Program Overview

PhD Program in Cancer Research

The Institute of Cancer Research offers a PhD program in cancer research, focusing on the role of the non-coding genome in the evolution of myeloma.

Project Background

Multiple myeloma (MM) is a type of blood cancer that results from the uncontrolled clonal expansion of plasma cells in the bone marrow. Despite recent advances, MM is essentially an incurable malignancy, and most patients die from progressive disease caused by the emergence of drug-resistant clones. The project aims to identify and decipher the functional impact of non-coding changes in the myeloma genome and how they influence clonal selection.

Project Aims

The project has four main aims:

• Define the epigenetic profile of myeloma
• Identify sequence changes under evolutionary constraints within non-coding regions
• Perform functional screens to establish the biological consequences of identified changes
• Examine the relationship between these changes and the evolutionary dynamics of myeloma

Research Proposal

The project will exploit longitudinal tumor sampling from over 100 patients enrolled in a phase 3 clinical trial, using whole-genome sequencing and RNA-sequencing. The project will combine laboratory and experimental techniques with bioinformatics analysis to address the study aims.

Stage 1: Reducing the Genomic Space (0-12 months)

The project will define the epigenetic profile of MM tumors using a combination of ATAC-seq and histone ChIP-seq. Micro-C profiles will be generated to resolve enhancer-promoter interactions, allowing for the linking of CREs to target genes.

Stage 2: Data Integration (12-24 months)

A search for mutations under positive selection will be made with the restricted genomic space defined by Stage 1 profiling. The project will examine the relationships between presumptive target genes and search for structural variants influencing gene expression.

Stage 3: Functional Analyses (24-36 months)

The project will perform functional assessments, including reporter assays, CRISPR or Perturb-Seq, and bespoke functional assessments, to confirm functionality and demonstrate which mutations are likely to be deleterious and how they act.

Stage 4: Write-up and Submission of Papers (36-48 months)

The final stage of the project will involve writing up the results and submitting papers for publication.

Candidate Profile

The ideal candidate will have a degree in a quantitative discipline (maths, physics, computer science, engineering, natural sciences) and intended learning outcomes, including skills in mathematical modeling of biological systems, computational biology, bioinformatics analysis of genomic data, and scientific writing and presentation skills.

Literature References

The project is supported by several literature references, including:

• Kaiser et al. (2023) - Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma
• Hoang et al. (2020) - An enhanced genetic model of relapsed IGH-translocated multiple myeloma evolutionary dynamics
• Diamond et al. (2021) - Positive selection as the unifying force for clonal evolution in multiple myeloma
• Rasche et al. (2022) - The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states
• Landau et al. (2020) - Accelerated single cell seeding in relapsed multiple myeloma
• Hoang et al. (2019) - Mutational processes contributing to the development of multiple myeloma
• Ajore et al. (2022) - Functional dissection of inherited non-coding variation influencing multiple myeloma risk

PhD Briefing PDF Document

A PhD briefing PDF document is available for download, providing further information about the project.