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Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma
BACKGROUND: Data indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Less data are available on the clonal changes occurring during melanoma progression. We therefore wished to analyse these changes in skin melanomas in common sites...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686548/ https://www.ncbi.nlm.nih.gov/pubmed/31391014 http://dx.doi.org/10.1186/s12885-019-5990-9 |
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author | Doma, V. Kárpáthy, S. Rásó, E. Barbai, T. Tímár, J. |
author_facet | Doma, V. Kárpáthy, S. Rásó, E. Barbai, T. Tímár, J. |
author_sort | Doma, V. |
collection | PubMed |
description | BACKGROUND: Data indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Less data are available on the clonal changes occurring during melanoma progression. We therefore wished to analyse these changes in skin melanomas in common sites of visceral metastases as compared to the primary tumor. METHODS: An autopsy cohort of 50 patients with BRAF- and NRAS-mutant cutaneous metastatic melanomas including 139 visceral metastases was analysed for mutant allele fractions (MAF), determined by pyrosequencing and corrected for tumor/normal ratio. MAF levels were also classified as high (> 40%), medium (15–40%) or low (< 15%). RESULTS: Contrary to NRAS mutant cases, in BRAF-mutant melanomas MAFs were found to be significantly increased in visceral metastases compared to the primary due to the significantly higher levels in lung-, adrenal gland-, intestinal- and kidney metastases. The incidence of the three MAF variants in BRAF-mutant primaries was similar, whereas the high MAF cases were found to be increased in metastases. On the other hand, medium MAF levels were more common in case of NRAS-mutant tumors. Only 31.3% of BRAF mutant- and 50% of NRAS mutant cases maintained the MAF profile of the primary in metastasis. In the majority of multiple metastatic tumors, (BRAF:71.8%, NRAS:75%) metastases were relatively homogeneous regarding MAF. However, in 6/32(18.7%) of BRAF mutant cases low MAF primaries switched to high MAF in metastases. In heterogeneous BRAF mutant metastatic cases low to high or high to low MAF conversions occurred in a further 4/32(12.5%) cases in individual metastases as compared to the primary tumors. At lower frequency, in NRAS mutant tumor such changes also observed (2/12,16.7%). CONCLUSION: We provided evidence for the selection of BRAF-mutant melanoma cells during metastatic progression to the lung, intestine, adrenal gland and kidney. Our findings suggest that in visceral metastases of malignant melanoma BRAF- or NRAS-MAFs are rather heterogeneous and cannot be predicted from data of the primary tumor. These data may have clinical significance when using targeted therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5990-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-6686548 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-66865482019-08-12 Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma Doma, V. Kárpáthy, S. Rásó, E. Barbai, T. Tímár, J. BMC Cancer Research Article BACKGROUND: Data indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Less data are available on the clonal changes occurring during melanoma progression. We therefore wished to analyse these changes in skin melanomas in common sites of visceral metastases as compared to the primary tumor. METHODS: An autopsy cohort of 50 patients with BRAF- and NRAS-mutant cutaneous metastatic melanomas including 139 visceral metastases was analysed for mutant allele fractions (MAF), determined by pyrosequencing and corrected for tumor/normal ratio. MAF levels were also classified as high (> 40%), medium (15–40%) or low (< 15%). RESULTS: Contrary to NRAS mutant cases, in BRAF-mutant melanomas MAFs were found to be significantly increased in visceral metastases compared to the primary due to the significantly higher levels in lung-, adrenal gland-, intestinal- and kidney metastases. The incidence of the three MAF variants in BRAF-mutant primaries was similar, whereas the high MAF cases were found to be increased in metastases. On the other hand, medium MAF levels were more common in case of NRAS-mutant tumors. Only 31.3% of BRAF mutant- and 50% of NRAS mutant cases maintained the MAF profile of the primary in metastasis. In the majority of multiple metastatic tumors, (BRAF:71.8%, NRAS:75%) metastases were relatively homogeneous regarding MAF. However, in 6/32(18.7%) of BRAF mutant cases low MAF primaries switched to high MAF in metastases. In heterogeneous BRAF mutant metastatic cases low to high or high to low MAF conversions occurred in a further 4/32(12.5%) cases in individual metastases as compared to the primary tumors. At lower frequency, in NRAS mutant tumor such changes also observed (2/12,16.7%). CONCLUSION: We provided evidence for the selection of BRAF-mutant melanoma cells during metastatic progression to the lung, intestine, adrenal gland and kidney. Our findings suggest that in visceral metastases of malignant melanoma BRAF- or NRAS-MAFs are rather heterogeneous and cannot be predicted from data of the primary tumor. These data may have clinical significance when using targeted therapies. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12885-019-5990-9) contains supplementary material, which is available to authorized users. BioMed Central 2019-08-07 /pmc/articles/PMC6686548/ /pubmed/31391014 http://dx.doi.org/10.1186/s12885-019-5990-9 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Doma, V. Kárpáthy, S. Rásó, E. Barbai, T. Tímár, J. Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title | Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title_full | Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title_fullStr | Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title_full_unstemmed | Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title_short | Dynamic and unpredictable changes in mutant allele fractions of BRAF and NRAS during visceral progression of cutaneous malignant melanoma |
title_sort | dynamic and unpredictable changes in mutant allele fractions of braf and nras during visceral progression of cutaneous malignant melanoma |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686548/ https://www.ncbi.nlm.nih.gov/pubmed/31391014 http://dx.doi.org/10.1186/s12885-019-5990-9 |
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