|Year : 2015 | Volume
| Issue : 3 | Page : 279-284
|BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population
Ismail Yilmaz MD 1, Mehmet Gamsizkan2, Zafer Kucukodaci1, Ufuk Berber1, Dilaver Demirel1, Aptullah Haholu1, Gizem Narli1
1 Department of Pathology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey
2 Department of Pathology, Erzurum Military Hospital, Erzurum, Turkey
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|Date of Web Publication||14-Aug-2015|
| Abstract|| |
Background: KIT and mitogen-activated protein kinase cascade are important for melanomagenesis. In the present study, we analyzed the frequency of BRAF, NRAS, KIT, GNAQ and GNA11 gene mutations and investigated their association with clinicopathological features of melanomas in Turkish population. Materials and Methods: Forty-seven primary cutaneous melanomas were included in our study. Sanger sequencing method was used for mutation analysis in all cases. Results: Mean age was 62.1 (29-101) years. Female:male ratio was 17:30. Among 47 melanomas, 14 (29.8%) BRAF, 10 (21.3%) NRAS, 4 (8.5%) KIT and 1(2.1%) GNAQ gene mutations were detected. Two of the KIT mutations were found in acral lentiginous melanoma (ALM). In the head and neck region, mutation frequency was significantly lower than in other locations (P = 0.035). The only GNAQ gene mutation (p.Q209L) was detected in a melanoma arising from blue nevus located on the scalp. None of the melanomas harbored NRAS exon 2, KIT exon 13/17/18, GNAQ exon 4 and GNA11 exon 4/5 mutations. Overall mutation frequency did not show significant difference between metastatic (8/14, 57.1%) and nonmetastatic (18/33, 54.5%) patients. We did not observe any significant association between mutation status and gender or age of various patients. Conclusions: Our results support that BRAF and NRAS gene mutations are common in cutaneous melanomas. The activating mutations of KIT gene are rare and especially seen in ALM. GNAQ and GNA11 mutations are infrequent in cutaneous melanomas and may be associated only with melanomas arising from blue nevus.
Keywords: Gene mutation, melanoma, mutation analysis
|How to cite this article:|
Yilmaz I, Gamsizkan M, Kucukodaci Z, Berber U, Demirel D, Haholu A, Narli G. BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population. Indian J Pathol Microbiol 2015;58:279-84
|How to cite this URL:|
Yilmaz I, Gamsizkan M, Kucukodaci Z, Berber U, Demirel D, Haholu A, Narli G. BRAF, KIT, NRAS, GNAQ and GNA11 mutation analysis in cutaneous melanomas in Turkish population. Indian J Pathol Microbiol [serial online] 2015 [cited 2021 Oct 25];58:279-84. Available from: https://www.ijpmonline.org/text.asp?2015/58/3/279/162831
| Introduction|| |
Melanoma is one of the most aggressive tumors and its incidence has increased in recent years.  The wealth of new knowledge regarding the biology of melanoma and its molecular mechanisms have led to new investigations of targeted therapies.
Stem cell growth factor receptor (KIT) and mitogen-activated protein kinase (MAPK) cascade including RAS-RAF-MEK-ERK are important pathway mediating cellular responses to growth signals regulating cell proliferation, survival, and differentiation.  KIT is a cytokine receptor that is expressed on the surface of melanocytes. Altered forms of this receptor are associated with some melanoma types. , NRAS and BRAF mutations are mainly involved in the pathogenesis of melanoma. BRAF is a member of the RAF kinase family of growth signal transduction protein kinases and it plays a role in regulating the MAPK pathway.  NRAS is a member of RAS family of GTPases and the most commonly mutated isoform in melanoma.  GNAQ and GNA11 genes encode members of the q class G-protein α-subunits that mediate signals from G-protein-coupled receptors to the MAPK pathway. , These are frequently related with blue nevus, uveal and leptomeningeal melanocytic neoplasms. ,,,
There is limited information about mutation frequencies of melanoma from the Middle East region. In the present study, we analyzed the frequency of BRAF, NRAS, KIT, GNAQ and GNA11 gene mutations in our cutaneous melanoma series and investigated their association with histological type, tumor localization, metastasis status, age and gender.
| Materials and Methods|| |
Forty-seven primary cutaneous melanomas between 2003 and 2012 were included in our study. All melanomas were obtained from the archives of the Department of Pathology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul, Turkey. For this retrospective study, patient clinical characteristics such as age, gender, location and metastasis status were collected. This study was approved by the medical ethics committee of Gulhane Military Medical Academy, Haydarpasa Training Hospital (Approval No: 186/01.02.2012) and was conducted according to the Declaration of Helsinki Principles.
Mutations in exon 9, 11, 13, 17 and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were analyzed by polymerase chain reaction (PCR) based direct sequencing using formalin-fixed paraffin-embedded tumor samples. These exons were selected for mutation analysis of genes because these are well-known hotspot regions for oncogenic mutations observed in melanomas. Tumor targets were manually microdissected from 5 μm, about 5-10 unstained histological sections. After standard deparaffinization and rehydration, DNA's were isolated from each target by using QIAamp DNA FFPE Tissue Kit (50) (catalog #: 56404) (QIAGEN, Hilden, Germany) according to the manufacturer's instructions. DNA concentrations of samples were assessed spectrophotometrically by using Nanodrop 1000 spectrophotometer (Thermo Scientific, USA). PCR amplifications of exon 9, 11, 13, 17 and 18 of KIT gene, exon 15 of BRAF gene, exon 2 and 3 of NRAS gene, exon 4 and 5 of GNAQ and GNA11 genes were performed in a Thermal Cycler (ABI, Applied Biosystems, USA) by using HotStarTaq DNA Polymerase kit (catalog #: 203205) (QIAGEN, Hilden, Germany) and appropriate primers listed in the [Table 1]. PCR reactions were run as total volume of 50 μl reaction mixture, which consisted of nuclease free water, 5 μl × 10 PCR Buffer, 25 mM MgCl 2 ([2 μl for BRAF exon 15, KIT exon 9, 11, 17, 18 and NRAS exon 3] [1 μl for KIT exon 13, GNAQ exon 4 and 5] [None for GNA11 exon 4 and 5, NRAS exon 2]), 2 μl 10 mM dNTP mix (ABI, Applied Biosystems, USA), 5 μl of each primer (4 pmol/μl) and 100 ng of each patient DNA. After an initial denaturation at 95°C for 15 min, 42 cycles were performed of 30 s denaturation at 95°C, 30 s annealing at 60°C (BRAF exon 15, NRAS exon 3, GNAQ exon 5)/at 58°C (KIT exons 9 and 18)/at 56°C (GNA11 exon 4, GNAQ exon 4)/at 55°C (GNA11 exon 5, NRAS exon 2)/at 54°C (KIT exon 17) or at 53°C (KIT exons 11 and 13) and 30 s extension at 72°C, followed by a final extension of 10 min at 72°C. The intensity of PCR products were checked by running 5 μl of each PCR reaction with 2 μl of loading dye on a 2% agarose gel. Reagent contamination control was done by examining lane for "No DNA" blank tube. Then, all succeeded PCR products were purified using PureLink ® PCR Purification Kit (catalog #: K3100-01) (Invitrogen Life Technologies, USA) according to the manufacturer's instructions. The purified amplicons were submitted to direct sequencing in both directions (forward and reverse) using reagents from the Big Dye Terminator v3.1 Cycle Sequencing kit (ABI, Applied Biosystems, USA) according to the manufacturer's protocol. After ethanol precipitation subsequent products were run on the ABI-3730 (48 capillary) automatic sequencer (Applied Biosystems, USA). Bidirectional sequence traces were analysed with SeqScape ® Software v3.0 (Applied Biosystems, USA) and manual reviewed. All mutations were confirmed by repeated bidirectional sequencing on the ABI sequencer.
Statistical analysis were performed using SPSS for Windows version 15.0 (SPSS, Inc., Chicago, IL, USA). Chi-square and Fisher's exact test were used to compare the mutational groups based on gender and tumor localization. Student's t-test was also used to compare the mutational groups based on age of patient. The P value was set at <0.05.
| Results|| |
The mean age at diagnosis among 47 patients included in this study was 62.1 years (range 23-101 years). There were 30 males and 17 females. The most common histological form was the nodular melanoma (NM), which was found in 16 patients (34%), followed by superficial spreading melanoma (SSM) in 14 (26.2%), acral lentiginous melanoma (ALM) in 4 (8.5%), lentigo maligna melanoma in 2 (4.3%), nevoid melanoma (nevoid M) in 1 (2.1%), melanoma arising blue nevus in 1 (2.1%), and unclassified type/not otherwise specified in 9 (19.1%). Seventeen melanomas were located in trunk, 20 in extremities and 10 in the head and neck region. Sun-induced damage was defined microscopically by the presence or absence of marked solar elastosis. While 17 patients had chronically sun damaged (CSD) skin, 26 patients did not have the same. Four tumors were located in the acral skin.
Among 47 cases, mutation analysis showed that 26 patients (55.3%) harbored a mutation from within these five genes. Fourteen BRAF, 10 NRAS, 4 KIT and 1 GNAQ gene mutations were detected [Table 2]. Three out of 47 cases had mutations in two genes. A single patient (2.1%) had mutations in both BRAF and NRAS. Two patients (4.3%) had mutations in both KIT and NRAS. All mutations were somatic mutations [Figure 1]. None of the melanomas harbored NRAS exon 2, KIT exon 13/17/18, GNAQ exon 4 and GNA11 exon 4/5 mutations. Twenty-one (44.7%) of the cases were wild type for all these five genes.
|Figure 1: Samples of forward and reverse sequencing electropherograms of mutated cases for BRAF, GNAQ, KIT and NRAS genes. In the upper part mutated cases and the corresponding region of the IVS-000 polyclonal control DNA's reference sequence (lower) are shown|
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|Table 2: The distribution of mutations in BRAF, NRAS, C-KIT, GNAQ and GNA11 genes|
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BRAF exon 15 was the most commonly identified mutation (14/47; 29.8%). The majority (13/14; 92.9%) of BRAF mutations were represented by valine to glutamic acid substitution at position 600, caused by thymine to adenine transition (GTG>GAG) at codon 1799 (12/13), and thymine and guanine to adenine and adenine transition (GTG>GAA) at codon 1799 and 1800 (1/13). Only one of the BRAF mutation (7.1%) was represented by valine to lysine substitution at position 600 (p.V600K), caused by guanine and thymine to adenine and adenine transition (GTG>AAG) at codon 1798 and 1799.
NRAS mutations were detected in 10 cases (10/47; 21.3%). Substitutions at position 61 glutamine amino acid (Q61) in NRAS exon 3 accounted for all of NRAS mutations. Glutamine to arginine/leucine/lysine substitution (Q61R/L/K), caused by a single (CAA>AGA, CAA>CGA, CAA>CTA,) cytosine to adenine and adenine to guanine or thymine transition at codon 181 and 182, respectively.
Four tumors showed mutations in KIT (4/47; 8.5%). In one case (1/47; 2.1%), mutation affecting valine amino acid at position 559 (V559G) in KIT exon 11 resulted in a substitution to glycine, caused by a single (GTT>GGT) thymine to guanine transition at codon 1676 (c.1676T>G). In two cases (2/47; 4.3%), mutation affecting proline amino acid at position 577 (P577S) in KIT exon 11 resulted in a substitution to serine, caused by a single (CCT>TCT) cytosine to thymine transition at codon 1729 (c.1729C>T). In one case (1/47; 2.1%), mutation affecting valine amino acid at position 473 (V473M) in KIT exon 9 resulted in a substitution to methionine, caused by a single (GTG>ATG) guanine to adenine transition at codon 1417 (c.1417G>A). Two of the KIT mutations were observed in ALM located on upper extremity and two were NM located on scalp and back.
GNAQ exon 5 mutation was detected in 2.1% (1/47) of our melanoma cases. Mutation affecting glutamine amino acid at position 209 of GNAQ exon 5 resulted in a substitution to leucine, caused by a single (CAA>CTA) adenine to thymine transition at codon 626 (c.626A>T; p.Q209L). This unique case was a malignant melanoma arising from blue nevus. The case was 59-year-old woman with a nodule measuring 4 cm in diameter on the scalp. The patient died of disease with liver metastasis after 2 years.
None of the melanomas harbored NRAS exon 2, KIT exon 13/17/18, GNAQ exon 4 and GNA11 exon 4/5 mutations. Overall mutation frequencies did not differ between metastatic (8/14, 57.1%) and nonmetastatic (18/33, 54.5%) patients. Although there were no significant statistical differences, BRAF mutations were slightly more common in metastatic cases (P = 0.08). In addition, NRAS mutations were frequently seen in nonmetastatic melanomas (P < 0.001). BRAF mutation frequency was higher in trunk compared to other sites. This relation was statistical significant (P = 0.018). NRAS mutation frequency was also higher in extremities compared to other sites, but there was no significant relation (P = 0.073). In the head and neck region, total mutation frequency was significantly lower than other locations (P = 0.035). There were no statistical significant differences between presence of mutation and metastasis status (P = 0.87). We did not observe any significant association between mutation status, gender and age of patients [Table 3].
|Table 3: The distribution of mutations according to clinical and histological parameters|
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| Discussion|| |
BRAF mutation frequency varies across different regions in the world. The percentage of BRAF mutations in North America, Europe and Australia is about 50%; ,, in Japan is between 26% and 41.8%; , in China between 14.7% and 25.5% , and in Korea is 11.9%,  in descending order. In our study, BRAF mutation frequency (29.8%) was lower in comparison to western countries and Australia. BRAF mutations are more common (about 70%) in melanomas arising in non-CSD, whereas their frequency is low in melanomas arising in CSD (about 15%). , Lee et al.  reported that BRAF mutations were frequently detected in SSM and in melanomas arising in non-CSD. In the present study, 65% BRAF mutations were identified in melanomas arising in non-CSD and in 35% melanomas arising in CSD. Our results show that BRAF V600E is the most common mutation in melanomas. This finding is compatible with documented literature. , In our study, BRAF mutations are frequently found in SSM and NM like a previous study.  We also found no BRAF mutation in ALM. BRAF mutations were slightly more common in metastatic cases. Some studies reported that young age was associated with high rate of BRAF mutation; ,,, However, we did not find any statistical significance in terms of age. In our study, truncal localization was related with high rate of BRAF mutation, as noted in a previous study. 
Curtin et al.  reported that mutations or DNA copy number increases of KIT gene were especially seen in mucosal, acral, and CSD melanomas, but not in non-CSD melanomas. Torres-Cabala et al.  found that immunohistochemical expression of KIT in <10% of the cells of the invasive component of acral lentiginous/mucosal melanomas was a strong negative predictor of KIT mutation. When the melanoma cells loose KIT expression, they can acquire proliferative advantage and escape from the epidermal boundaries. Our KIT mutation frequency in cutaneous melanomas was similar (8.5%), compared to the literature and we predominantly detected KIT mutations in ALM. 
The most common mutated isoform of RAS in melanomas is NRAS, with 15% cases harboring point mutations.  Ellerhorst et al.  found that NRAS mutation was correlated with higher melanoma thickness. Lee et al.  reported that NRAS mutation was common in NM and in melanomas arising in CSD. In our study, NRAS mutation frequency was similar with previous studies (15-20%) as it was 21.3%. ,, Also like previous studies, we found that NRAS mutations were more common on extremities (7/10; 70%) and in NM (4/10; 40%). , We detected NRAS mutations more frequently in nonmetastatic melanomas; therefore, NRAS mutations may be related with low metastatic potential.
Somatic mutations in GNAQ were also determined in blue nevi (83%) and ocular melanoma of the uvea (46%).  GNAQ mutations can be found in leptomeningeal melanocytic neoplasms, as well. , In our study, GNAQ mutation was detected in only a single case, and that was a melanoma arising from blue nevus, like previous studies.  This case was 59 years old female patient in whom GNAQ-exon 5 (c.626A>T; p.Q209L) mutation was detected.
Several research studies regarding molecular mechanism have also led towards opportunities for identifying new therapeutic targets. For example, BRAF inhibitors like vemurafenib have been used for patients with BRAF mutation in the advanced stage. Imatinib has also been efficiently used in a subset of melanoma patients with KIT mutations. Effective direct inhibitors have not been developed for melanomas harboring NRAS mutation, so far. In addition, no direct anti-GNAQ or anti-GNA11 therapies currently exist for melanomas harboring GNAQ or GNA11 mutations, and there are currently no Food and Drug Administration-approved therapies for these patients. However, multiple MAPK-targeted therapies have been conducted in a preliminary setting on uveal melanoma cell lines. Increased cell death in uveal melanoma cell lines has been reported by using of MEK inhibitor combination therapy with a PI3K inhibitor or an mTOR inhibitor.  Besides, protein kinase C inhibitors may have antitumor activity against to uveal melanoma.  We also believe that mutation frequency of this study can give more information for treatment strategies to Turkish oncologists.
In summary, our study identified potential therapeutic target percentage in melanomas among Turkish population. BRAF and NRAS mutations were the most frequently identified mutations in cutaneous melanomas. Activating mutations of KIT gene were rare, compared to BRAF and NRAS. GNAQ mutations can be related with melanomas arising from blue nevus and we are currently working on a new project about the molecular alterations in melanomas arising from blue nevus with the contribution of Turkish Dermatopathology Working Group.
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Department of Pathology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, Istanbul - 34660
Source of Support: Gulhane Military Medical Academy, Haydarpasa
Training Hospital, Istanbul, Turkey., Conflict of Interest: None
[Table 1], [Table 2], [Table 3]
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