The clinical significance of c-Kit mutations in metastatic oral mucosal melanoma in China

c-Kit mutations are frequently detected in mucosal melanomas, but their clinical significance in metastatic oral mucosal melanomas (OMM) remains unclear. The main purpose of this study was to investigate the clinical and pathological features of metastatic OMMs with c-Kit mutations and the efficiency of the tyrosine kinase inhibitor imatinib in treating metastatic OMMs. We found thatresidual primary lesion and neck lymph nodes could act as independent prognostic factors in metastatic OMM patients. c-Kit mutations were detected in 22 out of 139 (15.8%) metastatic OMM patients. Under chemotherapy, the overall survival (OS) of c-Kit mutant patients was significantly shorter than that of wild-type patients. The Ki67 expression was significantly higher in c-Kit mutant patients than in wild-type patients. In distant metastatic OMM patients with c-Kit mutations, the treatment with c-Kit inhibitor resulted in a better OS. In conclusion, residual primary lesion, cervical lymph nodes and c-Kit mutations act as adverse prognostic factors of metastatic OMMs. The Kit inhibitor imatinib could benefit metastatic OMM patients with c-Kit mutations.

[1]  W. Guo,et al.  Mutation scanning of BRAF, NRAS, KIT, and GNAQ/GNA11 in oral mucosal melanoma: a study of 57 cases. , 2016, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[2]  R. de Bree,et al.  Update on primary head and neck mucosal melanoma , 2016, Head & neck.

[3]  W. Guo,et al.  Prognostic factors of oral mucosal melanoma: histopathological analysis in a retrospective cohort of 82 cases , 2015, Histopathology.

[4]  L. Harrison,et al.  Mucosal melanoma of the head and neck: a systematic review of the literature. , 2014, International journal of radiation oncology, biology, physics.

[5]  Tim K. Lee,et al.  Extracutaneous melanoma epidemiology in British Columbia , 2014, Melanoma research.

[6]  A. Olszewski,et al.  Epidemiology and survival outcomes of ocular and mucosal melanomas: A population‐based analysis , 2014, International journal of cancer.

[7]  W. Guo,et al.  Neck dissection for oral mucosal melanoma: caution of nodular lesion. , 2014, Oral oncology.

[8]  R. Kefford,et al.  The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma , 2014, Oncogene.

[9]  J. Gaughan,et al.  Outcomes in patients with mucosal melanomas , 2013, Journal of surgical oncology.

[10]  J. Blay,et al.  Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial , 2013, The Lancet.

[11]  Johan Lennartsson,et al.  Stem cell factor receptor/c-Kit: from basic science to clinical implications. , 2012, Physiological reviews.

[12]  M. Postow,et al.  Mucosal Melanoma: Pathogenesis, Clinical Behavior, and Management , 2012, Current Oncology Reports.

[13]  David C Whiteman,et al.  The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin , 2011, Pigment cell & melanoma research.

[14]  K. Flaherty,et al.  Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  D. Schadendorf,et al.  Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). , 2011, European journal of cancer.

[16]  L. Kanter‐Lewensohn,et al.  KIT Pathway Alterations in Mucosal Melanomas of the Vulva and Other Sites , 2011, Clinical Cancer Research.

[17]  David E Fisher,et al.  New Strategies in Metastatic Melanoma: Oncogene-Defined Taxonomy Leads to Therapeutic Advances , 2011, Clinical Cancer Research.

[18]  K. Flaherty,et al.  Large-Scale Analysis of KIT Aberrations in Chinese Patients with Melanoma , 2011, Clinical Cancer Research.

[19]  S. Woodman,et al.  Targeting KIT in melanoma: a paradigm of molecular medicine and targeted therapeutics. , 2010, Biochemical pharmacology.

[20]  Jeffrey E Gershenwald,et al.  Final version of 2009 AJCC melanoma staging and classification. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  D. Silvers,et al.  GAB2 Amplifications Refine Molecular Classification of Melanoma , 2009, Clinical Cancer Research.

[22]  V. Sondak,et al.  c-KIT signaling as the driving oncogenic event in sub-groups of melanomas. , 2009, Histology and histopathology.

[23]  S. Agarwala Current systemic therapy for metastatic melanoma , 2009, Expert review of anticancer therapy.

[24]  T. Saida,et al.  Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas , 2009, International journal of cancer.

[25]  J. Fletcher,et al.  Imatinib Targeting of KIT-Mutant Oncoprotein in Melanoma , 2008, Clinical Cancer Research.

[26]  Susan Muller,et al.  KIT Gene Mutations and Copy Number in Melanoma Subtypes , 2008, Clinical Cancer Research.

[27]  M. Ross,et al.  Phase II trial of imatinib mesylate in patients with metastatic melanoma , 2008, British Journal of Cancer.

[28]  B. Bastian,et al.  Dose‐dependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation , 2008, Pigment cell & melanoma research.

[29]  A. D. Van den Abbeele,et al.  Major response to imatinib mesylate in KIT-mutated melanoma. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  Safdar Ali,et al.  Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST). , 2007, Gene.

[31]  Narasimhan P. Agaram,et al.  L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition , 2007, International journal of cancer.

[32]  D. Pinkel,et al.  Somatic activation of KIT in distinct subtypes of melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  M. Atkins,et al.  Multicenter Phase II trial of high‐dose imatinib mesylate in metastatic melanoma , 2006, Cancer.

[34]  David Polsky,et al.  Focus on melanoma. , 2002, Cancer cell.

[35]  R. Henrique,et al.  Prognostic value of Ki-67 expression in localized cutaneous malignant melanoma. , 2000, Journal of the American Academy of Dermatology.

[36]  C. Flaitz,et al.  Oral mucosal melanoma: epidemiology and pathobiology. , 2000, Oral oncology.

[37]  C. Begg,et al.  Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[38]  L. Karnell,et al.  The National Cancer Data Base report on cutaneous and noncutaneous melanoma , 1998, Cancer.

[39]  M. Umeda,et al.  Primary malignant melanoma of the oral cavity--its histological classification and treatment. , 1994, The British journal of oral & maxillofacial surgery.

[40]  A. Ullrich,et al.  Human proto‐oncogene c‐kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. , 1987, The EMBO journal.

[41]  E. McFadden,et al.  Toxicity and response criteria of the Eastern Cooperative Oncology Group , 1982, American journal of clinical oncology.

[42]  Daan Brandenbarg The National. , 1892 .

[43]  J. Stockman KIT as a Therapeutic Target in Metastatic Melanoma , 2013 .

[44]  S. Vlajković,et al.  Primary mucosal melanomas: a comprehensive review. , 2012, International journal of clinical and experimental pathology.

[45]  D. Schadendorf,et al.  Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.