{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T22:43:12Z","timestamp":1793227392064,"version":"4.5.0"},"reference-count":60,"publisher":"Springer Science and Business Media LLC","issue":"3","license":[{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T00:00:00Z","timestamp":1612742400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Curr. Treat. Options in Oncol."],"published-print":{"date-parts":[[2021,3]]},"DOI":"10.1007\/s11864-021-00818-3","type":"journal-article","created":{"date-parts":[[2021,2,9]],"date-time":"2021-02-09T19:51:05Z","timestamp":1612900265000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["BRAF Heterogeneity in Melanoma"],"prefix":"10.1007","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2679-8546","authenticated-orcid":false,"given":"Takamichi","family":"Ito","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maho","family":"Murata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Kaku-Ito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhisa","family":"Furue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masutaka","family":"Furue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,8]]},"reference":[{"key":"818_CR1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.3322\/caac.20121","volume":"61","author":"R Siegel","year":"2011","unstructured":"Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212\u201336.","journal-title":"CA Cancer J Clin"},{"key":"818_CR2","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1093\/jnci\/djr077","volume":"103","author":"BA Kohler","year":"2011","unstructured":"Kohler BA, Ward E, McCarthy BJ, Schymura MJ, Ries LA, Eheman C, et al. Annual report to the nation on the status of cancer, 1975\u20132007, featuring tumors of the brain and other nervous system. J Natl Cancer Inst. 2011;103:714\u201336.","journal-title":"J Natl Cancer Inst"},{"issue":"7","key":"818_CR3","doi-asserted-by":"publisher","first-page":"CD012806","DOI":"10.1002\/14651858.CD012806.pub2","volume":"7","author":"J Dinnes","year":"2019","unstructured":"Dinnes J, Ferrante di Ruffano L, Takwoingi Y, Cheung ST, Nathan P, Matin RN, et al. Ultrasound, CT, MRI, or PET-CT for staging and re-staging of adults with cutaneous melanoma. Cochrane Database Syst Rev. 2019;7(7):CD012806. https:\/\/doi.org\/10.1002\/14651858.CD012806.pub2.","journal-title":"Cochrane Database Syst Rev"},{"key":"818_CR4","unstructured":"Bastian BC, de la Fouchardiere A, Elder DE, Gerami P, Lazar AJ, Massi D, et al. WHO classification of skin tumors. 4th ed: IARC; 2018."},{"issue":"7","key":"818_CR5","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.humpath.2014.04.001","volume":"45","author":"JR Bradish","year":"2014","unstructured":"Bradish JR, Cheng L. Molecular pathology of malignant melanoma: changing the clinical practice paradigm toward a personalized approach. Hum Pathol. 2014;45(7):1315\u201326.","journal-title":"Hum Pathol"},{"key":"818_CR6","doi-asserted-by":"crossref","first-page":"949","DOI":"10.1038\/nature00766","volume":"417","author":"H Davies","year":"2002","unstructured":"Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417:949\u201354.","journal-title":"Nature."},{"key":"818_CR7","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1479-5876-10-85","volume":"10","author":"PA Ascierto","year":"2012","unstructured":"Ascierto PA, Kirkwood JM, Grob JJ, Simeone E, Grimaldi AM, Maio M, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85.","journal-title":"J Transl Med"},{"key":"818_CR8","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nature12624","volume":"501","author":"CE Meacham","year":"2013","unstructured":"Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328\u201337.","journal-title":"Nature."},{"key":"818_CR9","doi-asserted-by":"crossref","first-page":"e29336","DOI":"10.1371\/journal.pone.0029336","volume":"7","author":"M Yancovitz","year":"2012","unstructured":"Yancovitz M, Litterman A, Yoon J, Ng E, Shapiro RL, Berman RS, et al. Intra- and inter-tumor heterogeneity of BRAF(V600E) mutations in primary and metastatic melanoma. PLoS One. 2012;7:e29336.","journal-title":"PLoS One"},{"issue":"3","key":"818_CR10","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1038\/sj.bjc.6606072","volume":"104","author":"J Lin","year":"2011","unstructured":"Lin J, Goto Y, Murata H, Sakaizawa K, Uchiyama A, Saida T, et al. Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression. Br J Cancer. 2011;104(3):464\u20138.","journal-title":"Br J Cancer"},{"issue":"28","key":"818_CR11","doi-asserted-by":"crossref","first-page":"e285","DOI":"10.1097\/MD.0000000000000285","volume":"93","author":"I Verlinden","year":"2014","unstructured":"Verlinden I, van den Hurk K, Clarijs R, Willig AP, Stallinga CM, Roemen GM, et al. BRAFV600E immunopositive melanomas show low frequency of heterogeneity and association with epithelioid tumor cells: a STROBE-compliant article. Medicine (Baltimore). 2014;93(28):e285.","journal-title":"Medicine (Baltimore)"},{"key":"818_CR12","doi-asserted-by":"crossref","unstructured":"\u2022 Grzywa TM, Paskal W, W\u0142odarski PK. Intratumor and intertumor heterogeneity in melanoma. Transl Oncol. 2017;10(6):956\u201375 A comprehensive review on intratumor and intertumor heterogeneity of melanoma, including BRAF and other genes.","DOI":"10.1016\/j.tranon.2017.09.007"},{"issue":"5","key":"818_CR13","doi-asserted-by":"crossref","first-page":"8069","DOI":"10.18632\/oncotarget.14094","volume":"8","author":"W Bruno","year":"2017","unstructured":"Bruno W, Martinuzzi C, Andreotti V, Pastorino L, Spagnolo F, Dalmasso B, et al. Heterogeneity and frequency of BRAF mutations in primary melanoma: comparison between molecular methods and immunohistochemistry. Oncotarget. 2017;8(5):8069\u201382.","journal-title":"Oncotarget."},{"issue":"11","key":"818_CR14","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1016\/j.humpath.2014.07.014","volume":"45","author":"KE Fisher","year":"2014","unstructured":"Fisher KE, Cohen C, Siddiqui MT, Palma JF, Lipford EH 3rd, Longshore JW. Accurate detection of BRAF p.V600E mutations in challenging melanoma specimens requires stringent immunohistochemistry scoring criteria or sensitive molecular assays. Hum Pathol. 2014;45(11):2281\u201393.","journal-title":"Hum Pathol"},{"issue":"4","key":"818_CR15","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.jmoldx.2015.02.004","volume":"17","author":"PJ Lamy","year":"2015","unstructured":"Lamy PJ, Castan F, Lozano N, Mont\u00e9lion C, Audran P, Bibeau F, et al. Next-generation genotyping by digital PCR to detect and quantify the BRAF V600E mutation in melanoma biopsies. J Mol Diagn. 2015;17(4):366\u201373.","journal-title":"J Mol Diagn"},{"issue":"8","key":"818_CR16","doi-asserted-by":"crossref","first-page":"1609","DOI":"10.1016\/j.jid.2020.01.027","volume":"140","author":"GA Chang","year":"2020","unstructured":"Chang GA, Wiggins JM, Corless BC, Syeda MM, Tadepalli JS, Blake S, et al. TERT, BRAF, and NRAS mutational heterogeneity between paired primary and metastatic melanoma tumors. J Invest Dermatol. 2020;140(8):1609\u201318.e7.","journal-title":"J Invest Dermatol"},{"issue":"3","key":"818_CR17","doi-asserted-by":"crossref","first-page":"690","DOI":"10.3390\/jcm9030690","volume":"9","author":"T Ito","year":"2020","unstructured":"Ito T, Kaku-Ito Y, Murata M, Furue K, Shen CH, Oda Y, et al. Immunohistochemical BRAF V600E expression and intratumor BRAF V600E heterogeneity in acral melanoma: implication in melanoma-specific survival. J Clin Med. 2020;9(3):690.","journal-title":"J Clin Med"},{"issue":"24","key":"818_CR18","doi-asserted-by":"publisher","first-page":"6191","DOI":"10.3390\/ijms20246191","volume":"20","author":"T Ito","year":"2019","unstructured":"Ito T, Kaku-Ito Y, Murata M, Ichiki T, Kuma Y, Tanaka Y, et al. Intra- and inter-tumor BRAF heterogeneity in acral melanoma: an immunohistochemical analysis. Int J Mol Sci. 2019;20(24):6191. https:\/\/doi.org\/10.3390\/ijms20246191.","journal-title":"Int J Mol Sci"},{"key":"818_CR19","unstructured":"NCCN Guidelines Version 4. 2020 Cutaneous Melanoma. https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/cutaneous_melanoma.pdf. Accessed 27 Sep 2020."},{"issue":"2","key":"818_CR20","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.humpath.2014.08.018","volume":"46","author":"A Thiel","year":"2015","unstructured":"Thiel A, Moza M, Kyt\u00f6l\u00e4 S, Orpana A, Jahkola T, Hernberg M, et al. Prospective immunohistochemical analysis of BRAF V600E mutation in melanoma. Hum Pathol. 2015;46(2):169\u201375.","journal-title":"Hum Pathol"},{"key":"818_CR21","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ejca.2017.05.015","volume":"81","author":"A Valachis","year":"2017","unstructured":"\u2022 Valachis A, Ullenhag GJ. Discrepancy in BRAF status among patients with metastatic malignant melanoma: a meta-analysis. Eur J Cancer. 2017;81:106\u201315 A meta-analysis showing intertumor heterogeneity between primary\u2013metastatic and metastatic\u2013metastatic melanoma lesions.","journal-title":"Eur J Cancer"},{"issue":"2","key":"818_CR22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1111\/1346-8138.15151","volume":"47","author":"Y Nakamura","year":"2020","unstructured":"Nakamura Y, Asai J, Igaki H, Inozume T, Namikawa K, Hayashi A, et al. Japanese dermatological association guidelines: outlines of guidelines for cutaneous melanoma 2019. J Dermatol. 2020;47(2):89\u2013103.","journal-title":"J Dermatol"},{"key":"818_CR23","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ejca.2019.11.015","volume":"126","author":"C Garbe","year":"2020","unstructured":"Garbe C, Amaral T, Peris K, Hauschild A, Arenberger P, Bastholt L, et al. European consensus-based interdisciplinary guideline for melanoma. Part 2: treatment-update 2019. Eur J Cancer. 2020;126:159\u201377.","journal-title":"Eur J Cancer"},{"issue":"1","key":"818_CR24","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.jaad.2018.08.055","volume":"80","author":"SM Swetter","year":"2019","unstructured":"Swetter SM, Tsao H, Bichakjian CK, Curiel-Lewandrowski C, Elder DE, Gershenwald JE, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. 2019;80(1):208\u201350.","journal-title":"J Am Acad Dermatol"},{"issue":"1","key":"818_CR25","doi-asserted-by":"crossref","first-page":"adv00040","DOI":"10.2340\/00015555-3382","volume":"100","author":"C Pellegrini","year":"2020","unstructured":"Pellegrini C, Cardelli L, Padova M, Nardo LD, Ciciarelli V, Rocco T, et al. Intra-patient heterogeneity of BRAF and NRAS molecular alterations in primary melanoma and metastases. Acta Derm Venereol. 2020;100(1):adv00040.","journal-title":"Acta Derm Venereol"},{"key":"818_CR26","doi-asserted-by":"crossref","unstructured":"\u2022 Kaji T, Yamasaki O, Takata M, Otsuka M, Hamada T, Morizane S, et al. Comparative study on driver mutations in primary and metastatic melanomas at a single Japanese institute: a clue for intra- and inter-tumor heterogeneity. J Dermatol Sci. 2017;85(1):51\u20137 A comparative study on driver mutations in melanoma showing intratumor and intertumor heterogeneity.","DOI":"10.1016\/j.jdermsci.2016.10.006"},{"issue":"2","key":"818_CR27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/DAD.0000000000000404","volume":"38","author":"B Yaman","year":"2016","unstructured":"Yaman B, Kandilo\u011flu G, Akalin T. BRAF-V600 mutation heterogeneity in primary and metastatic melanoma: a study with pyrosequencing and immunohistochemistry. Am J Dermatopathol. 2016;38(2):113\u201320.","journal-title":"Am J Dermatopathol"},{"issue":"5","key":"818_CR28","doi-asserted-by":"crossref","first-page":"630","DOI":"10.2340\/00015555-2326","volume":"96","author":"L Manfredi","year":"2016","unstructured":"Manfredi L, Meyer N, Tournier E, Grand D, Uro-Coste E, Rochaix P, et al. Highly concordant results between immunohistochemistry and molecular testing of mutated V600E BRAF in primary and metastatic melanoma. Acta Derm Venereol. 2016;96(5):630\u20134.","journal-title":"Acta Derm Venereol"},{"issue":"9","key":"818_CR29","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1016\/j.jid.2016.05.103","volume":"136","author":"M Casula","year":"2016","unstructured":"Casula M, Colombino M, Manca A, Carac\u00f2 C, Botti G, Ascierto PA, et al. Low levels of genetic heterogeneity in matched lymph node metastases from patients with melanoma. J Invest Dermatol. 2016;136(9):1917\u201320.","journal-title":"J Invest Dermatol"},{"issue":"4","key":"818_CR30","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/modpathol.2014.136","volume":"28","author":"JR Bradish","year":"2015","unstructured":"Bradish JR, Richey JD, Post KM, Meehan K, Sen JD, Malek AJ, et al. Discordancy in BRAF mutations among primary and metastatic melanoma lesions: clinical implications for targeted therapy. Mod Pathol. 2015;28(4):480\u20136.","journal-title":"Mod Pathol"},{"issue":"4","key":"818_CR31","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1097\/CMR.0000000000000166","volume":"25","author":"C Nardin","year":"2015","unstructured":"Nardin C, Puzenat E, Pr\u00e9tet JL, Algros MP, Doussot A, Puyraveau M, et al. BRAF mutation screening in melanoma: is sentinel lymph node reliable? Melanoma Res. 2015;25(4):328\u201334.","journal-title":"Melanoma Res"},{"issue":"35","key":"818_CR32","doi-asserted-by":"crossref","first-page":"37895","DOI":"10.18632\/oncotarget.5634","volume":"6","author":"I Satzger","year":"2015","unstructured":"Satzger I, Marks L, Kerick M, Klages S, Berking C, Herbst R, et al. Allele frequencies of BRAFV600 mutations in primary melanomas and matched metastases and their relevance for BRAF inhibitor therapy in metastatic melanoma. Oncotarget. 2015;6(35):37895\u2013905.","journal-title":"Oncotarget."},{"issue":"4","key":"818_CR33","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1001\/jamadermatol.2014.3689","volume":"151","author":"H Eriksson","year":"2015","unstructured":"Eriksson H, Zebary A, Vassilaki I, Omholt K, Ghaderi M, Hansson J. BRAFV600E protein expression in primary cutaneous malignant melanomas and paired metastases. JAMA Dermatol. 2015;151(4):410\u20136.","journal-title":"JAMA Dermatol"},{"issue":"12","key":"818_CR34","doi-asserted-by":"crossref","first-page":"3078","DOI":"10.1038\/jid.2015.229","volume":"135","author":"E Riveiro-Falkenbach","year":"2015","unstructured":"Riveiro-Falkenbach E, Villanueva CA, Garrido MC, Ruano Y, Garc\u00eda-Mart\u00edn RM, Godoy E, et al. Intra- and inter-tumoral homogeneity of BRAF(V600E) mutations in melanoma tumors. J Invest Dermatol. 2015;135(12):3078\u201385.","journal-title":"J Invest Dermatol"},{"issue":"3","key":"818_CR35","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/PAS.0000000000000136","volume":"38","author":"AM Menzies","year":"2014","unstructured":"Menzies AM, Lum T, Wilmott JS, Hyman J, Kefford RF, Thompson JF, et al. Intrapatient homogeneity of BRAFV600E expression in melanoma. Am J Surg Pathol. 2014;38(3):377\u201382.","journal-title":"Am J Surg Pathol"},{"issue":"5","key":"818_CR36","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1038\/jid.2013.378","volume":"134","author":"M Saint-Jean","year":"2014","unstructured":"Saint-Jean M, Qu\u00e9reux G, Nguyen JM, Peuvrel L, Brocard A, Vall\u00e9e A, et al. Is a single BRAF wild-type test sufficient to exclude melanoma patients from vemurafenib therapy? J Invest Dermatol. 2014;134(5):1468\u201370.","journal-title":"J Invest Dermatol"},{"issue":"3","key":"818_CR37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.yexmp.2014.09.008","volume":"97","author":"M Saroufim","year":"2014","unstructured":"Saroufim M, Habib RH, Gerges R, Saab J, Loya A, Amr SS, et al. Comparing BRAF mutation status in matched primary and metastatic cutaneous melanomas: implications on optimized targeted therapy. Exp Mol Pathol. 2014;97(3):315\u201320.","journal-title":"Exp Mol Pathol"},{"issue":"1","key":"818_CR38","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/path.4318","volume":"233","author":"K Harbst","year":"2014","unstructured":"Harbst K, Lauss M, Cirenajwis H, Winter C, Howlin J, T\u00f6rngren T, et al. Molecular and genetic diversity in the metastatic process of melanoma. J Pathol. 2014;233(1):39\u201350.","journal-title":"J Pathol"},{"issue":"8","key":"818_CR39","doi-asserted-by":"crossref","first-page":"e70826","DOI":"10.1371\/journal.pone.0070826","volume":"8","author":"L Boursault","year":"2013","unstructured":"Boursault L, Haddad V, Vergier B, Cappellen D, Verdon S, Bellocq JP, et al. Tumor homogeneity between primary and metastatic sites for BRAF status in metastatic melanoma determined by immunohistochemical and molecular testing. PLoS One. 2013;8(8):e70826.","journal-title":"PLoS One"},{"issue":"11","key":"818_CR40","doi-asserted-by":"crossref","first-page":"2833","DOI":"10.1038\/bjc.2013.622","volume":"109","author":"L Heinzerling","year":"2013","unstructured":"Heinzerling L, Baiter M, K\u00fchnapfel S, Schuler G, Keikavoussi P, Agaimy A, et al. Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations. Br J Cancer. 2013;109(11):2833\u201341.","journal-title":"Br J Cancer"},{"key":"818_CR41","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1186\/1479-5876-11-202","volume":"11","author":"M Colombino","year":"2013","unstructured":"Colombino M, Lissia A, Capone M, De Giorgi V, Massi D, Stanganelli I, et al. Heterogeneous distribution of BRAF\/NRAS mutations among Italian patients with advanced melanoma. J Transl Med. 2013;11:202.","journal-title":"J Transl Med"},{"issue":"3","key":"818_CR42","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.jdermsci.2013.07.013","volume":"72","author":"A Zebary","year":"2013","unstructured":"Zebary A, Omholt K, Vassilaki I, H\u00f6iom V, Lind\u00e9n D, Viberg L, et al. KIT, NRAS, BRAF and PTEN mutations in a sample of Swedish patients with acral lentiginous melanoma. J Dermatol Sci. 2013;72(3):284\u20139.","journal-title":"J Dermatol Sci"},{"issue":"5","key":"818_CR43","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1111\/bjd.12504","volume":"169","author":"H Ekedahl","year":"2013","unstructured":"Ekedahl H, Cirenajwis H, Harbst K, Carneiro A, Nielsen K, Olsson H, et al. The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Br J Dermatol. 2013;169(5):1049\u201355.","journal-title":"Br J Dermatol"},{"issue":"20","key":"818_CR44","doi-asserted-by":"crossref","first-page":"2522","DOI":"10.1200\/JCO.2011.41.2452","volume":"30","author":"M Colombino","year":"2012","unstructured":"Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, et al. BRAF\/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30(20):2522\u20139.","journal-title":"J Clin Oncol"},{"issue":"5","key":"818_CR45","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1158\/1078-0432.CCR-1169-3","volume":"10","author":"M Shinozaki","year":"2004","unstructured":"Shinozaki M, Fujimoto A, Morton DL, Hoon DS. Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res. 2004;10(5):1753\u20137.","journal-title":"Clin Cancer Res"},{"key":"818_CR46","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/1477-3163-3-6","volume":"3","author":"R Houben","year":"2004","unstructured":"Houben R, Becker JC, Kappel A, Terheyden P, Br\u00f6cker EB, Goetz R, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6.","journal-title":"J Carcinog"},{"issue":"17","key":"818_CR47","first-page":"6483","volume":"9","author":"K Omholt","year":"2003","unstructured":"Omholt K, Platz A, Kanter L, Ringborg U, Hansson J. NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression. Clin Cancer Res. 2003;9(17):6483\u20138.","journal-title":"Clin Cancer Res"},{"key":"818_CR48","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1186\/s12885-015-1515-3","volume":"15","author":"Z H\u00e9lias-Rodzewicz","year":"2015","unstructured":"H\u00e9lias-Rodzewicz Z, Funck-Brentano E, Baudoux L, Jung CK, Zimmermann U, Marin C, et al. Variations of BRAF mutant allele percentage in melanomas. BMC Cancer. 2015;15:497.","journal-title":"BMC Cancer"},{"issue":"10","key":"818_CR49","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1097\/DAD.0000000000001418","volume":"41","author":"M Fernandes","year":"2019","unstructured":"Fernandes M, Barcelos D, Comodo AN, Guimar\u00e3es DP, Lopes Carapeto FC, Cardili L, et al. Acral lentiginous melanomas harbour intratumor heterogeneity in BRAF exon 15, with mutations distinct from V600E\/V600K. Am J Dermatopathol. 2019;41(10):733\u201340.","journal-title":"Am J Dermatopathol"},{"issue":"1","key":"818_CR50","first-page":"adv00045","volume":"100","author":"K Sakaizawa","year":"2020","unstructured":"Sakaizawa K, Ashida A, Kiniwa Y, Okuyama R. BRAF mutation heterogeneity in melanoma lesions. Acta Derm Venereol. 2020;100(1):adv00045.","journal-title":"Acta Derm Venereol"},{"issue":"12","key":"818_CR51","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.3390\/cancers11121981","volume":"11","author":"LH Betancourt","year":"2019","unstructured":"Betancourt LH, Szasz AM, Kuras M, Rodriguez Murillo J, Sugihara Y, Pla I, et al. The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma-association with clinical outcome and tumor phenotypes. Cancers (Basel). 2019;11(12):1981.","journal-title":"Cancers (Basel)"},{"issue":"2","key":"818_CR52","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1097\/DAD.0000000000000635","volume":"39","author":"F Cintra Lopes Carapeto","year":"2017","unstructured":"Cintra Lopes Carapeto F, Neves Comodo A, Germano A, Pereira Guimar\u00e3es D, Barcelos D, Fernandes M, et al. Marker protein expression combined with expression heterogeneity is a powerful indicator of malignancy in acral lentiginous melanomas. Am J Dermatopathol. 2017;39(2):114\u201320.","journal-title":"Am J Dermatopathol"},{"issue":"5","key":"818_CR53","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/bjc.2012.12","volume":"106","author":"K Sakaizawa","year":"2012","unstructured":"Sakaizawa K, Goto Y, Kiniwa Y, Uchiyama A, Harada K, Shimada S, et al. Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level. Br J Cancer. 2012;106(5):939\u201346.","journal-title":"Br J Cancer"},{"issue":"3","key":"818_CR54","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1097\/PAS.0b013e318271249e","volume":"37","author":"KJ Busam","year":"2013","unstructured":"Busam KJ, Hedvat C, Pulitzer M, von Deimling A, Jungbluth AA. Immunohistochemical analysis of BRAF(V600E) expression of primary and metastatic melanoma and comparison with mutation status and melanocyte differentiation antigens of metastatic lesions. Am J Surg Pathol. 2013;37(3):413\u201320.","journal-title":"Am J Surg Pathol"},{"issue":"7","key":"818_CR55","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.3390\/jcm9072266","volume":"9","author":"T Ito","year":"2020","unstructured":"Ito T, Kaku-Ito Y, Wada-Ohno M, Furue M. Narrow-margin excision for invasive acral melanoma: is it acceptable? J Clin Med. 2020;9(7):2266.","journal-title":"J Clin Med"},{"issue":"8","key":"818_CR56","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1111\/1346-8138.13834","volume":"44","author":"M Wada","year":"2017","unstructured":"Wada M, Ito T, Tsuji G, Nakahara T, Hagihara A, Furue M, et al. Acral lentiginous melanoma versus other melanoma: a single-center analysis in Japan. J Dermatol. 2017;44(8):932\u20138.","journal-title":"J Dermatol"},{"issue":"1","key":"818_CR57","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jaad.2014.10.008","volume":"72","author":"T Ito","year":"2015","unstructured":"Ito T, Wada M, Nagae K, Nakano-Nakamura M, Nakahara T, Hagihara A, et al. Acral lentiginous melanoma: who benefits from sentinel lymph node biopsy? J Am Acad Dermatol. 2015;72(1):71\u20137.","journal-title":"J Am Acad Dermatol"},{"issue":"13","key":"818_CR58","doi-asserted-by":"crossref","first-page":"1971","DOI":"10.1016\/j.ejca.2011.04.013","volume":"47","author":"A Fusi","year":"2011","unstructured":"Fusi A, Berdel R, Havemann S, Nonnenmacher A, Keilholz U. Enhanced detection of BRAF-mutants by pre-PCR cleavage of wild-type sequences revealed circulating melanoma cells heterogeneity. Eur J Cancer. 2011;47(13):1971\u20136.","journal-title":"Eur J Cancer"},{"issue":"2","key":"818_CR59","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/pcmr.12569","volume":"30","author":"N Mesbah Ardakani","year":"2017","unstructured":"Mesbah Ardakani N, Leslie C, Grieu-Iacopetta F, Lam WS, Budgeon C, Millward M, et al. Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma. Pigment Cell Melanoma Res. 2017;30(2):233\u201342.","journal-title":"Pigment Cell Melanoma Res"},{"issue":"4","key":"818_CR60","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1038\/bjc.2013.29","volume":"108","author":"JS Wilmott","year":"2013","unstructured":"Wilmott JS, Menzies AM, Haydu LE, Capper D, Preusser M, Zhang YE, et al. BRAF(V600E) protein expression and outcome from BRAF inhibitor treatment in BRAF(V600E) metastatic melanoma. Br J Cancer. 2013;108(4):924\u201331.","journal-title":"Br J Cancer"}],"container-title":["Current Treatment Options in Oncology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11864-021-00818-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1007\/s11864-021-00818-3\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1007\/s11864-021-00818-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,3]],"date-time":"2021-03-03T21:17:56Z","timestamp":1614806276000},"score":1,"resource":{"primary":{"URL":"http:\/\/link.springer.com\/10.1007\/s11864-021-00818-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,8]]},"references-count":60,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2021,3]]}},"alternative-id":["818"],"URL":"https:\/\/doi.org\/10.1007\/s11864-021-00818-3","relation":{},"ISSN":["1527-2729","1534-6277"],"issn-type":[{"value":"1527-2729","type":"print"},{"value":"1534-6277","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,8]]},"assertion":[{"value":"11 January 2021","order":1,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 February 2021","order":2,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with Ethical Standards"}},{"value":"Takamichi Ito declares that he has no conflict of interest. Yuka Tanaka declares that he has no conflict of interest. Maho Murata declares that he has no conflict of interest. Yumiko Kaku-Ito declares that he has no conflict of interest. Kazuhisa Furue declares that he has no conflict of interest. Masutaka Furue declares that he has no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This article does not describe any studies with human or animal subjects performed by any of the authors.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Human and animal rights and informed consent"}}],"article-number":"20"}}