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

Abstract

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.

Case Report: A Missense Mutation of KIT in Hyperpigmentation and Lentigines Unassociated With Systemic Disorders: Report of a Chinese Pedigree and a Literature Review

“…Somatic KIT mutations have been reported in both primary and metastatic melanomas, especially in triple-negative melanomas lacking BRAF, NRAS, or NF mutations, accounting for 6–20% of melanomas arising on mucosal, acral, and chronically sun-damaged sites ( 3 , 9 , 11 )/ In a recent large retrospective study of a Chinese patient with melanoma, the frequency of KIT mutation was 9.4%, which was comparable with that of the Caucasian population. While a more enriched mutation hotspot region was observed in the cohort, with KIT mutations most frequently found in exon 11 (72.3%) ( 12 ). However, the study was based in a single center.…”

Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH

“…3e,f), pointing to potential enhancers that may be rewired to the 5′ located NRAS gene via ecDNA circularization. An NRAS G12R missense mutation, which locks NRAS in the GTP-bound active https://doi.org/10.1038/s41588-022-01190-0 conformation and previously linked to melanoma 18 , was identified on ecDNAs with an allele frequency of 100%, suggesting strong selection for the mutated allele on ecDNAs (Fig. 2d).…”

“…17 Berlin Institute of Health, Berlin, Germany. 18 Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA. 19 Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.…”