The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma
Open accessAbstract
The rationale for using small molecule inhibitors of oncogenic proteins as cancer therapies depends, at least in part, on the assumption that metastatic tumors are primarily clonal with respect to mutant oncogene. With the emergence of BRAF(V600E) as a therapeutic target, we investigated intra- and inter-tumor heterogeneity in melanoma using detection of the BRAF(V600E) mutation as a marker of clonality. BRAF mutant-specific PCR (MS-PCR) and conventional sequencing were performed on 112 tumors from 73 patients, including patients with matched primary and metastatic specimens (n = 18). Nineteen patients had tissues available from multiple metastatic sites. Mutations were detected in 36/112 (32%) melanomas using conventional sequencing, and 85/112 (76%) using MS-PCR. The better sensitivity of the MS-PCR to detect the mutant BRAF(V600E) allele was not due to the presence of contaminating normal tissue, suggesting that the tumor was comprised of subclones of differing BRAF genotypes. To determine if tumor subclones were present in individual primary melanomas, we performed laser microdissection and mutation detection via sequencing and BRAF(V600E)-specific SNaPshot analysis in 9 cases. Six of these cases demonstrated differing proportions of BRAF(V600E)and BRAF(wild-type) cells in distinct microdissected regions within individual tumors. Additional analyses of multiple metastatic samples from individual patients using the highly sensitive MS-PCR without microdissection revealed that 5/19 (26%) patients had metastases that were discordant for the BRAF(V600E) mutation. In conclusion, we used highly sensitive BRAF mutation detection methods and observed substantial evidence for heterogeneity of the BRAF(V600E) mutation within individual melanoma tumor specimens, and among multiple specimens from individual patients. Given the varied clinical responses of patients to BRAF inhibitor therapy, these data suggest that additional studies to determine possible associations between clinical outcomes and intra- and inter-tumor heterogeneity could prove fruitful.
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Cites
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720
High frequency of BRAF mutations in nevi
Pollock, P. M., Harper, U. L., Hansen, K. S., Yudt, L. M., Stark, M., Robbins, C. M., Moses, T. Y., Hostetter, G., Wagner, U., Kakareka, J., et al. (2003) · Nature Genetics · doi:10.1038/ng1054 · Cited by 1,730
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., et al. (2010) · Nature · doi:10.1038/nature09627 · Cited by 1,460
Determinants of BRAF Mutations in Primary Melanomas
Maldonado, J. L., Fridlyand, J., Patel, H., Jain, A. N., Busam, K., Kageshita, T., Ono, T., Albertson, D. G., Pinkel, D., & Bastian, B. C. (2003) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djg123 · Cited by 664 · cited 1×
“These mutation rates are comparable to previously reported rates in melanoma [8,21,22,23,24,25,26,27].”
ResultRecovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy
Paraiso, K. H. T., Fedorenko, I. V., Cantini, L. P., Munko, A. C., Hall, M., Sondak, V. K., Messina, J. L., Flaherty, K. T., & Smalley, K. S. M. (2010) · British Journal of Cancer · doi:10.1038/sj.bjc.6605714 · Cited by 314
Sensi, M., Nicolini, G., Petti, C., Bersani, I., Lozupone, F., Molla, A., Vegetti, C., Nonaka, D., Mortarini, R., Parmiani, G., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209379 · Cited by 183
Su, Z., Dias-Santagata, D., Duke, M., Hutchinson, K., Lin, Y.-L., Borger, D. R., Chung, C. H., Massion, P. P., Vnencak-Jones, C. L., Iafrate, A. J., et al. (2011) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2010.11.010 · Cited by 176 · cited 1×
“Other investigators have also demonstrated that SNaPshot technology is more sensitive than sequencing in detecting mutations in tumor specimens [17,18].”
Background
Cited by
Cellular Heterogeneity and Molecular Evolution in Cancer
Almendro, V., Marusyk, A., & Polyak, K. (2013) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev-pathol-020712-163923 · Cited by 498
Hiatt, J. B., Pritchard, C. C., Salipante, S. J., O'Roak, B. J., & Shendure, J. (2013) · Genome Research · doi:10.1101/gr.147686.112 · Cited by 327
Intratumor and Intertumor Heterogeneity in Melanoma
Grzywa, T. M., Paskal, W., & Włodarski, P. K. (2017) · Translational Oncology · doi:10.1016/j.tranon.2017.09.007 · Cited by 299
Zhou, M., Hall, L., Goldgof, D., Russo, R., Balagurunathan, Y., Gillies, R., & Gatenby, R. (2014) · Translational Oncology · doi:10.1593/tlo.13730 · Cited by 97
Hugdahl, E., Kalvenes, M. B., Puntervoll, H. E., Ladstein, R. G., & Akslen, L. A. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.44 · Cited by 75
Metadata
- Authors
- Yancovitz, M., Litterman, A., Yoon, J., Ng, E., Shapiro, R. L., Berman, R. S., Pavlick, A. C., Darvishian, F., Christos, P., Mazumdar, M., Osman, I., & Polsky, D.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-01-03
- Volume
- 7
- Issue
- 1
- Pages
- e29336
- ISSN
- 1932-6203 (ISSN-L)
- OpenAlex
- W2079421845
- Cited by
- 283
- References
- 8
- FWCI
- 16.84
- Type
- journal article
- Language
- en
- Open access
- gold
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- Yancovitz, M., Litterman, A., Yoon, J., Ng, E., Shapiro, R. L., Berman, R. S., Pavlick, A. C., Darvishian, F., Christos, P., Mazumdar, M., Osman, I., & Polsky, D. (2012). Intra- and Inter-Tumor Heterogeneity of BRAFV600EMutations in Primary and Metastatic Melanoma. PLoS ONE. https://doi.org/10.1371/journal.pone.0029336
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