Genomic landscape of early stage Mycosis Fungoides and correlation with clinical outcome and risk of disease progression

蕈样真菌病（Mycosis Fungoides， MF），因其蕈状肿瘤而得名，是一种使人衰弱、危及生命且无法治愈的皮肤癌。这种疾病的早期表现为红色斑块和斑块，通常在几年甚至几十年的时间里，它们的大小和数量会慢慢增加。大约30%的患者会发展到晚期，其特征是整个皮肤受累和/或形成溃疡性肿瘤。更为罕见的是，MF可以通过扩散到血液、淋巴结和内脏而进一步发展。虽然早期MF患者的生存机会与同龄健康人相似，但晚期MF患者因疾病而死亡的机会要高得多。最近所有关于MF的基因研究都集中在疾病的晚期阶段，允许发现广泛的突变，这些突变部分解释了为什么这种疾病在扩散到血液和其他器官时变得更加危险和具有侵略性。我们在圣约翰皮肤病研究所进行了许多开创性的工作，该研究所是皮肤癌患者的主要国家转诊中心，也是国际公认的MF研究卓越中心。然而，由于技术上的挑战，目前还没有针对MF早期阶段的研究。因此，我们不知道这种情况是如何开始的。在我们的研究中，我将使用一种先进的技术，下一代测序（NGS），它可以从人体组织样本中读取肿瘤细胞的基因序列，即使它们在同一活检中被正常细胞所取代。这将产生一系列存在于肿瘤中但不存在于健康细胞中的破坏性基因变化（突变）。它还将帮助我们了解哪些突变发生在疾病早期，哪些突变是疾病进展的关键。本研究主要有三个部分：1)从早期MF患者的皮肤病变中分离肿瘤细胞，以确定哪些突变更有可能导致该疾病。2)比较患者之间和同一患者的多个样本之间的突变，以了解这种癌症是如何演变的。3)创建一个“预后试剂盒”，包括前两个步骤中突变基因的列表（基因面板），并在过去十年中被诊断为MF的患者的大量DNA样本上进行测试，并由我们的皮肤淋巴瘤团队进行长期随访。这项研究的结果不仅将增加我们对MF机制的科学知识，而且将对患者护理产生影响。短期内，预后试剂盒将用于为临床患者设计一种经济可行的诊断测试。该测试将有助于确定哪些患者需要更密集的治疗，更重要的是，哪些患者可以避免使用潜在毒性药物进行治疗。从长远来看，鉴定与预后不良相关的基因序列将有助于为那些可能死于该疾病的人设计更有效的治疗靶点。

Mycosis Fungoides (MF), so-called because of its mushroom-like tumours, is a debilitating, life-threatening and incurable skin cancer. Early stages of the disease presents with red patches and plaques that usually slowly increase in size and number over years or even decades. About 30% of patients will then progress to the advanced stages, characterized by whole skin involvement and/or formation of ulcerated tumours. More rarely, MF can further progress by spreading into the blood, lymph nodes and internal organs. While patients with early stage MF have a chance of survival similar to healthy people of their same age, patients with advanced stage MF have much higher chance of dying due to their disease. All recent genetic studies on MF have focused on advanced stages of disease, allowing discovery of a broad range of mutations that partially explain why the disease becomes more dangerous and aggressive when it spreads to the blood and other organs. Much of this pioneering work has been performed by us at St John's Institute of Dermatology, which is a major national referral centre for patients with skin cancer and an internationally recognised centre of excellence for MF research. However, due to technical challenges, there are no studies focusing on earlier stages of MF. Hence we have no knowledge on how this condition begins. In our study I will use an advanced technique, Next Generation Sequencing (NGS), which enables the reading of gene sequences in tumour cells from human tissue samples, even when they are out-numbered by normal cells in the same biopsy. This will generate a list of damaging changes in the genes (mutations) that are present in the tumours but not in healthy cells. It will also help us understand which of these mutations occur early in the disease and those that are key to disease progression. There are three main parts of this study:1) Isolate tumour cells from skin lesions of patients with early stage MF to identify which mutations are more likely to be causing the disease.2) Compare the mutations between patients and amongst multiple samples from the same patient to understand how this cancer evolves.3) Create a "prognostic kit" comprising a list of mutated genes (gene panel) from the previous two steps and test it on large number of DNA samples from patients diagnosed with MF in the last decade and under long term follow-up under our Cutaneous Lymphoma team. The outcomes of this study will not only increase our scientific knowledge of the mechanisms underlying MF, but will also impact on patient care. In the short term, the prognostic kit will be used to design an economically viable diagnostic test for patients in the clinic. The test will help to determine which patients require more intensive treatment and, more importantly, which can be spared treatment with potentially toxic drugs. In the longer term, identification of gene sequences associated with a poor prognosis will enable the design of targets for more effective treatments for those who might otherwise die of the disease.