10.5826/dpc.1303a146
Introduction: We have observed that most cutaneous melanoma patients under our supervision lack characteristic phenotypical features for melanoma. In contrast; history of cancers other than melanoma and age at onset before 50 were common. This observation was in favour of hereditary melanoma.
Objectives: The aim of this study was to search for the phenotypical and genetic features that distinguish between sporadic and hereditary melanomas.
Methods: All cutaneous melanoma patients (n=43) under our supervision were evaluated dermatologically in detail for phenotypical features. CDKN2A and MC1R mutations were detected with Sanger sequencing method. Assignment to hereditary and sporadic groups was done according to the "melanoma cancer syndrome assessment tool". Patients who were diagnosed before 50 years of age were also assigned to the hereditary melanoma group.
Results: Concerning phenotypic features, fair eye colour was statistically significantly higher in the sporadic group (p=0.000). CDKN2A was detected in only 1 patient in the hereditary group. MC1R mutations were found in 12 out of 13 (92.3%) in the hereditary melanoma group with a score ≥3 points, 13 out of 18 (72.2%) in the early onset group and 5 out of 12 (41.7%) in the sporadic melanoma group (p=0.024).
Discussion: Incidence of CDKN2A mutations in our hereditary group is in accordance with reported incidences from Mediterranean countries. The difference between the hereditary and sporadic melanoma groups in terms of MC1R mutations supports the idea that MC1R genetic testing might help to determine patients with higher risk for hereditary melanoma.
 
text/xml
2160-9381
2904
en
İsmail  Celik
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
mc1r
Phenotypic and Genetic Features that Differ Between Hereditary and Sporadic Melanoma: Results of a Preliminary Study from a Single Center from Turkey
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2022-10-16
2023-07-31
2023-08-24
e2023146
Dermatol Pract Concept
Introduction: We have observed that most cutaneous melanoma patients under our supervision lack characteristic phenotypical features for melanoma. In contrast; history of cancers other than melanoma and age at onset before 50 were common. This observation was in favour of hereditary melanoma.
Objectives: The aim of this study was to search for the phenotypical and genetic features that distinguish between sporadic and hereditary melanomas.
Methods: All cutaneous melanoma patients (n=43) under our supervision were evaluated dermatologically in detail for phenotypical features. CDKN2A and MC1R mutations were detected with Sanger sequencing method. Assignment to hereditary and sporadic groups was done according to the "melanoma cancer syndrome assessment tool". Patients who were diagnosed before 50 years of age were also assigned to the hereditary melanoma group.
Results: Concerning phenotypic features, fair eye colour was statistically significantly higher in the sporadic group (p=0.000). CDKN2A was detected in only 1 patient in the hereditary group. MC1R mutations were found in 12 out of 13 (92.3%) in the hereditary melanoma group with a score ≥3 points, 13 out of 18 (72.2%) in the early onset group and 5 out of 12 (41.7%) in the sporadic melanoma group (p=0.024).
Discussion: Incidence of CDKN2A mutations in our hereditary group is in accordance with reported incidences from Mediterranean countries. The difference between the hereditary and sporadic melanoma groups in terms of MC1R mutations supports the idea that MC1R genetic testing might help to determine patients with higher risk for hereditary melanoma.
 
İsmail  Celik
2023/07/31
10.5826/dpc.1303a146
e2023146
Hacettepe University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
2160-9381
mc1r
en
e2023146
Müller C, Wendt J, Rauscher S, et al. Characterization of patients at high risk of melanoma in Austria. Br J Dermatol. 2016;174(6):1308-1317. DOI: 10.1111/bjd.14407. PMID: 26800492.
Phenotypic and Genetic Features that Differ Between Hereditary and Sporadic Melanoma: Results of a Preliminary Study from a Single Center from Turkey
https://dpcj.org/index.php/dpc/article/download/2904/2214
        Phenotypic and Genetic Features that Differ
        Between Hereditary and Sporadic Melanoma:
        Results of a Preliminary Study from a Single
                     Center from Turkey
                       Aysel Cakir¹, Gonca Elcin¹, Saadettin Kilickap², Özay Gököz³,
                                     Zihni Ekim Taskiran4, İsmail Celik²


1 Hacettepe University Faculty of Medicine, Department of Dermatology and Venerology, Ankara, Turkey
2 Hacettepe University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
3 Hacettepe University Faculty of Medicine, Department of Medical Pathology, Ankara, Turkey
4 Hacettepe University Faculty of Medicine, Department of Medical Genetics, Ankara, Turkey



Key words: melanoma, hereditary melanoma, sporadic melanoma, cdkn2a, mc1r
Citation: Cakir A, Elcin G, Kilickap S, Gököz Ö, Taskiran ZE, Celik İ Phenotypic and Genetic Features that Differ Between Hereditary and
Sporadic Melanoma: Results of a Preliminary Study from a Single Center from Turkey. Dermatol Pract Concept. 2023;13(3):e2023146.
DOI: https://doi.org/10.5826/dpc.1303a146
Accepted: January 12, 2023; Published: July 2023
Copyright: ©2023 Cakir et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: This study was supported by the Hacettepe University Faculty of Medicine, Scientific Search Projects Support Unit
(Project number: 16087).
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Aysel Cakir, Lokman Hekim Akay Hospital, Büklüm Cad. No: 4, 06700 Kavaklıdere/Çankaya/Ankara
Telephone: +905301023765 E-mail: drayselcakir@hotmail.com




  ABSTRACT             Introduction: Most melanoma patients under our supervision lack characteristic phenotypic features
                       for melanoma. In contrast, history of cancers other than melanoma and early age at onset were com-
                       mon. This observation was in favor of hereditary melanoma.
                       Objectives: To search for the phenotypic and genetic features that differ between sporadic and hered-
                       itary melanomas.
                       Methods: In order to reveal phenotypic features, detailed physical exam was conducted to all mela-
                       noma patients (N = 43) and for genetic features. CDKN2A and MC1R mutations were detected with
                       Sanger sequencing method. Assignment to hereditary and sporadic groups was done according to the
                       “melanoma cancer syndrome assessment tool”. Patients who were diagnosed before the age of 50 were
                       also assigned to the hereditary melanoma group.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023146                                                                        1
                       Results: Thirty-one patients were assigned to the hereditary group and 12 to the sporadic group. Fair
                       eye color was statistically significantly higher in the sporadic group (P = 0.000). CDKN2A was detect-
                       ed in only 1 patient in the hereditary group. MC1R mutations were found in 12 out of 13 (92.3%) in
                       the hereditary group with a score ≥3 points, 13 out of 18 (72.2%) in the early age at onset group and
                       5 out of 12 (41.7%) in the sporadic group (P = 0.024).
                       Conclusions: Incidence of CDKN2A mutations in our hereditary group is in accordance with the re-
                       ported incidences from Mediterranean countries. The difference between the hereditary and sporadic
                       groups in terms of MC1R mutations supports the idea that MC1R genetic testing might help to deter-
                       mine patients with higher risk for hereditary melanoma.




Introduction                                                           should rise suspicion for these cancer syndromes [8]. This
                                                                       overlap might likely to have major implications for genetic
Cutaneous melanoma is a malignant solid tumor that                     testing. It is possible that families that fail to meet the genetic
arises from melanocytes in the skin. Melanoma accounts                 testing criteria for a melanoma-dominant syndrome, still
for approximately 2-5% of all skin cancers, but is the most            may carry an increased risk for melanoma cancer syndromes.
common cause of skin cancer-related deaths. If melanoma                Leachman et al. offered a comprehensive cancer gene assess-
is diagnosed early, it can be treated by simple excision, thus         ment tool for families with a hereditary pattern of cancer that
cancer-related morbidity and mortality may be prevented [1].           includes melanoma [8].
Therefore, it is important to identify groups at high risk for             The incidence of melanoma in Turkey according to the
melanoma development. Three main risk factors namely, en-              Ministry of Health Unified Database in 2014 is 1.8 per 100000
vironmental factors, phenotypic features and genetic features          in men and 1.2 per 100000 in women which might be consid-
and intermittent intense sun exposure play role in melanoma            ered as quite low when compared with the incidence of mela-
development. The most common environmental risk factor for             noma in Europe where it ranges from 2.2 to 19.2 per 100000
the development of melanoma is intermittent intense sun expo-          people [9,10]. Interestingly, we have observed that most of
sure [2]. Fair skin, fair hair and eye color, freckles, multiple so-   the melanoma patients under our supervision had dark hair,
lar lentigines, tendency to sunburn and inability to tan are the       darker skin color and had less sun exposure than expected
best-known phenotypic risk factors. Approximately 5-10% of             for melanoma development. In contrast, we have realized that
melanomas develop due to genetic factors and this type of              most of them had personal and/or family history of cancers
melanomas are called hereditary melanomas [3]. Genes asso-             other than melanoma and/or were diagnosed before 50 years
ciated with melanoma range from rare but high-penetrating              of age. Thus, we have hypothesized that, in our patient group
tumor suppressor genes such as cyclin-dependent kinase inhib-          genetic risk factors rather than phenotypic features may play a
itor 2A (CDKN2A), to very common but medium-penetrating                more important role at the development of cancer/melanoma.
genes such as the melanocortin 1 receptor gene (MC1R). The
first gene described as a risk factor for hereditary melanoma is
                                                                       Objectives
CDKN2A. Germline mutations in the CDKN2A gene are re-
sponsible for 40% of the hereditary melanoma patients [4,5].           The aim of this study was to define the phenotypic and ge-
MC1R normally determines the hair and skin color and can               netic features that differentiate hereditary melanomas from
lead to melanoma development through both pigment-related              sporadic melanomas.
and non-pigment-related pathways [6]. MC1R increases the
penetration of CDKN2A from 50% to 84% thus called the
                                                                       Methods
"melanoma modifier gene" [7].
    Leachman et al suggested that in addition to                       After the approval of the ethics committee, 43 histologically
melanoma-dominant pattern of inheritance like CDKN2A                   confirmed patients with cutaneous melanoma were recruited
gene mutations, melanoma can also be a part of other cancer            for this prospective study between February 2017 and
syndromes like hereditary breast ovarian cancer syndrome, Li           October 2017 at the Department of Dermatology, University
Fraumeni syndrome, xeroderma pigmentosum, phosphatase                  of Hacettepe Faculty of Medicine, Ankara, Turkey.
and tensin homolog (PTEN) hamartoma syndrome. They sug-                    A face-to-face questionnaire was applied to all patients.
gested that patients with a family history of pancreatic cancers,      After the dermatological examinations of the patients were
neurologic cancers, renal cell carcinoma and/or mesothelioma           completed, a whole-body nevus examination was performed



2                                                                          Original Article | Dermatol Pract Concept. 2023;13(3):e2023146
using the Dermlite® hand dermatoscope, and then the nevi                 The stage of melanoma at diagnosis, anatomical loca-
were recorded using the Fotofinder® Universe Version                 tion of melanoma, histopathological features of melanoma
2.0.39.3- (X64) digital dermatoscope.                                (Breslow thickness, presence of ulceration, presence and
    Sociodemographic features (age, sex, occupation, place           number of mitoses, presence of lymphocytic infiltration,
of birth, place of current residence, phenotypic features (hair      late regression, presence of lympho-vascular invasion) were
color, eye color, skin phototype and presence of freckles), treat-   noted on a separate sheet, namely the examination form. The
ments taken before to the diagnosis of melanoma (whether             presence of re-excision after diagnosis and/or sentinel lymph
the patients received immunosuppressive therapy and/or any           node biopsy were recorded at the examination form. Total
phototherapy such as narrowband ultraviolet B, psoralen ul-          number of nevi, anatomic location of the nevi, number of
traviolet A (PUVA) and /or local PUVA therapy), sun exposure         typical and atypical nevi, number and size of giant congeni-
(the patients history of working outdoors and its duration,          tal melanocytic nevi, number of actinic keratosis, presence of
whether they participated in outdoor sports and similar activ-       solar lentigo, presence of photo aging, presence and number
ities, the habit and duration of vacation in sunny holiday re-       of pigmented lesions in the iris on inspection were recorded
sorts, the habit and duration of sunbathing, the history and age     on the examination form. Body mass index was calculated
of second-degree sunburns, the history and age of indoor tan-        for each patient. Additional findings such as benign skin tu-
ning, the characteristics of sun protection habits, including us-    mors (eg cherry angiomas) were also recorded.
ing sunscreen), genetic factors (the personal history and family
history including the presence of melanoma and other cancers         Assignment of Patients to Subgroups
in the individual and/or their first and second degree relatives)    As shown in Figure 1 the assignment of patients into hered-
were questioned and recorded in the questionnaire form.              itary or sporadic melanoma subgroups was done according



                                                                     All patients
                                                                       (N = 43)


                                           Utilization of melanoma cancer assessment tool



                                         Leachman Score <3
                                                  (N = 30)


                                             Age at onset



                         Age >50                                     Age = <50               Leachman score ≥3
                          (N = 12)                                    (N = 18)                        (N = 13)



                       SPORADIC                                                     HEREDITARY
                          (N = 12)                                                      (N = 30)

                  Figure 1. Assignment of melanoma patients into sporadic and hereditary subgroups.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023146                                                                   3
        Table 1. Details of Leachman scores of 13 patients who received ≥3 points with the utilization
                              of Melanoma Cancer Syndrome Assessment Tool.
    Patient
    number     Cancer type              Occurrence in the first or second degree relative                 Leachman Score
    1          Melanoma                 Mother, maternal uncle,                                                   6.5
               Breast cancer            Melanoma proband, aunt and sister Father and paternal
               Prostate cancer          uncle
    2          Pancreatic cancer        Paternal grandfather                                                      4.5
               Renal cell carcinoma     Father
    3          Melanoma                 Paternal uncle                                                            4
               Colon cancer             Daughter
    4          Breast cancer            2 sisters                                                                 3.5
               Colon cancer             Maternal uncle
    5          Breast cancer            Sister                                                                    3.5
               Over cancer              Melanoma proband
    6          Breast cancer            Aunt                                                                      3.5
               Prostate cancer          Paternal uncle uncle and grandfather
    7          Pancreatic cancer        Aunt                                                                      3
    8          Pancreatic cancer        Sister                                                                    3
    9          Pancreatic cancer        Brother                                                                   3
 10            Second melanoma          Melanoma proband                                                          3
               Pancreatic cancer        Father
 11            Melanoma                 Sister                                                                    3
 12            Melanoma                 Sister                                                                    3
 13            Renal cell carcinoma     Father                                                                    3



to the “melanoma cancer syndrome assessment tool” [8]. As      was performed with the QIAquick PCR Purification Kit
shown in Table 1 according to this tool 13 patients received   (Qiagen GmbH) according to the manufacturer protocol.
≥3 points (Leachman score ≥3) and were assigned to the he-     For the sequencing of the PCR products, the sequence re-
reditary melanoma group. In addition, in this study patients   action consisting of purified PCR product, distilled water,
who received <3 points, but who were diagnosed before the      primer and BigDye® terminator mixture was prepared and
age of 50 were also assigned to the hereditary melanoma        allowed to react in the thermal cycler. For the sequenc-
group. Sporadic melanoma group consisted of 12 patients        ing reaction of PCR products forward and reverse primers
who scored less than 3 points and who were diagnosed af-       were used when necessary. Finally, after pre-sequence pu-
ter age 50.                                                    rification with ZR® DNA Sequencing Clean-up Kit (Zyno
        CDKN2A and MC1R germline gene mutations were           Research), samples were ABI 3500 Genetic Analyzer (Ap-
detected with Sanger sequencing method in laboratories of      plied Biosystems) and analyzed using Sequencing Analysis
Hacettepe University Faculty of Medicine, Department of        Software.
Medical Genetics.
                                                               Statistics
DNA Sequence Analysis with Sanger Method                       SPSS 23.0 (IBM) was used to analyze the data. Descriptive
Polymerase chain reaction (PCR) was performed, includ-         statistics were calculated with data. The accordance of the
ing the exon and exon-intron junction points of CDKN2A         quantitative data for normal distribution was evaluated
and MC1R genes. Primer sequences required for ampli-           by the Shapiro-Wilk test. The difference between the two
fication were designeed using the PerlPrimer program.          groups of normally distributed independent variables was
GoTaq® (Thermus aquaticus) DNA polymerease enzyme              compared with the significance test of the difference be-
(Promega) was used for the PCR reaction. The PCR re-           tween the two means. The variables not showing normal
action was completed under the amplification conditions        distribution were compared with Mann-Whitney U test.
specified in the Veriti Thermal Cycler device (Thermo          Qualitative variables were evaluated by Chi-Square test
Fischer Scientific), and the products were checked. Fol-       by cross tables. All analyses were tested at the 0.05 signifi-
lowing the amplification, the purification of PCR products     cance level.



4                                                                  Original Article | Dermatol Pract Concept. 2023;13(3):e2023146
Results                                                           in outdoor sports and/or similar activities (P = 1.000), history
                                                                  of summer vacation in sunny resorts (P = 0.672), time spent
Patients and Melanoma Characteristics                             on summer vacation in sunny resorts (P = 0.497), sunbathing
Twenty-seven (62.6%) of 43 patients were female and               (P = 1.000), second degree sunburn (P = 0.497), protection
16 (37.2%) were male. The mean age of patients was                with clothing (P = 0.311) and using sunscreen (P = 0.159).
50.72±12.21 years (22-75 years). The mean age at diagnosis           The histopathological features of melanoma were not
was 48.95±12.13 years (range 22-70 years). There were 10          statistically different in both group in terms of Breslow
patients diagnosed before the age of 40. Of 10 patients diag-     thickness (P = 1.000), presence of ulceration (P = 1.000),
nosed before age 40, 7 were female and 3 were male. There         presence of mitosis (P = 1.000), lymphocytic infiltration
were 22 patients diagnosed before the age of 50.                  (P = 0.721), late regression (P = 1.000) and/or sentinel lymph
    Regarding the phenotypic features, the only phenotypic        node biopsy (P = 1.000).
feature that differed in the hereditary and sporadic mela-
noma groups was the fair eye color, which was more com-           Mutational Analysis
mon in the sporadic melanoma group (P = 0.000). All 12            CDKN2A mutation was detected in only 1 patient in the
patients (12/12) assigned in the sporadic melanoma group          hereditary melanoma group (1/31); whereas no patient in the
had fair eye color. Whereas 13 out of 31 patients assigned to     sporadic melanoma group (0/12) had CDKN2A mutation.
the hereditary melanoma group had fair eye color.                 The only CDKN2A mutation positive patient belonged to
    All other sociodemographic data, features related to          the Leachman score ≥3 subgroup of hereditary melanoma
sun exposure and clinical characteristics questioned and/         (1/13). As shown in Figure 2 the mutation found was CD-
or examined in this study displayed similar distributions         KN2A heterozygous A118V.
namely; gender (p = 0.092), hair color (P = 1.000), skin pho-        MC1R mutations were found in 25 out of 31 (80.6%)
totype (P = 0.091), presence of freckles (P = 0.719), number      patients in the hereditary melanoma group; whereas 5
of nevi (P = 0.565), number of nevi in the head and neck          out of 12 (41.7%) patients in the sporadic melanoma
region (P = 0.208), number of nevi in the upper extremity         group (P = 0.024) (odds ratio=5.833). Among the 13 pa-
(P = 0.342), number of nevi on the trunk (P = 0.690), num-        tients with Leachman score ≥3, 12 had MC1R mutations
ber of nevi in the lower extremity (P = 0.650), number of         (92.3%) whereas, 13 out of 18 patients (72.2%) who scored
atypical nevi (P = 0.837), number of lesions excised from         <3 points but were diagnosed before 50 years of age had
the skin (P = 0.316), presence of solar lentigines (P = 0.507),   MC1R mutations.
presence of cherry angioma (P = 1.000), ≥1 pigmented le-             The most common MC1R variant in all patients was
sions in the iris (P = 0.052), history of working outdoors        the V60L variant. The distribution of different variants
(P = 0.453), outdoor-working time (P = 1.000), participating      of MC1R mutations observed in hereditary and sporadic




   Figure 2. Heterozygous CDKN2A c.353C>T p.A118V. mutation



Original Article | Dermatol Pract Concept. 2023;13(3):e2023146                                                                  5
               Table 2. MC1R gene variants in hereditary and sporadic melanoma patients.
    MC1R gene variants                               Hereditary Melanoma N=31 (%)
                                                Leachman Score ≥3               <50 years of age        Sporadic melanoma
       RHC variants            N (%)                (N=13) (%)                    (N=18) (%)                (N=12) (%)
 R160W                        7 (16.7)                 4 (23.5)                      1 (5)                       2 (40)
 R151C                         3 (7.1)                     -                         2 (10)                      1 (20)
 R142H                         2 (4.8)                  1 (5.9)                      1 (5)                          -
 Non-RHC variants
 V60L                         9 (21.4)                 5 (29.4)                      3 (15)                      1 (20)
 R163Q                         8 (19)                  3 (17.6)                      5 (25)                         -
 c.942A>G                     5 (11.9)                 2 (11.8)                      3 (15)                         -
 K278E                         2 (4.8)                  1 (5.9)                      1 (5)                          -
 C35Y                          1 (2.4)                  1 (5.9)                        -                            -
 V59L                          1 (2.4)                     -                         1 (5)                          -
 R67Q                          1 (2.4)                     -                         1 (5)                          -
 V92M                          1 (2.4)                     -                         1 (5)                          -
 I120T                         1 (2.4)                     -                           -                         1 (20)
 c.699A>G                      1 (2.4)                     -                         1 (5)                          -




melanoma groups did not show a statistically significant          study, CDKN2A mutation was detected in only 1 out of 43
difference. MC1R gene variants, red hair color (RHC) and          patients. This 1 patient belonged to the hereditary melanoma
non- red hair color (non-RHC) variants are listed in Table 2.     group with Leachman score ≥3 points (N=13). Although the
                                                                  sample size in our study is small, the incidence of CDKN2A

Conclusions                                                       in the hereditary melanoma group with Leachman score ≥3
                                                                  was 1/13 (7.7%), which is in accordance with rates recorded
The aim of this study was to determine the phenotypic             from Italy.
and genetic features that differ among the hereditary and            Unfortunately, hereditary melanoma definition is not
sporadic melanoma groups. In regard to the phenotypic             straight forward and differs from study to study. Because
features, results show that fair eye color was the only sta-      melanoma incidence is quite low in our country, we have de-
tistically significantly different feature among all phenotypic   cided to keep the criteria for the “hereditary melanoma” as
features examined in this study. All 12 patients assigned to      wide as possible in the current study in order not to miss any
the sporadic melanoma group in this study had fair eye color,     patients with relevant clues for a hereditary disease. Typical
namely blue, green or hazel. In accordance with this finding      features of true hereditary melanoma/cancer syndromes in-
and taking into consideration that a greater percentage of        clude features such as unilateral lineage, multi-generational
our population has dark eye color, we suggest that fair eye       inheritance, multiple primary lesions and early onset of dis-
color should be the alarming sign for dermatologist for a         ease [3]. Patients who exhibit all of these features are in fact
detailed whole body skin examination and a detailed expla-        quite rare. A score ≥ 3 in the Leachman scoring system helps
nation of sun protection to these patients.                       to differentiate patients with predisposition for hereditary
    CDKN2A mutations were found in 40% of melanoma                cancers. However, age is not used as a criterion in Leachman
families worldwide [4]. However, this rate varies geograph-       scoring system and we believe “early age at diagnosis” is a
ically. For example, this rate was 20% in Australia where         very strong predictor for any disease that is hereditary. This
melanoma is very common in contrast, it was 45% in North          was the reason for a second category in our study as “Leach-
America and 57% in Europe [11]. Regarding the Mediter-            man score <3 and age at onset <50 years”.
ranean area in Europe CDKN2A mutations were found in                 Our results with MC1R genetic testing confirm that add-
7.2% of melanoma families in North-eastern Italy and 8.3%         ing "age" had an impact on the differentiation between the
for Italy in general [12,13]. In Spain, a total of 30% of the     sporadic and the hereditary melanoma patients. As shown in
melanoma kindred studied were carriers of CDKN2A vari-            Table 2, MC1R variant positivity was highest in “Leachman
ant [14]. In another study conducted in Spain CDKN2A mu-          score ≥ 3” subgroup of patients, intermediate in the early
tation was found in 15 of 87 families (17.2%) [15]. In our        age at onset subgroup of hereditary melanoma patients and




6                                                                     Original Article | Dermatol Pract Concept. 2023;13(3):e2023146
lowest in the patients assigned for sporadic melanoma group       References
and the difference between the sporadic and hereditary
groups were statistically significant. The difference between      1. Jemal A, Siegel R, Ward E, et al. Cancer Statistics, 2008. CA
                                                                      ­Cancer J Clin. 2008;58(2):71-96. DOI: 10.3322/CA.2007.0010.
the two groups in terms of MC1R mutations supports the
                                                                       PMID: 18287387.
idea that MC1R genetic testing might help to determine pa-
                                                                   2. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of
tients with higher risk for hereditary melanoma.                       risk factors for cutaneous melanoma: II. Sun exposure. Eur
    In our patient group the presence of MC1R variants                 J Cancer. 2005;41(1):45-60. DOI: 10.1016/j.ejca.2004.10.016
was not associated with hair colour, eye color, skin photo-            . PMID: 15617990.
type, presence of solar lentigines, presence of freckles or the    3. Leachman SA, Carucci J, Kohlmann W, et al. Selection crite-
                                                                       ria for genetic assessment of patients with familial melanoma.
number of nevi. This data is in agreement with the fact that
                                                                       J Am Acad Dermatol. 2009;61(4):677.e1-E14. DOI: 10.1016/j
most of our patients had dark hair (85.7%) and approxi-
                                                                       .jaad.2009.03.016. PMID: 19751883. PMCID: PMC3307795.
mately 50% had skin phototype III and above. This finding          4. Goldstein AM, Chan M, Harland M, et al. High-risk melanoma
strengthens our hypothesis that genetic features may account           susceptibility genes and pancreatic cancer, neural system
for the majority of melanomas in our study group rather                tumors, and uveal melanoma across GenoMEL. Cancer Res.
than phenotypic features or environmental factors.                     2006;66(20):9818-9828. DOI: 10.1158/0008-5472.CAN-06-04
                                                                       94. PMID: 17047042.
    Studies have reported that MC1R mutations increase the
                                                                   5. Meyle KD, Guldberg P. Genetic risk factors for melanoma. Hum
risk of developing melanoma 2-4 times in individuals with
                                                                       Genet. 2009;126(4):499-510. dDOI: 10.1007/s00439-009-07
both familial and sporadic melanoma [12,16]. It is also re-            15-9. PMID: 19585149.
ported that this risk was particularly high in individuals with    6. Raimondi S, Sera F, Gandini S, et al. MC1R variants, mela-
darker skin colour and/or a lower number of nevi [12]. We              noma and red hair color phenotype: A meta-analysis. Int
know that one person can have more than one MC1R vari-                 J Cancer. 2008;122(12):2753-2760. DOI: 10.1002/ijc.23396.
                                                                       PMID: 18366057.
ant. To date more than 80 MC1R variants have been iden-
                                                                   7. Ward KA, Lazovich D, Hordinsky MK. Germline melanoma sus-
tified in Caucasians [6]. The variants and the frequencies of
                                                                       ceptibility and prognostic genes: A review of the literature. J Am
the variants monitored vary according to the geographical              Acad Dermatol. 2012;67(5):1055-1067. DOI: 10.1016/j.jaad.2
regions and prevalence of melanoma. As the variant number              012.02.042. PMID: 22583682.
of MC1R increases, the risk of new melanoma development            8. Leachman SA, Lucero OM, Sampson JE, et al. Identification, ge-
increases [12]. It has been reported that the most com-                netic testing, and management of hereditary melanoma. Cancer
                                                                       Metastasis Rev. 2017;36(1):77-90. DOI: 10.1007/s10555-017
mon variant among MC1R variant in Caucasians is V60L
                                                                       -9661-5. PMID: 28283772. PMCID: PMC5385190.
[12,13,16–20]. In our study, in accordance with the litera-
                                                                   9. Forsea AM, Del Marmol V, De Vries E, Bailey EE, Geller AC.
ture, the most common variant was also V60L. Our data is               Melanoma incidence and mortality in Europe: New estimates,
consistent with the current literature.                                persistent disparities. Br J Dermatol. 2012;167(5):1124-1130.
    In conclusion, in Turkey, there was no previous data on            DOI: 10.1111/j.1365-2133.2012.11125.x. PMID: 22759278.
the CDKN2A and MC1R germline gene mutations in indi-              10. Turkish Ministry of Health-public health institution. Cancer
                                                                       Statistics of Turkey (Türkiye kanser istatistikleri). 2017:1-48.
viduals with neither hereditary nor sporadic melanoma. Our
                                                                       https://hsgm.saglik.gov.tr/tr/kanser-istatistikleri/yillar/2017
study gives at least an estimation of the occurrence of CD-
                                                                       -turkiye-kanser-i-statistikleri.html
KN2A and MC1R germline gene mutations in melanoma                 11. Goldstein AM, Chan M, Harland M, et al. Features associ-
patients in Turkey. Located at the capital city our hospital           ated with germline CDKN2A mutations: A GenoMEL study
drains patients from all over Turkey and has a wide range of          of melanoma-prone families from three continents. J Med
different patient profiles. The small sample size of this study       Genet. 2007;44(2):99-106. DOI: 10.1136/jmg.2006.043802.
                                                                      PMID: 16905682. PMCID: PMC2598064.
may also be a reflection of the low incidence of melanoma
                                                                  12. Landi MT, Kanetsky PA, Tsang S, et al. MC1R, ASIP, and DNA
in our country. For those countries where melanoma is rare
                                                                      repair in sporadic and familial melanoma in a mediterranean
and where the majority of the population has dark skin, we            population. J Natl Cancer Inst. 2005;97(13):998-1007. DOI:
suggest using “early age at onset” as an additional criterion         10.1093/jnci/dji176. PMID: 15998953.
to melanoma cancer syndrome assessment tool for a more            13. Pellegrini C, Maturo MG, Martorelli C, et al. Characterization
precise detection of hereditary cancer/melanoma cases.                of melanoma susceptibility genes in high-risk patients from Cen-
                                                                      tral Italy. Melanoma Res. 2017;27(3):258-267. DOI: 10.1097
                                                                      /CMR.0000000000000323. PMID: 28146043. PMCID: PMC
Acknowledgements: The patients in this manuscript have                7050442.
given written informed consent to publication of their case       14. De Torre C, Garcia-Casado Z, Martínez-Escribano JA, et al.
                                                                      Influence of loss of function MC1R variants in genetic sus-
details. This study was supported by the Hacettepe Univer-
                                                                      ceptibility of familial melanoma in Spain. Melanoma Res.
sity Faculty of Medicine, Scientific Search Projects Support
                                                                      2010;20(4):342-348. DOI: 10.1097/CMR.0b013e32833b159d.
Unit (Project number: 16087).                                         PMID: 20539244.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023146                                                                         7
15. Huertas C, Garcia-Casado Z, Bañuls J, et al. Characteristics of   18. Casula M, Muggiano A, Cossu A, et al. Role of key-regulator
    Familial Melanoma in Valencia, Spain, Based on the Presence           genes in melanoma susceptibility and pathogenesis among
    of CDKN2A Mutations and MC1R Variants. Acta Derm Ve-                  patients from South Italy. BMC Cancer. 2009;9:352. DOI:
    nereol. 2018;98(5):512-516. DOI: 10.2340/00015555-2898.               10.1186/1471-2407-9-352. PMID: 19799798. PMCID: PMC
    PMID: 29405243.                                                       2763007.
16. Stratigos AJ, Dimisianos G, Nikolaou V, et al. Melanocortin       19. Koulermou G, Shammas C, Vassiliou A, et al. CDKN2A and
    receptor-1 gene polymorphisms and the risk of cutaneous mel-          MC1R variants found in Cypriot patients diagnosed with cuta-
    anoma in a low-risk southern european population. J Invest Der-       neous melanoma. J Genet. 2017;96(1):155-160. DOI: 10.1007/
    matol. 2006;126(8):1842-1849. DOI: 10.1038/sj.jid.5700292.            s12041-017-0742-6. PMID: 28360400.
    PMID: 16601669.                                                   20. Müller C, Wendt J, Rauscher S, et al. Characterization of
17. Gerstenblith MR, Goldstein AM, Fargnoli MC, Peris K,                  patients at high risk of melanoma in Austria. Br J Dermatol. 2016;
    Landi MT. Comprehensive evaluation of allele frequency dif-           174(6):1308-1317. DOI: 10.1111/bjd.14407. PMID: 26800492.
    ferences of MC1R variants across populations. Hum Mutat.
    2007;28(5):495-505. DOI: 10.1002/humu.20476. PMID: 172
    79550.




8                                                                          Original Article | Dermatol Pract Concept. 2023;13(3):e2023146
