CDKN2A Gene and Its’ Effect on Hereditary Melanoma

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Abstract

 

Melanoma is the most lethal type of skin cancer, not as a result of its prevalence but the ability to spread from the site of origin to very remote areas, cells or organs of the body (Ransohoff et al., 2016). Unfortunately, melanoma is on the rise throughout the world, as there are about 70,000 new cases per year in the United States alone, and 10% of all these cases are hereditary (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). Hereditary melanoma has been linked to the gene such as cyclin-dependent kinase inhibitor 2A(CDKN2A) and the protein cyclin-dependent kinase 4 (CDK4). CNKN2A gene is the most prevalent and encodes for two proteins p16b and p14, while the exact function of CDK4 in causing hereditary melanoma is still under investigation (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). While CDKN2A is highly linked to hereditary melanoma, it is also linked to other diseases such as head and neck squamous cell carcinoma, lung cancer, breast cancer, pancreatic cancer, and it has even been linked to lymphoblastic leukemia in children. Because of the gene CDKN2A and its impact for cellular function, this article seeks to discuss its prevalence in the body, disease screening recommendations, treatments, and preventions, if any; so as to foster a better understanding of the gene and how it can best be targeted. 

Background and Significance

 

CDKN2A is a vital gene that has been proven to be the origin of instruction for several proteins. The proteins mostly studied related to this gene are P14 and P16, which both function as tumor and cancer cell suppressors, keeping cells from dividing and growing too rapidly, and allowing cells to undergo apoptosis. The p16 protein attaches to two other proteins known as CDK4 and CDK6, which help to regulate the cell cycle through its entirety. The p14 protein protects another protein by the name of p53 from being broken down, which also serves some important roles including tumor suppressor, helping in the process of cell division, and programmed cell death. These p14 and p53 proteins come and work together in cells that are not able to go through cell division (NCBI, “CDKN2A gene,” 2019). The cytogenic location is located on the short arm of chromosome 9 at the position 21.3 (2019). The gene is also beneficial in the fact that it contains 8 exons which are highly influential in RNA production.

 

 

 

 

 

Figure 1.1 Cytogenic Location: 9p21.3

In relation to hereditary melanoma, a typical melanoma is simply described as skin cancer that arises when pigment cells (melanocytes) mutate into cancerous cells; but Hereditary Melanoma is a lethal type of skin cancer with strong genetic undertone that has the characteristic feature of also spreading from its sites of origin to other internal organs of the body (Taber et al., 2015). Individuals with distinctive features of hereditary melanoma such as the unilateral or multiple generational type are not common (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). Most individuals with hereditary melanoma show the mutation of CDKN2A, although there are increasing number of new loci implicated in its origin (Myriad Genetics, “Medical Management for Skin and Pancreatic Cancer,” 2019). Though hereditary melanoma is genetic it does not necessary mean that it is the single risk factor responsible for its existence; family members with the mutated gene type, and susceptible skin type can increase their chances of hereditary melanoma by uneven exposure to sunlight (Myriad Genetics, “Medical Management for Skin and Pancreatic Cancer,” 2019). Therefore, the environment where individual’s stay can play a big factor in families with mutant gene types as described above such as exposure to radiation and certain creams they apply on their body can cause a higher possibility of melanoma (Myriad Genetics, “Medical Management for Skin and Pancreatic Cancer,” 2019). Hereditary melanoma can affect any part of the skin, though the chest and back region for men while the legs of women are mostly affected (Myriad Genetics, “Medical Management for Skin and Pancreatic Cancer,” 2019).

 

Current Research Findings

As stated previously CDKN2A is the most prominent and significant gene for the associated cause of hereditary melanoma. CDKN2A has four exons (1α, 1β, 2, and 3) use to code for P16 and P14 proteins that acts as inhibitors of cyclin D1 and CDK4 that promotes cellular proliferation (Read et al., 2015). Mutation of the CDKN2A locus increases the multiplication of cells and reduces apoptosis during the cell cycle (Leachman, 2017). The CDKN2A is involved in regulating cell growth as such helps in tumor suppression in the cell. Several studies have implicated CDKN2A to hereditary melanoma some are as follows: Polish families with multiple melanomas have been found to have CDKN2A germline mutation (Read et al., 2015). Through research CDK2NA mutations can also cause families to be susceptible to melanoma-pancreatic cancer syndrome. Meaning that they are at a higher risk for developing both cancers in their system (Harinck et al., 2012). It is rare that these diseases affect children.

Figure 2.1 Risk of Melanoma and Pancreatic Cancer in Patients with p16 Mutation

The incidence and prevalence of hereditary melanoma as a result of CDKN2A mutation varies by the geographical region likely due to sun exposure patterns (Read, Wadt, & Hayward, 2015). In the United States of America about 50–76% of skin cancer among patients that are 50 to about 80 years old is as a result of CDKN2A mutation, while in Australia and Europe it is about 30–91%, and 13–58% respectively of the same age range (Lynch & Shaw, 2016). In another population-based study, it was found that the estimated risks of hereditary melanoma for those with CDKN2A mutation were about 14%, 24%, and 28% by ages 50, 70, and 80 years, respectively (Lynch & Shaw, 2016).

Some studies also shows that the onset of hereditary melanoma in patients with CDKN2A mutation families is about 33 to 35 years, when compared to those from families without the CDKN2A mutation with skin cancer, their median age of onset is about 53 to about 60 years, irrespective of their geographic location (Leachman, 2017).  There are reports of those from family line with CDKN2A mutation that have been diagnosed with melanoma in their early twenties with a tendency to have a second incidence likely within five years of first experience (Leachman, 2017). Generally about 7 – 15% of melanoma incidence occurring in people with family history of CDKN2A mutation, though the mutation of CDKN2A is attributable to causing a fraction of melanoma, it is still possible that there are other causes common to these family types that remain undiscovered (Lynch & Shaw, 2016).

Figure 2.2 New Melanoma Cases Yearly Throughout the Globe

Over the year’s melanoma cancers have been studied enough to create differential barriers between them. There are four main types of melanoma that people are mostly affected by which include superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, and lentiginous melanoma. Superficial spreading melanoma is type of cancer often appear either on the trunk or limbs and is the most common type of melanoma; it also turns black as it grows and spreads (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). As the name of the melanoma implies its spread is superficial, on the surface of skin. Nodular melanoma skin cancer appears on the trunk, head, or neck of the body. It grows quicker than superficial melanoma and it turns red rather than black (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). Lentigo maligna melanoma is a less common skin cancer than nodular and superficial melanoma but affect older people more, it also affects parts of the body that have been exposed to the sun over several years (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). It starts as a “Hutchinson’s freckle,” which looks like a stain on the skin (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). It grows slowly and is less lethal than the two previously mentioned. And lastly but not least, acral lentiginous melanoma is the rarest of all of the cancers listed. It affects mostly the palms of the hands, soles of the feet, or underneath the nails (Myriad Genetics, “Hereditary Melanoma Syndrome,” 2019). It is one of the skin cancers that is not related to sun exposure and affects people with darker skin.

Figure 2.3 Comparison of Normal Skin Cells vs. Melanoma Skin Cells

Significant Experimentation that have moved the Field Forward

According to a research study done in India, CDKN2A has been proven to be a gene suppressor gene while also being able to delete oral squamous cell carcinoma (Padhi SS et al. 2017). The experiment was done on a group of 104 OSCC (oral squamous cell carcinoma) patients from the eastern region of India who had recurrent and non-recurrent OSCC in their oral cancer cases. When the CDKN2A/p16 gene is inactivated it is usually found in the masses of solid tumors by about 80% of the oral squamous cell carcinoma. The experiment proved that there was direct involvement of CDKN2A/p16 in oral cancer. The lack of CDKN2A/p16 was prominent in the recurrent cases, while there was a <5-fold for non-recurrent cases. There was also a CGH analysis that exposed a copy number deletion in the recurrent cases which in the end tend to have a poorly constructed prognosis and low survival rates. The conclusion of this study was that CDKN2A/p16 deletion gives rise to alterations in oral cancer aiding in several molecular events that lead to malignant transformations that will continue to occur throughout the progression of the disease (Padhi SS et al. 2017).

Another research study in Brazil that included 59 Brazilians who were melanoma- prone concluded that 10% of all cutaneous melanoma occur in a familial context (de Avila al et al. 2014). The experiment screened CDKN2A alterations by performing sequencing and multiplex ligation probe amplification, and this in turn showed how CDKN2A is the major susceptible gene for familial melanoma; and how certain precursors such as an increased rate of CDKN2A mutation deletion should be considered and taken into account when doing genetic screening, especially in developing countries where there is a limited budget (de Avila al et al. 2014).

Figure 3.1 The Prevalence of Mutations in High Risk Melanoma Susceptibility Genes in Melanoma-Prone Families

Figure 3.2 Pedigree with Familial Hereditary Melanoma

 In relation to melanoma, a 13-year study was conducted by the University of Florence from 2000 to 2013. The study included 1065 patients with histopathologically proven melanoma diagnosis, in which were all treated at the dermatology clinic that the University of Florence. The research study states that patients who develop cutaneous melanoma have a higher risk of developing a second primary melanoma. These reasons concluded genetic factors to be most prevalent. The objective of this study was to analyze the clinical and dermatoscopic features of several melanomas, but mainly focusing on the features that were more frequently in the specific patient to help better understand and recognize earlier signs and the changes throughout time, especially in CDKN2A carriers. They were able to carry this experiment out by one obtaining medical records for all patients who were treated at the University of Florence. Secondly, pictures were taken and administered amongst three different dermatologist experts in dermoscopy to determine and evaluate the presence or absence of certain criteria for each image used in the clinical alongside with the main pattern for the dermoscopic images. The results were analyzed and shared to rate the clinical and dermoscopic features of multiple primary melanoma, or MPM. The results proved to show that 7.0% of the patients in the database carried an MPM disease. Among the 1065 patients seventy-five, or 7%, of them were MPM carriers. From that 7%, twelve more (16%) of the patients were selected and identified to have three or more MPM diseases. From there, four out of the twelve patients (33.3%) the CDKN2A melanoma susceptibility gene was observed, and in each patient similar and specific dermatoscopic patterns were evaluated from their lesions. In conclusion, with the risk of finding CDKN2A germline mutations, increases the risk of primary melanomas, which further increases with the presence of familial history of melanoma, and that can in turn lead to an abundance of MPM diseases. Also, with the study of dermoscopical patterns they now know that they can find the same patterns among melanocytic tumors (D Giorgi V et al. 2015).

Figure 3.3 CDKN2A Mutations in Multiple Primary Melanoma; Yeast Two-Hybrid Assay

Future Directions

According to the literatures referenced above the amount of research and studies done for the gene(s) CDKN2A/p16 are remarkable. Every year there seems to be more advancements in the understanding and progress made as far as these genes CDKN2A/p16 and other tumor suppressing genes are concerned. From the advancements with the knowledge of how these genes function and alternatively do not function has created a plethora of studies and ideas that have led to even greater discoveries. The growth and information available is also amazing when it comes to knowing how these genes can affect how the cells in your body functions which can lead to many different ailments and unfortunately cancers.

In comparison to hereditary melanoma the high risk associated with people having family with hereditary melanoma means that there is a serious need for dermatologic surveillance. This will include a routine skin checkup for family members with gene mutation including children (Taber et al., 2015). These routine checkups would also include examining the forehead, oral mucosa, finger nails and genital area about once every six months (Ransohoff et al., 2016). There are two major technique that is used in screening patients with high risk such as the Total Body Phortograpy (TBP) and the sequential digital dermoscopy imaging (SDDI) that allows earlier detection and treatment of hereditary melanoma (Taber et al., 2015). However, if early detection of the defect helps to resolve the issue with better outcome, it is suggested that patients should learn how to self-examine or with the help of a trusted friend or relative (Ransohoff et al., 2016). Hence more people with the mutated gene should be encouraged to lead a healthy lifestyle such as unnecessary exposure to intense sunlight and radiation.

The following should be obtained from the patient who is having the mutated gene of hereditary melanoma. This includes the exposure patterns of the patient with the weeks and months before medical examination. The physician should also note if there has been an earlier onset of the disease or any other related cancer. The age of diagnosis of any related cancer, the type of cancer, and the organ it affects (Taber et al., 2015). The family history of the above mentioned of the first and second degree relatives including the age at which they were diagnosed of the cancer (Taber et al., 2015).  The history of family relative should also include the skin and hair phenotype (Ransohoff et al., 2016). If there is more than usual positivity recorded in the family history then relevant medical test should be recommended.

Just like other types of cancer, skin cancer can be treated but unlike other cancer it is easier for it to be removed completely (Leachman, 2017). At the same time of surgery a skin biopsy can be taken to ascertain the kind of skin cancer. Depending on the affected area and the size of melanoma on the skin, a skin graft might be necessary (Leachman, 2017). However, when melanoma penetrates the surface of the skin into the lymph nodes, it might become necessary to also perform a lymph node biopsy (Leachman, 2017). There are other melanoma treatment that coincides with regular cancer treatment such as chemotherapy, biological therapy, use of drugs that influences the immune system, and sometimes photodynamic therapy and radiation can also be used (Leachman, 2017). The later treatments of melanoma aforementioned are used in very severe cases but they are not so common.

 

Commentary Session

The research findings and publications for the gene CDKN2A are astonishing and have come such a long way since the gene was first discovered. The detail of information is so vast and beneficial to many from professionals to curious undergradraduate students. The great amount of information has helped people with cancers and other diseases by either curing them or giving them hope and ways to treat the conditions that they suffer from. Being able to go back and trace a gene through your family lineage has also helped people catch onset diseases before they have become a problem in the body system. Reviews have been conducted about how the gene CDKN2A affects those with pancreatic cancer, head and neck squamous cell carcinoma, lung cancer, lymphoblastic leukemia in children, and most prevalently of them all, melanoma. With CDKN2A having such an effect in the human body it is important to know of any genetic pre-disorders before conceiving to understand and try to eliminate major risk factors that may come along with any genetic mutations. Although skin melanoma may not seem like a big deal to some people any type of disease or condition can be detrimental to someone’s health and mental stability. The discoveries that CDKN2A have done for the outlook in detail on melanoma are miraculous. Some people are bound to have this disease while others may acquire it with the mutations of CDKN2A from birth, but the studies and findings of this disease have helped overcome some of the stigma that goes along with the disease along the way. Hereditary Melanoma is a very lethal type of skin cancer with strong genetic undertone that has the characteristic feature of also spreading from its site of origin to other parts. The incidence and prevalence of hereditary melanoma is a result of CDKN2A mutation and it varies by the geographical region likely due to sun exposure patterns in different environments. The different types of melanoma include the superficial spreading, nodula, lentigo maligna, and acral lentiginous melanoma. Melanoma can be easily accessed at its earlier stages because it starts from the skin, therefore surgery can adequately remove the cancer. Though hereditary melanoma has strong genetic undertones as stated earlier, there are several preventive measures that can be taken to reduce the risk of melanoma in people with mutated causative gene such as wearing good clothes that can shield from the sun, the use of appropriate and recommended sunscreen at appropriate interval, avoid going out during high sun intensity between 11am to 3pm and keeping infants directly away from sunlight (Taber et al., 2015). With all of that information being stated and so many research studies and findings that have already been done, there is still some room for growth. Maybe one day in the future there will be a drug that can reverse or inhibit any mutated CDKN2A genes. Since there is so much research on the gene I would think that there would be a way to synthesize a drug to help combat the onset of the diseases. This drug could help bind to the CDKN2A or other proteins that function to help make the gene and guide the genes to continue to work efficiently. Doctors are now able to genetically test both parents and give a report on any findings, so I also feel as though there should be a way to test unborn fetus’ in the womb to know whether or not any of these diseases will later affect them in life; and that way the mothers’ can start taking the synthesized drug to make sure that the CDKN2A genes stay healthy, normal, functioning genes without any mutations ever occurring. Another detail that I found missing was the amount of research done on mass amounts of people in the United States of America. A lot of research has been conducted on several thousands of people in other foreign countries, but I did not come across a lot of research actually completed with mass amounts of people in the U.S., I just saw laboratory findings and treatments from dermatologist in the United States. There should also be more findings on how climates and geographical regions can affect this genetic mutation further into the future since global warming is only becoming worse. With global warming and weather changes taking a toll on our planet, the information about skin cancers and diseases should be vocalized and marketed more to the public. Most people that I know do not know or care about the importance of wearing sunscreen on a daily basis and how applying it could help everyone of all ethnicities and skin tones. I feel as though most believe that if they are not Caucasian then they cannot get the disease. While it is factual that Caucasians are more susceptible to the disease passed down through lineage or just developing it over time, other races and ethnicities can encounter melanoma as well. Once we start to get older and our skin starts to lose collagen and elasticity we should be even more inclined to take the necessary precautions against diseases such as melanoma, especially those who are genetically inclined to catch the disease. CDKN2A is extremely important to the way our cells function, communicate, duplicate and grow. Without the gene CDKN2A we would all have a higher susceptible rate to having or developing certain cancers and tumors. It is safe to say that the gene CDKN2A is a gene much needed for us humans to live healthier productive lives. 

References

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