Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma

Maria Colombino, Amelia Lissia, Mariaelena Capone, Vincenzo De Giorgi, Daniela Massi, Ignazio Stanganelli, Ester Fonsatti, Michele Maio, Gerardo Botti, Corrado Caracò, Nicola Mozzillo, Paolo A Ascierto, Antonio Cossu, Giuseppe Palmieri, Maria Colombino, Amelia Lissia, Mariaelena Capone, Vincenzo De Giorgi, Daniela Massi, Ignazio Stanganelli, Ester Fonsatti, Michele Maio, Gerardo Botti, Corrado Caracò, Nicola Mozzillo, Paolo A Ascierto, Antonio Cossu, Giuseppe Palmieri

Abstract

Background: Prevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population.

Methods: Genomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening.

Results: Overall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients' geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases.

Conclusions: Our findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.

Figures

Figure 1
Figure 1
Patients and tissues included into the study.

References

    1. Leong SP, Mihm MC Jr, Murphy GF, Hoon DS, Kashani-Sabet M, Agarwala SS, Zager JS, Hauschild A, Sondak VK, Guild V, Kirkwood JM. Progression of cutaneous melanoma: implications for treatment. Clin Exp Metastasis. 2012;29:775–796. doi: 10.1007/s10585-012-9521-1.
    1. Tuong W, Cheng LS, Armstrong AW. Melanoma: epidemiology, diagnosis, treatment, and outcomes. Dermatol Clin. 2012;30:113–124. doi: 10.1016/j.det.2011.08.006.
    1. Scheier B, Amaria R, Lewis K, Gonzalez R. Novel therapies in melanoma. Immunotherapy. 2011;3:1461–1469. doi: 10.2217/imt.11.136.
    1. Eggermont AM, Robert C. New drugs in melanoma: it’s a whole new world. Eur J Cancer. 2011;47:2150–2157. doi: 10.1016/j.ejca.2011.06.052.
    1. Ascierto PA, Grimaldi AM, Acquavella N, Borgognoni L, Calabrò L, Cascinelli N, Cesano A, Del Vecchio M, Eggermont AM, Faries M, Ferrone S, Fox BA, Gajewski TF, Galon J, Gnjatic S, Gogas H, Kashani-Sabet M, Kaufman HL, Larkin J, Lo RS, Mantovani A, Margolin K, Melief C, McArthur G, Palmieri G, Puzanov I, Ribas A, Seliger B, Sosman J, Suenaert P, Tarhini AA, Trinchieri G, Vidal-Vanaclocha F, Wang E, Ciliberto G, Mozzillo N, Marincola FM, Thurin M. Future perspectives in melanoma research. Meeting report from the “Melanoma Bridge. Napoli, December 2nd-4th 2012”. J Transl Med. 2013;11:137. doi: 10.1186/1479-5876-11-137.
    1. Nikolaou VA, Stratigos AJ, Flaherty KT, Tsao H. Melanoma: new insights and new therapies. J Invest Dermatol. 2012;132:854–863. doi: 10.1038/jid.2011.421.
    1. Mandalà M, Voit C. Targeting BRAF in melanoma: Biological and clinical challenges. Crit Rev Oncol Hematol. 2013;S1040–8428:00029–00032.
    1. Casula C, Muggiano A, Cossu A, Budroni M, Caracò C, Ascierto PA, Pagani E, Stanganelli I, Canzanella S, Sini MC, Palomba G. The Italian Melanoma Intergroup (IMI), Palmieri G. Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy. BMC Cancer. 2009;9:352. doi: 10.1186/1471-2407-9-352.
    1. van den Hurk K, Niessen HE, Veeck J, van den Oord JJ, Van Steensel MA, Zur Hausen A, Van Engeland M, Winnepenninckx VJ. Genetics and epigenetics of cutaneous malignant melanoma: a concert out of tune. Biochim Biophys Acta. 1826;2012:89–102.
    1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho J, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. Mutations in the BRAF gene in human cancer. Nature. 2002;417:949–954. doi: 10.1038/nature00766.
    1. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma. Lancet. 2005;365:687–701.
    1. Palmieri G, Capone ME, Ascierto ML, Gentilcore G, Stroncek DF, Casula M, Sini MC, Palla M, Mozzillo N, Ascierto PA. Main roads to melanoma. J Transl Med. 2009;7:86. doi: 10.1186/1479-5876-7-86.
    1. Pollock PM, Harper UL, Hansen KS, Yudt LM, Stark M, Robbins CM, Moses TY, Hostetter G, Wagner U, Kakareka J, Salem G, Pohida T, Heenan P, Duray P, Kallioniemi O, Hayward NK, Trent JM, Meltzer PS. High frequency of BRAF mutations in nevi. Nat Genet. 2003;33:19–20.
    1. Palmieri G, Casula M, Sini MC, Ascierto PA, Cossu A. Issues affecting molecular staging in the management of patients with melanoma. J Cell Mol Med. 2007;11:1052–1068. doi: 10.1111/j.1582-4934.2007.00091.x.
    1. Blokx WA, Van Dijk MC, Ruiter DJ. Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects. Histopathology. 2010;56:121–132. doi: 10.1111/j.1365-2559.2009.03452.x.
    1. Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, Cho KH, Aiba S, Bröcker EB, LeBoit PE, Pinkel D, Bastian BC. Distinct sets of genetic alterations in melanoma. N Engl J Med. 2005;353:2135–2147. doi: 10.1056/NEJMoa050092.
    1. Sensi M, Nicolini G, Petti C, Bersani I, Lozupone F, Molla A, Vegetti C, Nonaka D, Mortarini R, Parmiani G, Fais S, Anichini A. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene. 2006;25:3357–3364. doi: 10.1038/sj.onc.1209379.
    1. 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 MC, Franco R, Botti G, Caracò C, Mozzillo N, Ascierto PA, Palmieri G. BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol. 2012;30:2522–2529. doi: 10.1200/JCO.2011.41.2452.
    1. Wright AF, Carothers AD, Pirastu M. Population choice in mapping genes for complex diseases. Nat Genet. 1999;23:397–404. doi: 10.1038/70501.
    1. Arcos-Burgos M, Muenke M. Genetics of population isolates. Clin Genet. 2002;61:233–247. doi: 10.1034/j.1399-0004.2002.610401.x.
    1. Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Buzaid AC, Cochran AJ, Coit DG, Ding S, Eggermont AM, Flaherty KT, Gimotty PA, Kirkwood JM, McMasters KM, Mihm MC Jr, Morton DL, Ross MI, Sober AJ, Sondak VK. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–6206. doi: 10.1200/JCO.2009.23.4799.
    1. Casula M, Colombino M, Satta MP, Cossu A, Ascierto PA, Bianchi-Scarrà G, Castiglia D, Budroni M, Rozzo C, Manca A, Lissia A, Carboni A, Petretto E, Satriano SMR, Botti G, Mantelli M, Ghiorzo P, Stratton MR, Tanda F, Palmieri G. BRAF gene is somatically mutated but does not make a major contribution to malignant melanoma susceptibility: The Italian Melanoma Intergroup Study. J Clin Oncol. 2004;22:286–292.
    1. Haluska FG, Tsao H, Wu H, Haluska FS, Lazar A, Goel V. Genetic alterations in signaling pathways in melanoma. Clin Cancer Res. 2006;12:2301–2307. doi: 10.1158/1078-0432.CCR-05-2518.
    1. Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 1802;2010:396–405.
    1. Miller AJ, Mihm MC. Melanoma. N Engl J Med. 2006;355:51–65. doi: 10.1056/NEJMra052166.
    1. Mehnert JM, Kluger HM. Driver mutations in melanoma: lessons learned from bench-to-bedside studies. Curr Oncol Rep. 2012;14:449–457. doi: 10.1007/s11912-012-0249-5.
    1. Long GV, Menzies AM, Nagrial AM, Haydu LE, Hamilton AL, Mann GJ, Hughes TM, Thompson JF, Scolyer RA, Kefford RF. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol. 2011;29:1239–1246. doi: 10.1200/JCO.2010.32.4327.
    1. Amanuel B, Grieu F, Kular J, Millward M, Iacopetta B. Incidence of BRAF p.Val600Glu and p.Val600Lys mutations in a consecutive series of 183 metastatic melanoma patients from a high incidence region. Pathology. 2012;44:357–359. doi: 10.1097/PAT.0b013e3283532565.
    1. Menzies AM, Haydu LE, Visintin L, Carlino MS, Howle JR, Thompson JF, Kefford RF, Scolyer RA, Long GV. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin Cancer Res. 2012;18:3242–3249. doi: 10.1158/1078-0432.CCR-12-0052.
    1. Thomas NE, Alexander A, Edmiston SN, Parrish E, Millikan RC, Berwick M, Groben P, Ollila DW, Mattingly D, Conway K. Tandem BRAF mutations in primary invasive melanomas. J Invest Dermatol. 2004;122:1245–1250. doi: 10.1111/j.0022-202X.2004.22523.x.
    1. Patton EE, Widlund HR, Kutok JL, Kopani KR, Amatruda JF, Murphey RD, Berghmans S, Mayhall EA, Traver D, Fletcher CD, Aster JC, Granter SR, Look AT, Lee C, Fisher DE, Zon LI. BRAF mutations are sufficient to promote nevi formation and cooperate with p53 in the genesis of melanoma. Curr Biol. 2005;15:249–254. doi: 10.1016/j.cub.2005.01.031.
    1. Greene VR, Johnson MM, Grimm EA, Ellerhorst JA. Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. J Invest Dermatol. 2009;129:1483–1488. doi: 10.1038/jid.2008.374.
    1. Lin J, Goto Y, Murata H, Sakaizawa K, Uchiyama A, Saida T, Takata M. Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression. Br J Cancer. 2011;104:464–468. doi: 10.1038/sj.bjc.6606072.
    1. Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N, Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA. Melanoma Genetics Consortium. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002;94:894–903. doi: 10.1093/jnci/94.12.894.
    1. Casula M, Colombino M, Satta MP, Cossu A, Lissia A, Budroni M, Simeone E, Calemma R, Loddo C, Caracò C, Mozzillo N, Daponte A, Comella G, Canzanella S, Guida M, Castello G, Ascierto PA, Palmieri G. Factors predicting the occurrence of germline mutations in candidate genes among patients with cutaneous malignant melanoma from South Italy. Eur J Cancer. 2007;43:137–143. doi: 10.1016/j.ejca.2006.07.017.
    1. Lin J, Takata M, Murata H, Goto Y, Kido K, Ferrone S, Saida T. Polyclonality of BRAF mutations in acquired melanocytic nevi. J Natl Cancer Inst. 2009;101:1423–1427. doi: 10.1093/jnci/djp309.
    1. Yancovitz M, Litterman A, Yoon J, Shapiro RL, Berman RS, Pavlick AC, Darvishian F, Christos P, Mazumdar M, Osman I, Polsky D. Intra- and inter-tumor heterogeneity of BRAF(V600E) mutations in primary and metastatic melanoma. PLoS One. 2012;7:e29336. doi: 10.1371/journal.pone.0029336.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться