TY - JOUR

T1 - BRAFV600E Expression Is Homogenous and Associated with Nonrecurrent Disease and Better Survival in Primary Melanoma

AU - Naimy, Soraya

AU - Bzorek, Michael

AU - Eriksen, J. O.

AU - Dyring-Andersen, Beatrice

AU - Rahbek Gjerdrum, Lise Mette

PY - 2023

Y1 - 2023

N2 - Background: Superficial spreading melanomas (SSMs) are the most common type of melanoma and cause the majority of skin cancer deaths. More than 50% of cases harbor a mutation in the BRAF gene that activates the mitogen-activated protein kinase (MAPK) cancer signaling pathway. BRAF(V600E) is the most common BRAF mutation, and it represents an important biomarker that guides treatment selection. However, the relationship between the BRAF(V600E) gene expression and intratumoral protein distribution, on one side, and clinicopathological factors and patient outcomes, on the other, is not fully described. Additionally, whether MAPK cancer signaling activation in melanoma is due to increased biochemical activity of BRAF(V600E), increased mRNA levels, or both requires further investigation. Here, we addressed these questions by examining expression patterns of BRAF(V600E) in primary treatment-naive melanomas and correlating them to clinicopathological factors and patient outcomes. Methods: In 166 SSM cases, we performed immunohistochemical staining to investigate the protein expression of BRAF(V600E), and we measured BRAF mRNA levels using NanoString nCounter system. Results: Ninety-seven (49%) melanomas stained positive for BRAF(V600E), with nearly 100% intratumoral homogeneity observed. Positive BRAF(V600E) expression was significantly associated with nonrecurrent disease and was found to be an independent predictor of better prognosis in univariate and multivariable analyses. Furthermore, presence of tumor-infiltrating lymphocytes, sentinel lymph node biopsy negativity, and low Breslow thickness were all independent predictors of better prognosis. We observed no difference in the BRAF mRNA levels in BRAF(V600E)-negative and BRAF(V600E)-positive melanomas, respectively. Validation in a larger publicly available cohort confirmed that there is only a weak correlation (Spearman 0.4) between BRAF(V600E) mRNA and protein levels and no differences in mRNA between BRAF(V600E) mutated and non-mutated patients. Conclusion: Our findings indicated that BRAF(V600E) is homogeneously present throughout the whole tumor and is associated with nonrecurrent disease and better survival in primary melanoma. We also showed that BRAF(V600E) mutation does not result in higher transcriptional levels, suggesting that activation of the MAPK signaling pathway in BRAF(V600E) mutated patients can be attributed to the increased biochemical activity caused by the mutation.

AB - Background: Superficial spreading melanomas (SSMs) are the most common type of melanoma and cause the majority of skin cancer deaths. More than 50% of cases harbor a mutation in the BRAF gene that activates the mitogen-activated protein kinase (MAPK) cancer signaling pathway. BRAF(V600E) is the most common BRAF mutation, and it represents an important biomarker that guides treatment selection. However, the relationship between the BRAF(V600E) gene expression and intratumoral protein distribution, on one side, and clinicopathological factors and patient outcomes, on the other, is not fully described. Additionally, whether MAPK cancer signaling activation in melanoma is due to increased biochemical activity of BRAF(V600E), increased mRNA levels, or both requires further investigation. Here, we addressed these questions by examining expression patterns of BRAF(V600E) in primary treatment-naive melanomas and correlating them to clinicopathological factors and patient outcomes. Methods: In 166 SSM cases, we performed immunohistochemical staining to investigate the protein expression of BRAF(V600E), and we measured BRAF mRNA levels using NanoString nCounter system. Results: Ninety-seven (49%) melanomas stained positive for BRAF(V600E), with nearly 100% intratumoral homogeneity observed. Positive BRAF(V600E) expression was significantly associated with nonrecurrent disease and was found to be an independent predictor of better prognosis in univariate and multivariable analyses. Furthermore, presence of tumor-infiltrating lymphocytes, sentinel lymph node biopsy negativity, and low Breslow thickness were all independent predictors of better prognosis. We observed no difference in the BRAF mRNA levels in BRAF(V600E)-negative and BRAF(V600E)-positive melanomas, respectively. Validation in a larger publicly available cohort confirmed that there is only a weak correlation (Spearman 0.4) between BRAF(V600E) mRNA and protein levels and no differences in mRNA between BRAF(V600E) mutated and non-mutated patients. Conclusion: Our findings indicated that BRAF(V600E) is homogeneously present throughout the whole tumor and is associated with nonrecurrent disease and better survival in primary melanoma. We also showed that BRAF(V600E) mutation does not result in higher transcriptional levels, suggesting that activation of the MAPK signaling pathway in BRAF(V600E) mutated patients can be attributed to the increased biochemical activity caused by the mutation.

KW - Melanoma

KW - Skin cancer

KW - Immunohistochemical staining

KW - BRAF(V600E)

KW - Intratumor heterogeneity

KW - Melanoma outcome

KW - METASTATIC MALIGNANT-MELANOMA

KW - BRAF MUTATIONAL STATUS

KW - CLINICOPATHOLOGICAL CHARACTERISTICS

KW - NRAS MUTATIONS

KW - METAANALYSIS

KW - PATHWAYS

KW - V600E

U2 - 10.1159/000528159

DO - 10.1159/000528159

M3 - Journal article

C2 - 36657398

VL - 239

SP - 409

EP - 421

JO - Dermatology

JF - Dermatology

SN - 1018-8665

IS - 3

ER -