BRAF,<scp>KIT</scp> and <scp>NRAS</scp> mutations and expression of c‐<scp>KIT</scp>, phosphorylated extracellular signal‐regulated kinase and phosphorylated AKT in Japanese melanoma patients

Oyama, Satomi; Funasaka, Yoko; Watanabe, Atsushi; Tajima, Toshihiro; Kawana, Seiji; Saeki, Hidehisa

doi:10.1111/1346-8138.12822

Cited by 13 publications

(7 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, our study found that NRAS-mutated patients showed higher Clark level and deeper Breslow thickness compared to negative patients, and C-KIT mutation was also correlated with higher Clark level. However, most of the studies conducted to date did not reveal a significant correlation between C-KIT or NRAS mutation with level of tumor invasion (9,10,16,18,27), and Thomas et al (28) found that NRAS mutation was associated with lower ulceration rate, which was nonsignificant in our study. Discrepancies in the clinical relevance of C-KIT and NRAS mutations in different studies may be related to distinct ethnic groups and sample size, and may reveal genetic information particular to the Chinese population.…”

Section: Discussioncontrasting

confidence: 86%

BRAF, C-KIT, and NRAS mutations correlated with different clinicopathological features: an analysis of 691 melanoma patients from a single center

Ren¹,

Zhang²,

Kong³

et al. 2022

Ann Transl Med

View full text Add to dashboard Cite

Background: Discrepancies in genetic alterations found in melanoma are conspicuous between different ethnic groups. With the approval of BRAF-and MEK-targeted inhibitors in China, it is necessary to further elucidate the landscape of gene mutation in Chinese melanoma patients. Methods:The frequency and distribution of BRAF, C-KIT, and NRAS mutations in 691 melanoma patients was determined, and the statistical significance of correlations between different gene mutations and clinicopathological features was analyzed.Results: Among a total of 691 patients, BRAF mutation was found in 166 patients (24.0%), and V600E was the prominent genetic alteration (145/166, 87.3%). Statistical analyses showed that younger patients (<60) had a higher BRAF mutation rate than older patients (≥60, P=0.000), and the frequency of BRAF mutation was more likely to be lower in patients with the following: melanoma located in an extremity (P=0.000), acral-lentiginous melanoma subtype (P=0.000), thinner melanoma thickness (P=0.047), and no ulceration (P=0.030). The frequency of NRAS mutation was 12.6% (38/302), and primarily involved codon 61 in exon 3 and codon 12 in exon 2. Mutation of C-KIT was detected in 65 patients (9.4%), and the most common site of mutations was L576 in exon 11 (29/65, 44.6%). Patients with NRAS or C-KIT mutation had higher Clark level (P=0.035 and 0.047, respectively) and were more likely to have melanoma located in an extremity (P=0.003 and 0.009, respectively) than those without such mutation. The concordance of gene mutations between paired primary and metastatic lesions was 89.6% (60/67), and visceral metastases showed the highest distribution of gene mutations versus primary melanomas (100.0%) compared with lymph nodes (90.9%) and cutaneous metastases (83.3%). Conclusions:In this large cohort of Chinese melanoma patients, the frequencies of BRAF and NRAS mutations were lower than those observed in Caucasian cohorts, but the clinicopathological features of BRAF, C-KIT, and NRAS mutation were consistent. Paired primary and metastatic lesions showed high concordance of gene mutations.

show abstract

Section: Discussioncontrasting

confidence: 86%

BRAF, C-KIT, and NRAS mutations correlated with different clinicopathological features: an analysis of 691 melanoma patients from a single center

Ren¹,

Zhang²,

Kong³

et al. 2022

Ann Transl Med

View full text Add to dashboard Cite

show abstract

“…KIT overexpression was reported in over 50% of the cases of KIT -mutated melanomas but with no significant correlation between them [ 29 ]. Hence, KIT positivity is rather considered an indicator of KIT amplification than for an aberrant KIT status [ 33 ]. Evaluation of KIT expression in melanomas is also considered a possible screening method for tyrosine kinase inhibitor-targeted therapy efficacy [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Relevance of BRAF Subcellular Localization and Its Interaction with KRAS and KIT Mutations in Skin Melanoma

Beleaua

Jung²,

Braicu

et al. 2021

IJMS

View full text Add to dashboard Cite

Although skin melanoma (SKM) represents only one-quarter of newly diagnosed skin malignant tumors, it presents a high mortality rate. Hence, new prognostic and therapeutic tools need to be developed. This study focused on investigating the prognostic value of the subcellular expression of BRAF, KRAS, and KIT in SKM in correlation with their gene-encoding interactions. In silico analysis of the abovementioned gene interactions, along with their mRNA expression, was conducted, and the results were validated at the protein level using immunohistochemical (IHC) stains. For IHC expression, the encoded protein expressions were checked on 96 consecutive SKMs and 30 nevi. The UALCAN database showed no prognostic value for the mRNA expression level of KRAS and BRAF and demonstrated a longer survival for patients with low mRNA expression of KIT in SKMs. IHC examinations of SKMs confirmed the UALCAN data and showed that KIT expression was inversely correlated with ulceration, Breslow index, mitotic rate, and pT stage. KRAS expression was also found to be inversely correlated with ulceration and perineural invasion. When the subcellular expression of BRAF protein was recorded (nuclear vs. cytoplasmatic vs. mixed nucleus + cytoplasm), a direct correlation was emphasized between nuclear positivity and lymphovascular or perineural invasion. The independent prognostic value was demonstrated for mixed expression of the BRAF protein in SKM. BRAF cytoplasmic predominance, in association with KIT’s IHC positivity, was more frequently observed in early-stage nonulcerated SKMs, which displayed a low mitotic rate and a late death event. The present study firstly verified the possible prognostic value of BRAF subcellular localization in SKMs. A low mRNA expression or IHC cytoplasmic positivity for KIT and BRAF might be used as a positive prognostic parameter of SKM. SKM’s BRAF nuclear positivity needs to be evaluated in further studies as a possible indicator of perineural and lymphovascular invasion.

show abstract

“…The sequential activation of Ras/Raf/MEK/ERK signalling results in the cytoplasmic to nuclear translocation of phosphorylated ERK1/ERK2, leading to the proliferation and survival of melanoma cells. Immunohistological studies have confirmed the elevated levels of phosphorylated ERK in primary melanomas …”

mentioning

confidence: 81%

Melanoma therapy: Check the checkpoints

Furue

Kadono

2016

The Journal of Dermatology

View full text Add to dashboard Cite

Recent mutational and translational studies have revealed that the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway plays a key role in melanomagenesis. Mutations in NRAS and BRAF are found in the majority of melanomas resulting in the formation of constitutively active NRAS and BRAF molecules, which leads to the proliferation and survival of melanoma cells through the activation of MEK/ERK signals. Inhibitors of BRAF or MEK significantly extend the progression-free survival and overall survival of melanoma patients compared with conventional chemotherapies. Combining BRAF and MEK inhibitors further enhances the clinical effectiveness. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immune checkpoint molecule that downregulates T-cell activation by binding to B7 (CD80/CD86) molecules on antigen-presenting cells. Programmed death receptor ligand 1 on melanoma cells negatively regulates T-cell function by binding to the programmed death-1 (PD-1) receptor on T cells. Antibodies against CTLA-4 and PD-1 also enhance the survival of melanoma patients. In this review, we summarize the clinical effectiveness and adverse events of the BRAF inhibitors, MEK inhibitors and anti-immune checkpoint antibodies in melanoma treatment.

show abstract

BRAF,KIT and NRAS mutations and expression of c‐KIT, phosphorylated extracellular signal‐regulated kinase and phosphorylated AKT in Japanese melanoma patients

Cited by 13 publications

References 39 publications

BRAF, C-KIT, and NRAS mutations correlated with different clinicopathological features: an analysis of 691 melanoma patients from a single center

BRAF, C-KIT, and NRAS mutations correlated with different clinicopathological features: an analysis of 691 melanoma patients from a single center

Relevance of BRAF Subcellular Localization and Its Interaction with KRAS and KIT Mutations in Skin Melanoma

Melanoma therapy: Check the checkpoints

Contact Info

Product

Resources

About