Skip to main content
Top

08-08-2017 | Melanoma | Article

Tumour mutation status and sites of metastasis in patients with cutaneous melanoma

Journal: British Journal of Cancer

Authors: Nikki R Adler, Rory Wolfe, John Kelly, Andrew Haydon, Grant McArthur, Catriona A McLean, Victoria J Mar

Authors: Nikki R Adler, Rory Wolfe, John W Kelly, Andrew Haydon, Grant A McArthur, Catriona A McLean, Victoria J Mar

Publisher: Nature Publishing Group UK

Abstract

Background: Cutaneous melanoma can metastasise haematogenously and/or lymphogenously to form satellite/in-transit, lymph node or distant metastasis. This study aimed to determine if BRAF andNRAS mutant and wild-type tumours differ in their site of first tumour metastasis and anatomical metastatic pathway.

Methods: Prospective cohort of patients with a histologically confirmed primary cutaneous melanoma at three tertiary referral centres in Melbourne, Australia from 2010 to 2015. Multinomial regression determined clinical, histological and mutational factors associated with the site of first metastasis and metastatic pathway.

Results: Of 1048 patients, 306 (29%) developed metastasis over a median 4.7 year follow-up period. 73 (24%), 192 (63%) and 41 (13%) developed distant, regional lymph node and satellite/in-transit metastasis as the first site of metastasis, respectively. BRAF mutation was associated with lymph node metastasis (adjusted RRR 2.46 95% CI 1.07–5.69, P=0.04) and sentinel lymph node positivity (adjusted odds ratio [aOR] OR 1.55, 95% CI 1.14–2.10, P=0.005). BRAF mutation and NRAS mutation were associated with increased odds of developing liver metastasis (aOR 3.09, 95% CI 1.49–6.42,P=0.003; aOR 3.17, 95% CI 1.32–7.58, P=0.01) and central nervous system (CNS) metastasis (aOR 4.65, 95% CI 2.23–9.69, P<0.001; aOR 4.03, 95% CI 1.72–9.44, P=0.001). NRAS mutation was associated with lung metastasis (aOR 2.44, 95% CI 1.21–4.93, P=0.01).

Conclusions: BRAF mutation was found to be associated with lymph node metastasis as first metastasis and sentinel lymph node positivity. BRAF and NRAS mutations were associated with CNS and liver metastasis and NRAS mutation with lung metastasis. If these findings are validated in additional prospective studies, a role for heightened visceral organ surveillance may be warranted in patients with tumours harbouring these somatic mutations.

British Journal of Cancer 2017; 117, 1026–1035. doi:10.1038/bjc.2017.254

Keywords: cutaneous melanoma; melanoma; BRAF mutation; mutation status; metastasis; sentinel lymph node biopsy

Literature
Anderson S, Bloom KJ, Vallera DU, Rueschoff J, Meldrum C, Schilling R, Kovach B, Lee JR, Ochoa P, Langland R, Halait H, Lawrence HJ, Dugan MC (2012) Multisite analytic performance studies of a real-time polymerase chain reaction assay for the detection of BRAF V600E mutations in formalin-fixed, paraffin-embedded tissue specimens of malignant melanoma. Arch Pathol Lab Med 136: 1385–1391.CrossRef
Barbour AP, Tang YH, Armour N, Dutton-Regester K, Krause L, Loffler KA, Lambie D, Burmeister B, Thomas J, Smithers BM, Hayward NK (2014) BRAF mutation status is an independent prognostic factor for resected stage IIIB and IIIC melanoma: implications for melanoma staging and adjuvant therapy. Eur J Cancer 50: 2668–2676.CrossRef
Bauer J, Buttner P, Murali R, Okamoto I, Kolaitis NA, Landi MT, Scolyer RA, Bastian BC (2011) BRAF mutations in cutaneous melanoma are independently associated with age, anatomic site of the primary tumor, and the degree of solar elastosis at the primary tumor site. Pigment Cell Melanoma Res 24: 345–351.CrossRef
Broekaert SMC, Roy R, Okamoto I, van den Oord J, Bauer J, Garbe C, Barnhill RL, Busam KJ, Cochran AJ, Cook MG, Elder DE, McCarthy SW, Mihm MC, Schadendorf D, Scolyer RA, Spatz A, Bastian BC (2010) Genetic and morphologic features for melanoma classification. Pigment Cell Melanoma Res 23: 763–770.CrossRef
Bucheit AD, Syklawer E, Jakob JA, Bassett RL Jr, Curry JL, Gershenwald JE, Kim KB, Hwu P, Lazar AJ, Davies MA (2013) Clinical characteristics and outcomes with specific BRAF and NRAS mutations in patients with metastatic melanoma. Cancer 119: 3821–3829.CrossRef
Carlino MS, Haydu LE, Kakavand H, Menzies AM, Hamilton AL, Yu B, Ng CC, Cooper WA, Thompson JF, Kefford RF, O'Toole SA, Scolyer RA, Long GV (2014) Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma. Br J Cancer 111: 292–299.CrossRef
Chang DZ, Panageas KS, Osman I, Polsky D, Busam K, Chapman PB (2004) Clinical significance of BRAF mutations in metastatic melanoma. J Transl Med 2: 46.CrossRef
Cohn-Cedermark G, Mansson-Brahme E, Rutqvist LE, Larsson O, Singnomklao T, Ringborg U (1999) Metastatic patterns, clinical outcome, and malignant phenotype in malignant cutaneous melanoma. Acta Oncol 38: 549–557.CrossRef
Colombino M, Capone M, Lissia A, Cossu A, Rubino C, De Giorgi V, Massi D, Fonsatti E, Staibano S, Nappi O, Pagani E, Casula M, Manca A, Sini M, Franco R, Botti G, Caraco C, Mozzillo N, Ascierto PA, Palmieri G (2012) BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30: 2522–2529.CrossRef
Devitt B, Liu W, Salemi R, Wolfe R, Kelly J, Tzen CY, Dobrovic A, McArthur G (2011) Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res 24: 666–672.CrossRef
Dong XD, Tyler D, Johnson JL, DeMatos P, Seigler HF (2000) Analysis of prognosis and disease progression after local recurrence of melanoma. Cancer 88: 1063–1071.CrossRef
Edlundh-Rose E, Egyhazi S, Omholt K, Mansson-Brahme E, Platz A, Hansson J, Lundeberg J (2006) NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16: 471–478.CrossRef
Ekedahl H, Cirenajwis H, Harbst K, Carneiro A, Nielsen K, Olsson H, Lundgren L, Ingvar C, Jönsson G (2013) The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Br J Dermatol 169: 1049–1055.CrossRef
Ellerhorst JA, Greene VR, Ekmekcioglu S, Warneke CL, Johnson MM, Cooke CP, Wang LE, Prieto VG, Gershenwald JE, Wei Q, Grimm EA (2011) Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin Cancer Res 17: 229–235.CrossRef
Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D Group MS (2012) Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367: 107–114.CrossRef
Goel VK, Lazar AJ, Warneke CL, Redston MS, Haluska FG (2006) Examination of mutations in BRAF, NRAS, and PTEN in primary cutaneous melanoma. J Invest Dermatol 126: 154–160.CrossRef
Greaves WO, Verma S, Patel KP, Davies MA, Barkoh BA, Galbincea JM, Yao H, Lazar AJ, Aldape KD, Medeiros LJ, Luthra R (2013) Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn 15: 220–226.CrossRef
Hacker E, Hayward NK, Dumenil T, James MR, Whiteman DC (2010) The association between MC1R genotype and BRAF mutation status in cutaneous melanoma: findings from an Australian population. J Invest Dermatol 130: 241–248.CrossRef
Halaban R, Zhang W, Bacchiocchi A, Cheng E, Parisi F, Ariyan S, Krauthammer M, McCusker JP, Kluger Y, Sznol M (2010) PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res 23: 190–200.CrossRef
Halait H, Demartin K, Shah S, Soviero S, Langland R, Cheng S, Hillman G, Wu L, Lawrence HJ (2012) Analytical performance of a real-time PCR-based assay for V600 mutations in the BRAF gene, used as the companion diagnostic test for the novel BRAF inhibitor vemurafenib in metastatic melanoma. Am J Surg Pathol 21: 1–8.
Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr., Kaempgen E, Martin-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380: 358–365.CrossRef
Heinzerling L, Kuhnapfel S, Meckbach D, Baiter M, Kaempgen E, Keikavoussi P, Schuler G, Agaimy A, Bauer J, Hartmann A, Kiesewetter F, Schneider-Stock R (2013) Rare BRAF mutations in melanoma patients: implications for molecular testing in clinical practice. Br J Cancer 108: 2164–2171.CrossRef
Hocker T, Tsao H (2007) Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat 28: 578–588.CrossRef
Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Eng J Med 363: 711–723.CrossRef
Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150: 251–263.CrossRef
Jakob JA, Bassett RL Jr., Ng CS, Curry JL, Joseph RW, Alvarado GC, Rohlfs ML, Richard J, Gershenwald JE, Kim KB, Lazar AJ, Hwu P, Davies MA (2012) NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 118: 4014–4023.CrossRef
Jewell R, Chambers P, Harland M, Laye J, Conway C, Mitra A, Elliott F, Cook MG, Boon A, Newton-Bishop J (2012) Clinicopathologic features of V600E and V600K melanoma. Clin Cancer Res 18: 6792–6793.CrossRef
Kim SY, Kim SN, Hahn HJ, Lee YW, Choe YB, Ahn KJ (2015) Metaanalysis of BRAF mutations and clinicopathologic characteristics in primary melanoma. J Am Acad Dermatol 72: 1036–1046.CrossRef
Lang J, MacKie RM (2005) Prevalence of exon 15 BRAF mutations in primary melanoma of the superficial spreading, nodular, acral, and lentigo maligna subtypes. J Invest Dermatol 125: 575–579.CrossRef
Lee JH, Choi JW, Kim YS (2011) Frequencies of BRAF and NRAS mutations are different in histological types and sites of origin of cutaneous melanoma: a meta-analysis. Br J Dermatol 164: 776–784.CrossRef
Leiter U, Meier F, Schittek B, Garbe C (2004) The natural course of cutaneous melanoma. J Surg Oncol 86: 172–178.CrossRef
Liu W, Kelly JW, Trivett M, Murray WK, Dowling JP, Wolfe R, Mason G, Magee J, Angel C, Dobrovic A, McArthur GA (2007) Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma. J Invest Dermatol 127: 900–905.CrossRef
Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29: 1239–1246.CrossRef
Lovly CM, Dahlman KB, Fohn LE, Su Z, Dias-Santagata D, Hicks DJ, Hucks D, Berry E, Terry C, Duke M, Su Y, Sobolik-Delmaire T, Richmond A, Kelley MC, Vnencak-Jones CL, Iafrate AJ, Sosman J, Pao W (2012) Routine multiplex mutational profiling of melanomas enables enrollment in genotype-driven therapeutic trials. PLoS One 7: e35309.CrossRef
Maldonado JL, Fridlyand J, Patel H, Jain AN, Busam K, Kageshita T, Ono T, Albertson DG, Pinkel D, Bastian BC (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95: 1878–1890.CrossRef
Mar VJ, Wong SQ, Logan A, Nguyen T, Cebon J, Kelly JW, Wolfe R, Dobrovic A, McLean C, McArthur GA (2014) Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma. Pigment Cell Melanoma Res 27: 1117–1125.CrossRef
Maxwell R, Garzon-Muvdi T, Lipson EJ, Sharfman WH, Bettegowda C, Redmond KJ, Kleinberg LR, Ye X, Lim M (2016) BRAF-V600 mutational status affects recurrence patterns of melanoma brain metastasis. Int J Cancer 140: 2716–2727.CrossRef
Meier F, Will S, Ellwanger U, Schlagenhauff B, Schittek B, Rassner G, Garbe C (2002) Metastatic pathways and time courses in the orderly progression of cutaneous melanoma. Br J Dermatol 147: 62–70.CrossRef
Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, Kefford RF, Scolyer RA, Long GV (2012) Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res 18: 3242–3249.CrossRef
Mervic L (2012) Time course and pattern of metastasis of cutaneous melanoma differ between men and women. PLoS One 7: e32955.CrossRef
Poynter JN, Elder JT, Fullen DR, Nair RP, Soengas MS, Johnson TM, Redman B, Thomas NE, Gruber SB (2006) BRAF and NRAS mutations in melanoma and melanocytic nevi. Melanoma Res 16: 267–273.CrossRef
Reintgen DS, Cox C, Slingluff CL, Seigler HF (1992) Recurrent malignant melanoma: the identification of prognostic factors to predict survival. Ann Plast Surg 28: 45–49.CrossRef
Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C (2016) Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA 315: 1600–1609.CrossRef
Rubinstein JC, Sznol M, Pavlick AC, Ariyan S, Cheng E, Bacchiocchi A, Kluger HM, Narayan D, Halaban R (2010) Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032. J Transl Med 8: 67–67.CrossRef
Shinozaki M, Fujimoto A, Morton DL, Hoon DS (2004) Incidence of BRAF oncogene mutation and clinical relevance for primary cutaneous melanomas. Clin Cancer Res 10: 1753–1757.CrossRef
Smalley KS (2003) A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? Int J Cancer 104: 527–532.CrossRef
Soong S-J, Harrison RA, McCarthy WH, Urist MM, Balch CM (1998) Factors affecting survival following local, regional, or distant recurrence from localized melanoma. J Surg Oncol 67: 228–233.CrossRef
Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A (2012) Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N Engl J Med 366: 707–714.CrossRef
Spittle C, Ward MR, Nathanson KL, Gimotty PA, Rappaport E, Brose MS, Medina A, Letrero R, Herlyn M, Edwards RH (2007) Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. J Mol Diagn 9: 464–471.CrossRef
Tejera-Vaquerizo A, Barrera-Vigo MV, Fernandez-Canedo I, Blazquez-Sanchez N, Mendiola-Fernandez M, Fernandez-Orland A, Bosch-Garcia R, de Troya-Martin M, Herrera-Ceballos E (2007) Longitudinal study of different metastatic patterns in the progression of cutaneous melanoma. Actas Dermosifiliogr 98: 531–538.CrossRef
Thomas NE, Edmiston SN, Alexander A, Groben PA, Parrish E, Kricker A, Armstrong BK, Anton-Culver H, Gruber SB, From L, Busam KJ, Hao H, Orlow I, Kanetsky PA, Luo L, Reiner AS, Paine S, Frank JS, Bramson JI, Marrett LD, Gallagher RP, Zanetti R, Rosso S, Dwyer T, Cust AE, Ollila DW, Begg CB, Berwick M, Conway K Group GEMS (2015) Association between NRAS and BRAF mutational status and melanoma-specific survival among patients with higher-risk primary melanoma. JAMA Oncol 1: 359–368.CrossRef
Thomas NE, Edmiston SN, Alexander A, Millikan RC, Groben PA, Hao H, Tolbert D, Berwick M, Busam K, Begg CB, Mattingly D, Ollila DW, Tse CK, Hummer A, Lee-Taylor J, Conway K (2007) Number of nevi and early-life ambient UV exposure are associated with BRAF-mutant melanoma. Cancer Epidemiol Biomarkers Prev 16: 991–997.CrossRef
Ugurel S, Thirumaran RK, Bloethner S, Gast A, Sucker A, Mueller-Berghaus J, Rittgen W, Hemminki K, Becker JC, Kumar R, Schadendorf D (2007) B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One 2: e236.CrossRef
Viros A, Fridlyand J, Bauer J, Lasithiotakis K, Garbe C, Pinkel D, Bastian BC (2008) Improving melanoma classification by integrating genetic and morphologic features. PLoS Med 5: e120.CrossRef
Voskoboynik M, Mar V, Mailer S, Colebatch A, Fennessy A, Logan A, Hewitt C, Cebon J, Kelly J, McArthur G (2016) Clinicopathological characteristics associated with BRAFK601E and BRAFL597 mutations in melanoma. Pigment Cell Melanoma Res 29: 222–228.CrossRef
Willmore-Payne C, Holden JA, Tripp S, Layfield LJ (2005) Human malignant melanoma: detection of BRAF- and c-kit-activating mutations by high-resolution amplicon melting analysis. Hum Pathol 36: 486–493.CrossRef