Advertisement

Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Esophageal melanomas harbor frequent NRAS mutations unlike melanomas of other mucosal sites

  • 242 Accesses

  • 24 Citations

Abstract

Mucosal melanomas have genetic alterations distinct from those in cutaneous melanomas. For example, NRAS- and BRAF-activating mutations occur frequently in cutaneous melanomas, but not in mucosal melanomas. We examined 16 esophageal melanomas for genetic alterations in NRAS, BRAF, and KIT to determine whether they exhibit genetic features common to melanomas arising from other mucosal sites. A sequencing analysis identified NRAS mutations in six cases; notably, four of these mutations were located in exon 1, an uncommon mutation site in cutaneous and other mucosal melanomas. BRAF and KIT mutations were found in one case each. Immunohistochemistry showed KIT expression in four cases, including the tumor with a KIT mutation and two other intramucosal tumors. The low frequency of BRAF mutations and the presence of a KIT mutation-positive case are findings similar to those of mucosal melanomas of other sites, but the prevalence of NRAS mutations was even higher than that of cutaneous melanomas. The present study implies that esophageal melanomas have genetic alterations unique from those observed in other mucosal melanomas.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    van't Veer LJ, Burgering BM, Versteeg R et al (1989) N-ras mutations in human cutaneous melanoma from sun-exposed body sites. Mol Cell Biol 9:3114–3116

  2. 2.

    Jiveskog S, Ragnarsson-Olding B, Platz A et al (1998) N-ras mutations are common in melanomas from sun-exposed skin of humans but rare in mucosal membranes or unexposed skin. J Invest Dermatol 111:757–761

  3. 3.

    Davies H, Bignell GR, Cox C et al (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

  4. 4.

    Curtin JA, Fridlyand J, Kageshita T et al (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353:2135–2147

  5. 5.

    Curtin JA, Busam K, Pinkel D et al (2006) Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 24:4340–4346

  6. 6.

    Rivera RS, Nagatsuka H, Gunduz M et al (2008) C-kit protein expression correlated with activating mutations in KIT gene in oral mucosal melanoma. Virchows Arch 452:27–32

  7. 7.

    Antonescu CR, Busam KJ, Francone TD et al (2007) L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. Int J Cancer 121:257–264

  8. 8.

    Kato H, Watanabe H, Tachimori Y et al (1991) Primary malignant melanoma of the esophagus: report of four cases. Jpn J Clin Oncol 21:306–313

  9. 9.

    Li B, Lei W, Shao K et al (2007) Characteristics and prognosis of primary malignant melanoma of the esophagus. Melanoma Res 17:239–242

  10. 10.

    Lohmann CM, Hwu WJ, Iversen K et al (2003) Primary malignant melanoma of the oesophagus: a clinical and pathological study with emphasis on the immunophenotype of the tumours for melanocyte differentiation markers and cancer/testis antigens. Melanoma Res 13:595–601

  11. 11.

    Turnbull AD, Rosen P, Goodner JT et al (1973) Primary malignant tumors of the esophagus other than typical epidermoid carcinoma. Ann Thorac Surg 15:463–473

  12. 12.

    Scotto J, Fraumeni JF Jr, Lee JA (1976) Melanomas of the eye and other noncutaneous sites: epidemiologic aspects. J Natl Cancer Inst 56:489–491

  13. 13.

    Tateishi R, Taniguchi H, Wada A et al (1974) Argyrophil cells and melanocytes in esophageal mucosa. Arch Pathol 98:87–89

  14. 14.

    Hocker T, Tsao H (2007) Ultraviolet radiation and melanoma: a systematic review and analysis of reported sequence variants. Hum Mutat 28:578–588

  15. 15.

    Cohen Y, Rosenbaum E, Begum S et al (2004) Exon 15 BRAF mutations are uncommon in melanomas arising in nonsun-exposed sites. Clin Cancer Res 10:3444–3447

  16. 16.

    Edwards RH, Ward MR, Wu H et al (2004) Absence of BRAF mutations in UV-protected mucosal melanomas. J Med Genet 41:270–272

  17. 17.

    Wong CW, Fan YS, Chan TL et al (2005) BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs. J Clin Pathol 58:640–644

  18. 18.

    Lasota J, Jasinski M, Sarlomo-Rikala M et al (1999) Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 154:53–60

  19. 19.

    Hodi FS, Friedlander P, Corless CL et al (2008) Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26:2046–2051

  20. 20.

    Lutzky J, Bauer J, Bastian BC (2008) Dose-dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res 21:492–493

  21. 21.

    Montone KT, van Belle P, Elenitsas R et al (1997) Proto-oncogene c-kit expression in malignant melanoma: protein loss with tumor progression. Mod Pathol 10:939–944

  22. 22.

    Janku F, Novotny J, Julis I et al (2005) KIT receptor is expressed in more than 50% of early-stage malignant melanoma: a retrospective study of 261 patients. Melanoma Res 15:251–256

Download references

Acknowledgements

This work was supported by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control, a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan, and a program for promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NiBio), Japan.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Author information

Correspondence to Yae Kanai.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sekine, S., Nakanishi, Y., Ogawa, R. et al. Esophageal melanomas harbor frequent NRAS mutations unlike melanomas of other mucosal sites. Virchows Arch 454, 513–517 (2009). https://doi.org/10.1007/s00428-009-0762-6

Download citation

Keywords

  • NRAS
  • BRAF
  • KIT
  • Esophageal melanoma