Title: Molecular risk stratification of early stage melanoma by identifying early genetic events and ultra-sensitive detection of circulating tumour DNA
Funder: Cancer Research UK

Abstract: In the UK, nearly 15,000 patients are diagnosed every year with early stage, non-metastatic melanoma. While traditional pathological staging provides valuable prognostic information, it does not identify all patients who progress to metastatic disease. 5% of patients with Stage I melanoma, and 16% with Stage II, die from melanoma within 10 years of diagnosis. Although these proportions appear modest compared to Stage III/IV disease, melanoma related deaths are more numerous in Stage I/II as 91% of all patients are diagnosed at this early stage. Thus, significant improvements to mortality in early stage melanoma will have a wide impact. In the first part of my Fellowship, I aim to determine the mutational landscape of early stage melanoma using whole genome sequencing of melanoma clinically limited to the skin (Stage I/II). In the second part of my project, I aim to identify any minimally residual disease post-surgery, or early recurrence, using patient specific panels of 1000s of mutations allowing ultrasensitive detection of circulating tumour DNA in the parts per million (ppm) range. The final part of my project will investigate the evolution of the mutational profile of cutaneous melanoma, as interpreted through comparisons across primary tumour, sequential ctDNA samples, and metastatic disease. I aim to explore if there any specific mutations that are more common in disease relapse and allow better risk stratification for effective adjuvant therapies. This research has clinical application in the detection of minimally residual disease after surgical resection in early stage melanoma, and as a non-invasive monitoring method for the identification of disease recurrence before clinical signs or symptoms. With further refinements, there may be a role to play in the early detection of cancer by non-invasive means in high risk groups such as patients with multiple melanomas, familial melanoma or patients with solid organ transplants. Through this proposal, I aim to develop our understanding of key genetic changes in early stage melanoma and their relationship with the biological progression of disease. More broadly, this approach develops proof-of-concept methodology that may be applied to risk stratification and lead to tools for personalised management of Stage I/II cancers.

Lay abstract: In the UK, nearly 15,000 patients are diagnosed every year with early stage, non-metastatic melanoma. While traditional pathological staging provides valuable prognostic information, it does not identify all patients who progress to metastatic disease. 5% of patients with Stage I melanoma, and 16% with Stage II, die from melanoma within 10 years of diagnosis. Although these proportions appear modest compared to Stage III/IV disease, melanoma related deaths are more numerous in Stage I/II as 91% of all patients are diagnosed at this early stage. Thus, significant improvements to mortality in early stage melanoma will have a wide impact. In the first part of my Fellowship, I aim to determine the mutational landscape of early stage melanoma using whole genome sequencing of melanoma clinically limited to the skin (Stage I/II). In the second part of my project, I aim to identify any minimally residual disease post-surgery, or early recurrence, using patient specific panels of 1000s of mutations allowing ultrasensitive detection of circulating tumour DNA in the parts per million (ppm) range. The final part of my project will investigate the evolution of the mutational profile of cutaneous melanoma, as interpreted through comparisons across primary tumour, sequential ctDNA samples, and metastatic disease. I aim to explore if there any specific mutations that are more common in disease relapse and allow better risk stratification for effective adjuvant therapies. This research has clinical application in the detection of minimally residual disease after surgical resection in early stage melanoma, and as a non-invasive monitoring method for the identification of disease recurrence before clinical signs or symptoms. With further refinements, there may be a role to play in the early detection of cancer by non-invasive means in high risk groups such as patients with multiple melanomas, familial melanoma or patients with solid organ transplants. Through this proposal, I aim to develop our understanding of key genetic changes in early stage melanoma and their relationship with the biological progression of disease. More broadly, this approach develops proof-of-concept methodology that may be applied to risk stratification and lead to tools for personalised management of Stage I/II cancers.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS