DNA甲基化与皮肤肿瘤的研究进展

DNA甲基化是表观遗传学的重要内容之一,该DNA修饰方式在不改变基因序列的前提下实现对基因表达的调控.多项研究证实,DNA甲基化异常与黑素瘤、皮肤基底细胞癌、皮肤鳞状细胞癌、皮肤T细胞淋巴瘤的发生密切相关,而DNA甲基化检测技术为检测DNA甲基化提供技术平台.通过甲基化检测技术分析基因异常甲基化已成为当前皮肤肿瘤早期诊断、治疗、预后评估等的方向.     

皮肤T细胞淋巴瘤的表观遗传学研究进展

皮肤T细胞淋巴瘤(CTCL)是一组少见疾病,属于结外非霍奇金淋巴瘤,是原发于皮肤的一种T淋巴细胞克隆性增生所致的疾病。目前尚无有效的治疗办法,近年来其发病率呈上升趋势。CTCL发病机制不明,大量研究表明CTCL的发生与表观遗传学有着密切关系。表观遗传学在基因转录调节中起着重要作用,主要包括组蛋白乙酰化、磷酸化、泛素化,DNA甲基化及microRNAs(miRNAs)等。随着甲基化转移酶抑制剂及组蛋白酶抑制剂等表观治疗药物在临床的成功应用,以及其对肿瘤细胞所具有的高选择性,表观遗传成为CTCL研究的热点。该文就表观遗传学中DNA甲基化、组蛋白修饰及miRNAs在CTCL诊断及治疗等方面的最新研究进展作一综述。     

皮肤恶性肿瘤的DNA异常甲基化研究进展

对肿瘤研究的不断深入发现除了基因突变之外,表观遗传改变也与肿瘤的发生发展密切相关。肿瘤表观遗传的改变以DNA的异常甲基化为主,其主要的机制是由肿瘤抑制基因启动子超甲基化引起基因沉默。DNA的异常甲基化几乎存在于任何类型的人类肿瘤中,包括皮肤恶性肿瘤。现对DNA甲基化、DNA甲基化与肿瘤、DNA甲基化在基底细胞癌、鳞状细胞癌、黑色素瘤和皮肤淋巴瘤等皮肤恶性肿瘤中的研究进行综述。     

皮肤T细胞淋巴瘤表观遗传学机制及临床应用

皮肤T细胞淋巴瘤是最常见的原发皮肤淋巴瘤,阐明其发病机制已成为亟待攻克的重要课题。近20年的优秀研究成果,表明了表观遗传学在此类肿瘤发病及进展中至关重要的作用,不仅为临床早期诊断、预后判断提供了崭新思路,而且表观遗传学改变的可逆性也为药物疾病逆转提供了可能。本文将对本领域研究进行梳理与总结,以期对皮肤T细胞淋巴瘤表观遗传学机制研究与临床应用现状有一个清晰的展示。     

表观遗传学机制在SLE发病中的作用

系统性红斑狼疮是一种累及全身多器官系统的自身免疫性疾病,其发病机制尚不明确.表观遗传学是指发生在基因表达水平的可遗传的变化,但不涉及基因序列的改变.其涉及的机制主要有DNA甲基化、组蛋白修饰、microRNA等.研究显示,表观遗传学异常与系统性红斑狼疮发病密切相关.主要阐述DNA甲基化、组蛋白修饰和microRNA在系统性红斑狼疮发病中的作用.     

系统性硬皮病表观遗传学发病机制的进展

表观遗传学是研究DNA序列未发生改变的情况下,基因表达的可遗传变异的一门学科,其涉及的机制主要包括DNA甲基化、组蛋白修饰和MicroRNA等.系统性硬皮病是一种累及皮肤及多种器官的自身免疫性结缔组织疾病,其发病机制复杂.近年来,有关系统性硬皮病表观遗传学机制的研究取得一定进展,特别是DNA甲基化、组蛋白修饰参与系统性硬皮病自身抗体的产生和胶原合成异常,如有研究发现,患者CD4+T细胞基因调控序列甲基化水平的降低导致CD70和CD40L表达升高,从而参与系统性硬皮病发病;Flil基因启动子区域组蛋白的异常修饰导致Fli1表达下降,胶原合成增加.基因低甲基化、组蛋白低乙酰化和MicroRNA修饰可能会成为系统性硬皮病早期生物学标记和治疗目标.     

表观遗传学与黑素瘤的研究进展

表观遗传学是一种分子现象,其表型变化从一代传递到下一代,在DNA结构上无明显的改变,包括DNA甲基化、组蛋白修饰、染色质重塑和RNA干扰等,其中又以DNA甲基化研究最为广泛,进展最为迅速.黑素瘤是外胚叶神经嵴来源的恶性肿瘤,在所有皮肤肿瘤中恶性程度最高,致死性极强.近年来,越来越多的研究发现,表观遗传学改变对黑素瘤的发生发展具有重要意义.概述表观遗传学的DNA甲基化、组蛋白修饰及非编码序列与黑素瘤发病的相关研究进展,为黑素瘤的诊断及预后提供帮助.     

系统性红斑狼疮表观遗传学机制研究新进展

系统性红斑狼疮(SLE)是一种严重威胁人类健康的自身免疫性疾病,其发生和发展过程涉及遗传因素和诸多环境因素.近年研究表明多种表观遗传机制的异常参与了SLE的发病机制.表观遗传学是指在核苷酸序列不发生改变的前提下,基因发生了稳定的可遗传的变化,最终导致表型的改变.DNA甲基化、组蛋白修饰是最主要的表观遗传调控方式,而MicroRNA在表观遗传调控中也扮演了重要的角色.该文就SLE表观遗传学机制研究的最新进展进行综述.     

银屑病表观遗传学进展

银屑病是一种复杂的多基因遗传病,有家族遗传倾向,但并非每个子代均发病.表观遗传是指DNA序列不发生变化但基因表达却发生可遗传的改变,它从以下3个层面上调控基因的表达:DNA甲基化、组蛋白修饰及非编码RNA调控(如RNA干扰),与遗传印记、X染色体失活等临床现象有关.肿瘤及多种自身免疫性疾病都有表观遗传学的改变.综述银屑病表观遗传学方面的研究进展,以探讨银屑病的发病机制.     

皮下脂膜炎样T细胞淋巴瘤与皮肤结外鼻型NK/T细胞淋巴瘤的鉴别

皮下脂膜炎样T细胞淋巴瘤和皮肤结外鼻型NK/T细胞淋巴瘤是两类特殊而少见的皮肤淋巴瘤.当后者累及皮下脂肪组织时,二者在临床表现、组织病理、免疫表型上有重叠,鉴别非常困难.该文对这两种皮肤淋巴瘤与EB(Epstein-Barr)病毒感染的关系、临床表现、组织病理学特点、免疫表型、分子遗传学特征及预后等方面作一对比性综述.     

紫杉醇抑制Hut78细胞生长及诱导凋亡的实验研究

目的：研究紫杉醇对皮肤T细胞淋巴瘤（cutaneous T cell lymphoma,CTCL）Hut78细胞株的生长抑制及诱导凋亡作用,并探讨其诱导凋亡作用的机制。方法：将紫杉醇按不同浓度、不同作用时间分别处理Hut78细胞,四甲基偶氮唑蓝（MTT）法测定Hut78细胞的生长抑制率,端粒酶重复序列扩增及酶联免疫吸附法（TRAP—PCR—ELISA）检测端粒酶活性的变化,采用形态学观察和流式细胞仪检测其诱导Hut78细胞凋亡的情况。结果：紫杉醇明显下调端粒酶活性表达,对Hut78细胞具有生长抑制及诱导凋亡的作用,且呈时间依赖和剂量依赖性。表现为G2／M期阻滞,出现典型的凋亡细胞特征,流式细胞仪检测可见明显的凋亡峰。结论：紫杉醇能下调端粒酶的活性,诱导细胞凋亡是其发挥抗癌作用的机制之一。     

Examination of cutaneous T-cell lymphoma for human herpesviruses by using the polymerase chain reaction

The etiology of cutaneous T-cell lymphoma remains unknown, although an association with viral infection, in particular certain retroviruses and human herpesviruses, has been suggested. The purpose of this study was to examine skin biopsies of cutaneous T-cell lymphoma for the presence of Epstein-Barr virus, herpes simplex virus type 1 and type 2, and human herpesvirus-6 by using the polymerase chain reaction. Lesional skin biopsies from 30 patients with cutaneous T-cell lymphoma were studied. Control specimens included biopsies from 9 patients with lymphomatoid papulosis and 10 patients with pityriasis lichenoides et varioliformis acuta. DNA extracted from each specimen, as well as from a known positive control for each virus, was examined by using the polymerase chain reaction with viral-specific primers. Each DNA specimen was also amplified with control primers for human β globin. The specificity of the amplified products was confirmed by Southern analysis. Neither Epstein-Barr virus nor herpes simplex virus was detected in any of the patient specimens examined. Human herpesvirus-6 was detected in one specimen of cutaneous T-cell lymphoma and one specimen of lymphomatoid papulosis. These results do not support a role for any of these herpesviruses in the pathogenesis of cutaneous T-cell lymphoma.     

Cutaneous CD8+ squamous T-cell bullous lymphoma

INTRODUCTION: Bullous forms of cutaneous T-cell lymphomas are rare. A new group of cutaneous T-cell lymphomas has recently been identified as a distinct clinicopathological and immunophenotype entity. These cutaneous T-cell lymphomas express a CD8+ phenotype, rarely expressed in other cutaneous T-cell lymphomas. CASE REPORT: We describe a cutaneous CD8+ squamous T-cell lymphoma with polymorphic clinical features, strongly epidermotropic lymphoid infiltrate and spongiosis, classical for this type of lymphoma. DISCUSSION: Bullous lesions in cutaneous T-cell lymphoma should evoke the possibility of a cutaneous CD8+ T-cell lymphoma, once other bullous diseases have been excluded. Spongiosis, rare in other types of T-cell lymphoma, and strongly epidermotropic pleomorphic lymphoid infiltrate are classical histological features. The association of polymorphic lesions, bullas and atypical CD8+ epidermotropic phenotype should evoke this diagnosis even at the early stage. Treatment is difficult and classical chemotherapy often fails. Prognosis is poor with a mean overall survival of 32 months.     

The new World Health Organization-European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants

Following consensus meetings of the two parent organizations, a new World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for primary cutaneous lymphomas has recently been published. This important development will now end the ongoing debate as to which of these was the preferred classification. The new classification will facilitate more uniformity in diagnosis, management and treatment of cutaneous lymphomas. In particular, it provides a useful distinction between indolent and more aggressive types of primary cutaneous lymphoma and provides practical advice on preferred management and treatment regimens. This will thereby prevent patients receiving high-grade treatment for low-grade biological disease. This review focuses on those diseases which have found new consensus agreement compared with the original WHO and EORTC classifications. In cutaneous T-cell lymphomas, these include folliculotropic mycosis fungoides, defining features of Sézary syndrome, primary cutaneous CD30+ lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis and borderline lesions) and subcutaneous panniculitis-like T-cell lymphoma. Primary cutaneous CD4+ small/medium-sized pleomorphic T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma and cutaneous gamma/delta T-cell lymphoma are allocated provisional entry status and thereby afford better definitions for some cases of currently unspecified primary cutaneous peripheral T-cell lymphoma. In cutaneous B-cell lymphomas, diseases which have found new consensus agreement include primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicular centre lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type and primary cutaneous diffuse large B-cell lymphoma, other. CD4+/CD56+ haematodermic neoplasm (early plasmacytoid dendritic cell leukaemia/lymphoma) now appears as a precursor haematological neoplasm and replaces the previous terminology of blastic NK-cell lymphoma. Other haematopoietic and lymphoid tumours involving the skin, as part of systemic disease, will appear in the forthcoming WHO publication Tumours of the Skin. The new classification raises interesting new problems and questions about primary cutaneous lymphoma and some of these are discussed in this article. It is, however, a splendid signpost indicating the direction in which research in cutaneous lymphoma needs to go. In the interim, we have an international consensus classification which is clinically meaningful.     

Rimming of adipocytes by neoplastic lymphocytes: a histopathologic feature not restricted to subcutaneous T-cell lymphoma

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare cytotoxic T-cell lymphoma of the skin presenting with histopathologic features simulating those of a lobular panniculitis. The presence of neoplastic T-lymphocytes forming a rim around the individual fat cells in the subcutaneous lobules, so-called "rimming" of adipocytes, is considered a characteristic morphologic feature of this type of cutaneous lymphoma. In this study we reviewed a series of 45 biopsy specimens of primary and secondary cutaneous B- and T-cell lymphomas and one of myeloid leukemia involving the subcutaneous tissues and showing rimming of adipocytes (subcutaneous panniculitis-like T-cell lymphoma: n = 16; mycosis fungoides, tumor stage: n = 3; aggressive epidermotropic CD8(+) T-cell lymphoma: n = 2; cutaneous gamma/delta T-cell lymphoma: n = 4; extranodal NK/T-cell lymphoma, nasal type: n = 4; cutaneous medium-large pleomorphic T-cell lymphoma, NOS: n = 5; CD4(+)/CD56(+) hematodermic neoplasm (blastic NK-cell lymphoma): n = 7; secondary cutaneous large B-cell lymphoma: n = 3; secondary cutaneous lymphoplasmacytic lymphoma: n = 1; specific cutaneous manifestations of acute myelogenous leukemia: n = 1). We could demonstrate that rimming of adipocytes by neoplastic cells can be recognized not only in subcutaneous panniculitis-like T-cell lymphoma, but also in several different entities of malignant lymphoma with skin involvement. Precise classification of cases with prominent involvement of the subcutaneous tissues can only be achieved upon precise correlation of clinicopathologic and phenotypic features. Rimming of adipocytes should not be considered specific of subcutaneous panniculitis-like T-cell lymphoma.     

Phenytoin-induced pseudolymphoma. A report of a case and review of the literature

We report a patient with phenytoin-induced pseudolymphoma mimicking cutaneous T-cell lymphoma (CTCL). Despite withdrawal of phenytoin, there was persistence of the cutaneous eruption and lymphadenopathy. Southern blot analysis of immunoglobulin and T-cell receptor genes was therefore used to assess whether there was a clonal lymphoid expansion. However, no rearrangement of the beta T-cell receptor gene or immunoglobulin heavy-chain gene was detected in tissue DNA from skin and lymph nodes. One year later the patient became asymptomatic, although he is still at risk of developing a true malignant lymphoma in the future, a condition known as pseudo-pseudolymphoma. It is suggested that genotypic studies may help in the initial diagnosis and the subsequent management of such patients.     

Aggressive B-cell lymphoma induced by Epstein-Barr virus infection in erythrodermic cutaneous T-cell lymphoma

The coexistence of two cutaneous non-Hodgkin's lymphomas of different lineage is rare. We report a patient with an indolent erythrodermic cutaneous T-cell lymphoma followed by an aggressive B-cell lymphoma. To our best knowledge, this is the first report describing Epstein-Barr virus-associated B-cell lymphoma in a patient with cutaneous T-cell lymphoma. We suggest that the long-standing cutaneous T-cell lymphoma, as well as the long-term chemotherapy, suppressed host immunity and caused reactivation of latent Epstein-Barr virus.     

A Case of Aggressive NK/T-cell Lymphoma/Leukemia with Cutaneous Involvement in Adolescence

NK/T-cell lymphoma (NKTCL) is characterized by the expression of the NK-cell antigen CD56. Non-nasal NK/T-cell lymphomas are subdivided into primary cutaneous and 4 subtypes of secondary cutaneous lymphomas; nasal type, aggressive, blastic (blastoid), and other specific NK-like cell lymphoma. Aggressive NK/T-cell lymphoma/leukemia is a rare leukemic variant of nasal type NKTCL. We herein report a rare case of aggressive NK/T-cell lymphoma/leukemia with cutaneous involvement in adolescence.     

Primary cutaneous peripheral T-cell lymphoma,not otherwise specified,associated with lymphomatoid papulosis after a 9-year follow up: A case report

Lymphomatoid papulosis (LyP) is a self-limiting cutaneous T-cell lymphoproliferative disorder that may progress into malignant lymphoma. Most of the previously reported associated lymphomas are primary cutaneous anaplastic large-cell lymphoma and mycosis fungoides with a low mortality rate. We report a case of primary cutaneous peripheral T-cell lymphoma, not otherwise specified (pcPTCL-NOS), associated with LyP after long-term follow up. The patient was a 79-year old Japanese man followed up for 9 years. He suddenly developed a 3-cm ulcerated lesion on his forehead, which was diagnosed as an exacerbation of LyP. The lesion regressed after conservative treatment, but the patient soon developed multifocal pcPTCL-NOS. Thereafter, the patient developed pneumonia and cerebral infarction and died within a few months of the onset of malignant lymphoma. Aggressive cutaneous lymphoma may develop in LyP patients. The present case re-emphasizes the need for careful follow up of patients with persistent LyP.