Large Congenital Melanocytic Nevus With LMNA::NTRK1 Fusion: Expanding Targeted Therapy Options for Congenital Nevi and Melanoma

IF 1.1 4区 医学 Q3 DERMATOLOGY
Akanksha Nagarkar, Jackson Turbeville, Molly A. Hinshaw, Philip E. LeBoit, Jeffrey Gagan, Mark Raffeld, Kenneth Aldape, Niharika Shah, Frederic G. Barr, Liqiang Xi, Ina Lee, Christina K. Ferrone, Svetlana D. Pack, Rosandra Kaplan, Mary Frances Wedekind Malone, Marielle Yohe, Michael R. Sargen
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Abstract

Large congenital melanocytic nevi/nevus (LCMN) are caused by genetic events that activate the mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK) pathway. Individuals with LCMN are prone to developing aggressive melanomas during childhood. Targeted therapies are needed to treat this form of melanoma and manage LCMN symptoms such as pruritus and pain, which significantly impact quality of life. Here, we present the first case of an LCMN with an NTRK fusion driver event. The patient presented with an atypical proliferative nodule arising in the background nevus. RNA sequencing of the proliferative nodule with background nevus identified a pathogenic LMNA::NTRK1 fusion. The fusion resulted in constitutive expression of TrkA, demonstrated by strong cytoplasmic pan-TRK staining, along with activation of the MAPK/ERK pathway, as indicated by positive nuclear and cytoplasmic staining for phosphorylated ERK. The background nevus beneath the proliferative nodule also expressed pan-TRK and phosphorylated ERK, suggesting that the NTRK1 fusion occurred prior to the formation of the proliferative nodule. This case broadens the spectrum of driver events for LCMN and suggests that screening for TRK fusions in LCMN should be considered when systemic therapy is being considered for melanoma or symptom management.

Abstract Image

大型先天性黑素细胞痣与LMNA::NTRK1融合:扩大先天性痣和黑色素瘤的靶向治疗选择。
先天性大黑素细胞痣/痣(LCMN)是由激活丝裂原活化蛋白激酶(MAPK)和细胞外信号调节激酶(ERK)途径的遗传事件引起的。患有LCMN的个体在儿童期容易发展为侵袭性黑色素瘤。需要有针对性的治疗来治疗这种形式的黑色素瘤,并控制LCMN症状,如瘙痒和疼痛,这些症状会严重影响生活质量。在这里,我们提出了第一例具有NTRK聚变驱动事件的LCMN。患者表现为背景痣内的非典型增生性结节。背景痣增生性结节的RNA测序鉴定出致病性LMNA::NTRK1融合。融合导致TrkA的组成性表达,细胞质泛trk染色较强,同时MAPK/ERK通路激活,磷酸化ERK的核和细胞质染色呈阳性。增殖性结节下方的背景痣也表达泛trk和磷酸化的ERK,提示NTRK1融合发生在增殖性结节形成之前。该病例拓宽了LCMN驱动事件的范围,并提示在考虑对黑色素瘤或症状管理进行全身治疗时,应考虑筛查LCMN中的TRK融合。
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来源期刊
CiteScore
3.20
自引率
5.90%
发文量
174
审稿时长
3-8 weeks
期刊介绍: Journal of Cutaneous Pathology publishes manuscripts broadly relevant to diseases of the skin and mucosae, with the aims of advancing scientific knowledge regarding dermatopathology and enhancing the communication between clinical practitioners and research scientists. Original scientific manuscripts on diagnostic and experimental cutaneous pathology are especially desirable. Timely, pertinent review articles also will be given high priority. Manuscripts based on light, fluorescence, and electron microscopy, histochemistry, immunology, molecular biology, and genetics, as well as allied sciences, are all welcome, provided their principal focus is on cutaneous pathology. Publication time will be kept as short as possible, ensuring that articles will be quickly available to all interested in this speciality.
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