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

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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.