Association Between NRAS and BRAF Mutational Status and Melanoma-Specific Survival Among Patients With Higher Risk Primary Melanoma (original) (raw)
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Oncology Letters
Hotspot mutations of the BRAF and NRAS genes are the most common genetic alterations in invasive cutaneous melanoma; however, the prognostic significance of BRAF and NRAS co-mutations remains controversial. The present study aimed to determine the association between NRAS and BRAF mutation status and the clinicopathological characteristics of patients with stage IA-IIC melanoma. A total of 118 patients who underwent surgical treatment for stage IA-IIC melanoma at the Riga East University Hospital between 2012 and 2018 were retrospectively enrolled in the present study. BRAF and NRAS mutation status was assessed by digital droplet PCR using the BRAFV600, NRAS Q61 and NRAS G12/G13 Screening Assays. The association between mutation status and clinicopathological features and progression-free survival (PFS) was then analyzed. The BRAF V600 mutation was detected in 67 out of 118 patients (56.8%). The PFS did not differ between patients with BRAF wild-type and BRAF-mutant melanoma. NRAS mutations were detected in 35 out of 118 patients (29.6%). The NRAS mutational status was associated with Breslow thickness (P=0.035), tumor type (P=0.020; χ 2 =0.20), mitotic rate (P=0.025) and lymphovascular invasion (P=0.02; χ 2 =0.20). Patients with NRAS-mutant melanoma had significantly worse PFS compared with NRAS wild-type melanoma (HR=12.30; 95% CI=5.78-26.21, P<0.0001). Furthermore, BRAF and NRAS co-mutant melanoma was associated with a significantly worse PFS compared with BRAF-mutant melanoma (HR=6.30; 95% CI=3.10-12.70, P<0.0001). In conclusion, NRAS-mutant and NRAS/BRAF co-mutant stage IA-IIC melanoma was associated with worse PFS compared with NRAS wild-type and BRAF-mutant melanoma. The assessment of NRAS mutation status in melanoma in routine clinical practice may be beneficial for the risk stratification of disease progression for primary non-metastatic malignant melanoma.
Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma
Clinical Cancer Research, 2010
Purpose: NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci. Experimental Design: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging. Results: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth....
BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2012
The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues. In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites. BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastas...
Cancer Causes & Control, 2014
Purpose-Previous studies suggest that solar UV exposure in early life is predictive of cutaneous melanoma risk in adulthood, whereas the relation of BRAF mutation with sun exposure and disease prognosis has been less certain. We investigated the associations between BRAF V600E and NRAS Q61R mutations and known risk factors, clinicopathologic characteristics and clinical outcomes of melanoma in a case series of primary invasive cutaneous melanoma from the Nurses' Health Study (NHS). Methods-Somatic BRAF V600E and NRAS Q61R mutations of 127 primary invasive melanomas from the NHS cohort were determined by pyrosequencing using formalin-fixed, paraffinembedded block tissues. Logistic regression analyses were performed to detect the associations of mutations with melanoma risk factors, and Kaplan-Meier method was used to examine associations between mutations and survival.
Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma
2013
Background: Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population. Methods: Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening.
Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research
Annals of translational medicine, 2015
This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few...
Cutaneous Melanoma Subtypes Show Different BRAF and NRAS Mutation Frequencies
Clinical Cancer Research, 2006
Purpose: BRAF mutations are present in two thirds of cutaneous melanomas and many of the rest have NRAS mutations. However, cutaneous melanoma is a heterogeneous disease with many clinicopathologic subtypes. Of these, the majority fits into four categories: superficial spreading, nodular, lentigo maligna, and acral lentiginous melanoma (ALM). Thus far, there is very limited data combining BRAF and NRAS mutation analysis to explore differences between cutaneous melanoma subtypes. The aim of this study was to address this issue. Experimental Design: The frequency of BRAF and NRAS hotspot mutations, in exons 15 and 2, respectively, was assessed in 59 cutaneous melanomas comprising superficial spreading, nodular, lentigo maligna, and ALM using single-strand conformational polymorphism and RFLP-PCR analysis. Results: Only 2 of 21 (9.5%) ALM showed BRAF exon 15 mutation compared with 9 of 14 (64.3%) superficial spreading malignant melanomas, 4 of 11 (36.4%) nodular melanomas, and 7 of 13 ...
BRAF V600E mutation as a prognostic factor in cutaneous melanoma patients
Dermatologic Therapy, 2020
The prognostic significance of BRAF mutations in the natural course of melanoma is controversial. The aim of study was to assess the prognostic significance of BRAF V600E mutation in cutaneous melanoma patients. A total of 151 melanomas were included in the study. BRAF V600E mutation was detected using the Real Time PCR. BRAF V600E mutation rate was 51%. BRAF mutation rate was higher for young patients (61.4%) and upper limbs (63.2%), trunk (59.3%) and head&neck (59.2%) were the most frequently afflicted sites in BRAF-mutant patients, whereas lower limbs were mostly affected in BRAF-wild patients (77.8%). Likewise, acral melanomas rarely harbored BRAF mutation (17.1%). The disease-free survivals regarding the entire and stage III cohorts were longer in the BRAF-mutant group than in the BRAF-wild group (p=0.006 and p=0.004, respectively), whereas stage I-II patients had no survival differences between BRAF statuses (p=0.2). Likewise, BRAFmutant patients had better overall survival time compared to BRAF-wild patients in all stages (p=0.01), in stage III (p=0.01) and in stage IV patients (p=0.001). However, no differences between BRAF statuses were observed in stage I-II melanomas (p=0.3). In conclusion, BRAF V600E-mutant melanomas show favorable prognostic impact on both disease-free and overall survivals in all staged melanomas except local disease.