Hai-Yun Wang1,2, Xiao-Yan Wu1,2, Xiao Zhang1,2, Xin-Hua Yang1,2, Ya-Kang Long1,2, Yan-Fen Feng3,4, Fang Wang3,2. 1. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China. 2. Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China. 3. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China wangfang@sysucc.org.cn fengyf@sysucc.org.cn. 4. Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
Abstract
BACKGROUND: Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential. This study aimed to identify the molecular markers occurring in these patients and potentially improve treatment strategies. MATERIALS AND METHODS: The clinicopathological characteristics of 36 patients with primary vaginal melanomas were reviewed. Oncogenic mutations in BRAF, KIT, NRAS, GNAQ and GNA11 and the promoter region of telomerase reverse transcriptase (TERT) were investigated using the Sanger sequencing. The expression and copy number of programmed death-ligand 1 (PD-L1) were also assessed. RESULTS: Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively. PD-L1 expression and amplification were observed in 27.8% (10/36) and 5.6% (2/36) of cases, respectively. PD-L1 positive expression and/or amplification was associated with older patients (p = .008). Patients who had NRAS mutations had a poorer overall survival compared with those with a wild-type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08-8.83). Strikingly, two patients with/without PD-L1 expression receiving immune checkpoint inhibitors had a satisfying outcome. Multivariate analysis demonstrated that >10 mitoses per mm2 (HR, 2.96; 95% CI, 1.03-8.51) was an independent prognostic factor. CONCLUSIONS: NRAS mutations and PD-L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets. IMPLICATIONS FOR PRACTICE: This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD-L1 expression and copy number in 36 primary vaginal melanomas. NRAS mutations and PD-L1 expression were the most prevalent, but KIT and TERT mutations occurred at a lower occurrence in this rare malignancy. Two patients receiving immune checkpoint inhibitors had a satisfying outcome, signifying that the PD-L1 expression and amplification can be a possible predictive marker of clinical response. This study highlights the possible prospects of biomarkers that can be used for patient selection in clinical trials involving treatments with novel targeted therapies based on these molecular aberrations.
BACKGROUND: Primary vaginal melanomas are uncommon and aggressive tumors with poor prognosis, and the development of new targeted therapies is essential. This study aimed to identify the molecular markers occurring in these patients and potentially improve treatment strategies. MATERIALS AND METHODS: The clinicopathological characteristics of 36 patients with primary vaginal melanomas were reviewed. Oncogenic mutations in BRAF, KIT, NRAS, GNAQ and GNA11 and the promoter region of telomerase reverse transcriptase (TERT) were investigated using the Sanger sequencing. The expression and copy number of programmed death-ligand 1 (PD-L1) were also assessed. RESULTS: Mutations in NRAS, KIT, and TERT promoter were identified in 13.9% (5/36), 2.9% (1/34), and 5.6% (2/36) of the primary vaginal melanomas, respectively. PD-L1 expression and amplification were observed in 27.8% (10/36) and 5.6% (2/36) of cases, respectively. PD-L1 positive expression and/or amplification was associated with older patients (p = .008). Patients who had NRAS mutations had a poorer overall survival compared with those with a wild-type NRAS (33.5 vs. 14.0 months; hazard ratio [HR], 3.09; 95% CI, 1.08-8.83). Strikingly, two patients with/without PD-L1 expression receiving immune checkpoint inhibitors had a satisfying outcome. Multivariate analysis demonstrated that >10 mitoses per mm2 (HR, 2.96; 95% CI, 1.03-8.51) was an independent prognostic factor. CONCLUSIONS: NRAS mutations and PD-L1 expression were most prevalent in our cohort of primary vaginal melanomas and can be potentially considered as therapeutic targets. IMPLICATIONS FOR PRACTICE: This study used the Sanger sequencing, immunohistochemistry, and fluorescence in situ hybridization methods to detect common genetic mutations and PD-L1 expression and copy number in 36 primary vaginal melanomas. NRAS mutations and PD-L1 expression were the most prevalent, but KIT and TERT mutations occurred at a lower occurrence in this rare malignancy. Two patients receiving immune checkpoint inhibitors had a satisfying outcome, signifying that the PD-L1 expression and amplification can be a possible predictive marker of clinical response. This study highlights the possible prospects of biomarkers that can be used for patient selection in clinical trials involving treatments with novel targeted therapies based on these molecular aberrations.
Authors: A P M Heintz; F Odicino; P Maisonneuve; M A Quinn; J L Benedet; W T Creasman; H Y S Ngan; S Pecorelli; U Beller Journal: Int J Gynaecol Obstet Date: 2006-11 Impact factor: 3.561
Authors: Julie A Ellerhorst; Victoria R Greene; Suhendan Ekmekcioglu; Carla L Warneke; Marcella M Johnson; Carolyn P Cooke; Li-E Wang; Victor G Prieto; Jeffrey E Gershenwald; Qingyi Wei; Elizabeth A Grimm Journal: Clin Cancer Res Date: 2010-10-25 Impact factor: 12.531
Authors: Aaron M Goodman; David Piccioni; Shumei Kato; Amélie Boichard; Huan-You Wang; Garrett Frampton; Scott M Lippman; Caitlin Connelly; David Fabrizio; Vincent Miller; Jason K Sicklick; Razelle Kurzrock Journal: JAMA Oncol Date: 2018-09-01 Impact factor: 31.777
Authors: Helen Davies; Graham R Bignell; Charles Cox; Philip Stephens; Sarah Edkins; Sheila Clegg; Jon Teague; Hayley Woffendin; Mathew J Garnett; William Bottomley; Neil Davis; Ed Dicks; Rebecca Ewing; Yvonne Floyd; Kristian Gray; Sarah Hall; Rachel Hawes; Jaime Hughes; Vivian Kosmidou; Andrew Menzies; Catherine Mould; Adrian Parker; Claire Stevens; Stephen Watt; Steven Hooper; Rebecca Wilson; Hiran Jayatilake; Barry A Gusterson; Colin Cooper; Janet Shipley; Darren Hargrave; Katherine Pritchard-Jones; Norman Maitland; Georgia Chenevix-Trench; Gregory J Riggins; Darell D Bigner; Giuseppe Palmieri; Antonio Cossu; Adrienne Flanagan; Andrew Nicholson; Judy W C Ho; Suet Y Leung; Siu T Yuen; Barbara L Weber; Hilliard F Seigler; Timothy L Darrow; Hugh Paterson; Richard Marais; Christopher J Marshall; Richard Wooster; Michael R Stratton; P Andrew Futreal Journal: Nature Date: 2002-06-09 Impact factor: 49.962
Authors: Catherine D Van Raamsdonk; Vladimir Bezrookove; Gary Green; Jürgen Bauer; Lona Gaugler; Joan M O'Brien; Elizabeth M Simpson; Gregory S Barsh; Boris C Bastian Journal: Nature Date: 2008-12-10 Impact factor: 49.962