BRAF V600 mutations and pathological features in Japanese melanoma patients

Abstract

Ultraviolet radiation is a risk factor for BRAF V600 mutations frequently found in melanomas that cause constitutive BRAF activation. Primary sites of melanoma and the frequency of BRAF mutations might differ between races. Melanoma is rare in Japan (1500–2000 cases/year compared with 132 000/year worldwide) and the frequency and distribution of BRAF V600 mutations are unknown. We aimed to investigate the frequency of BRAF V600 mutations in a cohort of Japanese patients with melanoma and determine the relationship between mutations and clinical/pathologic features. DNA was extracted from 80 formalin-fixed, paraffin-embedded tumours from individuals diagnosed with melanoma. BRAF V600 mutations were detected using the Cobas 4800 System with z480 Analyzer and Cobas 4800 BRAF V600 Mutation Test reagents. BRAF V600 mutations were detected in 41.8% of tested tumours, with an invalid rate of 1.3%. The mutation rate was more than 60% in patients aged less than 60 years and more than 36% in patients with stage III/IV disease. No sex difference in the mutation rate was observed. BRAF V600 mutations were detected in 18.8% of acral lentiginous melanomas (ALMs), 64.7% of superficial spreading melanomas, 50.0% of lentigo maligna melanomas and 20.0% of nodular melanomas. Although the mutation rate was low in ALMs, 36.4% were mutation positive at stage III/IV compared with 9.5% at stage I/II. This study confirmed associations among BRAF V600 mutations, pathological features and subtypes of melanoma. BRAF V600 mutations were more frequent in late-stage ALMs than in early-stage ALMs. Superficial spreading melanomas had similar mutation rates at all stages. These insights suggest improved treatment predictions for stage III/IV melanoma patients.

BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods

“…This is consistent with literature reports that younger age and reduced Breslow thickness are associated with the BRAF V600E mutation 54. A number of studies have shown that superficial spreading melanomas (SSM) have a higher rate of BRAF V600 mutation than other melanoma subtypes 22 55. In our study, we too observed this, with 40% of SSM samples positive for the V600E mutation; however, the result was not statistically significant.…”

“…Dabrafenib and vemurafenib, both BRAF inhibitors, have shown improved progression-free and overall survival in patients with metastatic melanoma harbouring a BRAF V600 mutation 22 25–27. A similar improvement in patient survival has been reported with the use of the MEK inhibitor trametinib, which acts downstream of BRAF in the MAPK pathway 28.…”

Japanese real‐world study of sequential nivolumab and ipilimumab treament in melanoma

“…Mutations in BRAF have been noted in 50% of Caucasian patients, but in only 30–40% of Japanese patients . This difference is consistent with the fact that BRAF mutations are more frequently detected in superficial spreading melanoma (SSM), but are rarely detected in ALM …”

High concordance of BRAF mutational status in matched primary and metastatic melanoma

“…Gain‐of‐function mutations of BRAF (a signal transducer for a number of growth factor receptors) were shown to be of significance in a significant proportion of human cancer by Davies et al in 2002 . Subsequent studies suggest that BRAF mutations are present in 40%‐60% of melanoma . The most common mutant form of BRAF (B‐raf proto‐oncogene, serine/threonine kinase) in human cancer is BRAF V600E, which accounts for over 90% of BRAF mutations in melanoma .…”