

Author Contributions

Conceptualization: Yaelle Shaked and Tracey N Liebman. Writing—Drafting: Yaelle Shaked. Writing—Reviewing and editing: Yaelle Shaked, Alyssa Swearingen, and Tracey N Liebman. Supervision: Tracey N Liebman.

Funding

No funding or sponsorship was received for this study or publication of this article.

Declarations

Conflict of Interest

The authors, Yaelle Shaked, Alyssa Swearingen, and Tracey N Liebman, have no potential conflicts of interest or competing interests to disclose.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.