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Acral Lentiginous Melanomas Harbour Intratumor Heterogeneity in BRAF Exon 15, With Mutations Distinct From V600E/V600K

Fernandes, Mariana MSc*; Barcelos, Denise PhD*; Comodo, Andréia Neves PhD*; Guimarães, Daiane Pereira MSc*; Lopes Carapeto, Fernando Cintra MSc*; Cardili, Leonardo MSc*; de Sousa Morães, Lais MSc; Cerutti, AP, Janete PhD; Landman, AP, Gilles MD, PhD*

The American Journal of Dermatopathology: October 2019 - Volume 41 - Issue 10 - p 733–740
doi: 10.1097/DAD.0000000000001418
Original Study
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Abstract: The choice of appropriate therapeutic strategies may be influenced by intratumor heterogeneity and makes cancer treatment considerably more challenging. We aimed to evaluate the heterogeneity of BRAF exon 15 mutations in different areas of acral lentiginous melanoma (ALM). The entire exon 15 was sequenced in 4 different areas of paraffin-embedded samples from 26 patients with ALM. A total of 26 of 49 cases of ≥1 mm in depth of ALM identified by clinical, anatomical, and pathological data fulfilled the inclusion and exclusion criteria for this study. Tumors had a mean Breslow depth of 7.2 mm and an average mitotic index of 3 mitosis/mm2. Mutations distinct from the common V600E and V600K were detected in 31%, and intratumor heterogeneity was observed in 31% of samples. Interestingly, 63.5% of all mutations had been previously associated with cancer. Most (62.5%) of the missense BRAF exon 15 mutations found in the ALM samples examined here were deemed “detrimental” for protein function according to at least 2 functional prediction programs, and 3 mutations (37.5%) were predicted to be “neutral,” with no effect on protein function. BRAF exon 15 mutations were detected frequently in ALM and displayed heterogeneity, a finding to be further investigated.

*Department of Pathology, Universidade Federal de São Paulo, São Paulo, Brazil; and

Department of Morphology and Genetics, Federal University of São Paulo, São Paulo, Brazil.

Correspondence: Denise Barcelos, PhD, Rua Botucatu, 740, São Paulo 04023-062, Brazil (e-mail: barceabra@gmail.com).

Supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo) # 2012/11408-8 and Fundação CAPES (Ministério da Educação).

The funding organizations had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

The authors declare no conflicts of interest.

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