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Normal Phenotypes: Understand how cells and tissues maintain "normal" phenotypes whilst harbouring oncogenic mutations and how they transition to become a tumour.

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Professor Allan Balmain

Professor Allan Balmain, Co-Team Lead

Barbara Bass Bakar Distinguished Professor of Cancer Genetics


Dr Paul Brennan

Dr Paul Brennan, Co-Team Lead

Branch Head, Genomic Epidemiology


Professor Nuria Lopez-Bigas

Professor Nuria Lopez-Bigas, Co-Team Lead

ICREA Research Professor





UK, US, France, Spain


Cancer Research UK, National Cancer Institute, Asociación Española Contra el Cáncer


Epidemiology, genomics, animal modelling, machine learning, community engagement and cancer prevention

Stopping cancer before it starts

Funded by:


The PROMINENT team will investigate the promoter hypothesis – an alternative theory about the very early stages of cancer development – seeking to answer important questions about tumorigenesis and find new ways to prevent the disease.

Although the accumulation of mutations in cells has long been assumed to trigger tumorigenesis, recent studies suggest a much more complex relationship: cells often carry many known cancer-causing mutations yet remain phenotypically normal. These cells, despite their remarkable genetic similarities with cancer cells, do not form tumours.

Does an intrinsic mechanism within the cell or its environment protect against tumorigenesis? How do processes such as inflammation, ageing or exposure to certain carcinogens influence the behaviour of cells already carrying cancer-causing mutations? Through the Normal Phenotypes challenge, the PROMINENT team will consider deep biological questions regarding what makes cells ‘normal’, the protective mechanisms that keep them that way and the steps that trigger early tumour development.

The team will investigate an alternative model of carcinogenesis, the promoter hypothesis, in which cells exposed to mutagenic carcinogens accumulate cancer-driving mutations but remain dormant. After exposure to a ‘promoting’ stimulus, such as chronic wounding, these ‘initiated’ cells, through an unknown mechanism, gain a selective advantage allowing them to undergo clonal expansion and progress to malignancy.

With a deeper understanding of the very early stages of cancer development, the team plans to build a ‘roadmap’ as a cell travels down the pathway to malignancy, looking for opportunities to target the critical moment of transition and find new routes to prevention and treatment.

Addressing the Normal Phenotypes challenge

The team will be using a unique collection of resources, including a tissue bank of more than 4,000 mouse samples across all stages of carcinogenesis, and an extensively annotated collection of pairs of tumour and healthy tissue samples provided by more than 5,000 people across 20 countries, collected by the team taking on our Unusual Mutation Patterns challenge. Serial biopsies of normal tissues will also be collected from people participating in intervention studies focused on obesity and smoking. A range of genomic and screening techniques will be used, including human organoid culture and CRISPR-Cas9 gene editing. All data will be collected in a central repository and analysed with molecular-evolution and machine-learning models to identify the molecular signatures and mechanisms of cancer promotion.

The team hopes to answer four major questions:

  1. What are the environmental, lifestyle or endogenous risk factors that promote the selection of pre-initiated cells in normal tissue?
  2. Which cells carry initiating mutations, where are they located, how are they selected for during ageing, and what is their relationship with normal and cancer stem cells?
  3. Which mechanisms promote the first signs of neoplastic growth, and what additional changes cause transition to full malignancy?
  4. How can we intervene to prevent the earliest stages of neoplastic cell selection by tumour promoters?

Answering these questions and understanding the mechanisms causing initiated cells to transition to cancer cells could offer new possibilities for intervention and cancer prevention. In particular, the team hopes to investigate a novel group of compounds, which they refer to as ‘promolytics’, which may be able to prevent or reverse the promotion step.

By uniting across boundaries, the PROMINENT team hopes to bring a new perspective to fundamental questions surrounding early tumour development and identify novel routes to prevention.

Professor Allan Balmain

Professor Allan Balmain, Co-Team Lead

Barbara Bass Bakar Distinguished Professor of Cancer Genetics

As a research community, we’re on the verge of a major leap forward in our understanding of the factors that contribute to the risk of cancer, which could help to find new, informed ways to stop cancer before it even starts.
Professor Allan Balmain
Dr Paul Brennan
Professor Nuria Lopez-Bigas
Professor Kim Rhoads
Dr Luke Gilbert
Dr Kalvin Kuo
Dr Chris Counter
Dr Marc Gunter
Dr Emma Lundberg