First seeds of kidney cancer sown in adolescence

Insights from this study present an opportunity to develop approaches for early detection and early intervention in kidney cancer

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Image credit: Freeimages.com/Adam Ciesielski
The earliest critical genetic changes that can lead to kidney cancer have been mapped by scientists. The first key genetic change occurs in childhood or adolescence, and the resulting cells follow a consistent path to progress into kidney cancer four or five decades later, scientists from the Wellcome Sanger Institute, Francis Crick Institute and their collaborators have found.

The results, reported today (12 April) in Cell, suggest that whilst most of us carry these ‘kick-starter’ cells, they will not develop into cancer unless triggered by further mutations. The insights from this study present an opportunity to develop approaches for early detection and early intervention in kidney cancer, particularly in high-risk groups such as those with an inherited risk of the disease.

Kidney cancer was the seventh most common cancer in adults in the UK in 2014, with 12,500 new cases. Treatment options for the cancer include surgery, chemotherapy and radiotherapy.

To understand more about what kick starts kidney cancer, scientists used genomic archaeology techniques to dig into the genomes of kidney tumours and reconstruct the first genetic changes that take place.

Researchers from the Wellcome Sanger Institute, Francis Crick Institute and their collaborators sequenced and analysed the whole genomes of 95 kidney cancer tumours from 33 patients. The team discovered the first significant genetic changes, or driver mutations, in kidney cancer take place very early in life, on average in early teenage years.

The scientists found there are initially only a few hundred cells with these genetic changes, and it is likely that most of us have some of these rogue cells in our kidneys. However, kidney cancer develops in one to two per cent of the population. The cells remain dormant for four or five decades and do not progress into kidney cancer unless triggered by further mutations. Risk factors for these cells progressing to full-blown cancer include smoking, obesity and an inherited risk of kidney cancer.

“We can now say what the initiating genetic changes are in kidney cancer, and when they happen. What is remarkable is that the hallmark genomic event that characterises kidney cancer takes place on average 40 to 50 years before the cancer is diagnosed. These first seeds are sown in childhood or adolescence – knowing the sequence of events and their timings opens opportunities for early intervention.”

Dr Peter Campbell Corresponding author from the Wellcome Sanger Institute

Researchers discovered that the first mutation is the loss of chromosome 3p in more than 90 per cent of kidney cancer patients studied.

“We uncovered that the genetic change initiating kidney cancer in most people is the deletion of chromosome 3p, which takes with it several tumour suppressor genes. We also found around 35-40 per cent of patients simultaneously gain chromosome 5q in a process called chromothripsis – the shattering and rearrangement of chromosomes that causes several mutations at once.”

Dr Thomas Mitchell Joint first author from the Wellcome Sanger Institute and Addenbrooke’s Hospitals NHS Foundation Trust, University of Cambridge

“Understanding how cancers develop and evolve over time is likely to be critical in helping us piece together the information that will point the way to new treatment approaches and predicting outcomes. We hope that in the future this work will help tailor surgical and medical intervention to the right patients at the right time.”

Professor Charles Swanton Joint corresponding author from the Francis Crick Institute and Cancer Research UK’s chief clinician

More information

Publication:

Thomas Mitchell et al. (2018) Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx Renal. Cell. DOI: 10.1016/j.cell.2018.02.020

This study is one of three papers published in Cell. Visit here for more informationon the three kidney cancer studies. The other two papers in this series are:

  • Turajlic, S. et al. (2018) Deterministic evolutionary trajectories influence primary tumour growth: the TRACERx Renal study. Cell
  • Turajlic, S. et al. (2018) Tracking renal cancer evolution reveals constrained routes to metastases, results from the TRACERx Renal study. Cell

The studies are a result of the TRACERx (Tracking Cancer Evolution through Therapy) Renal consortium:

Approximately 1 in 52 men and 1 in 87 women will be diagnosed with kidney cancer in their lifetime, half of which will be aged 70 and over. Around 50 per cent of those with the disease will beat the cancer and live for 10 or more years.

Kidney cancer information, treatments and statistics were sourced from Cancer Research UK.

Funding:

This work was supported by EU FP7 (project PREDICT ID number 259303), Wellcome and Cancer Research UK.

Selected websites

  • Francis Crick Institute

    The Francis Crick Institute is a biomedical discovery institute dedicated to understanding the fundamental biology underlying health and disease. Its work is helping to understand why disease develops and to translate discoveries into new ways to prevent, diagnose and treat illnesses such as cancer, heart disease, stroke, infections, and neurodegenerative diseases.

    An independent organisation, its founding partners are the Medical Research Council (MRC), Cancer Research UK, Wellcome, UCL (University College London), Imperial College London and King’s College London. The Crick was formed in 2015, and in 2016 it moved into a brand new state-of-the-art building in central London which brings together 1500 scientists and support staff working collaboratively across disciplines, making it the biggest biomedical research facility under a single roof in Europe.

    The Francis Crick Institute will be world-class with a strong national role. Its distinctive vision for excellence includes commitments to collaboration; to developing emerging talent and exporting it to the rest of the UK; to public engagement; and to helping turn discoveries into treatments as quickly as possible to improve lives and strengthen the economy.

  • Cancer Research UK

    • Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research.
    • Cancer Research UK’s pioneering work into the prevention, diagnosis and treatment of cancer has helped save millions of lives.
    • Cancer Research UK receives no funding from the UK government for its life-saving research. Every step it makes towards beating cancer relies on vital donations from the public.
    • Cancer Research UK has been at the heart of the progress that has already seen survival in the UK double in the last 40 years.
    • Today, 2 in 4 people survive their cancer for at least 10 years. Cancer Research UK’s ambition is to accelerate progress so that by 2034, 3 in 4 people will survive their cancer for at least 10 years.
    • Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
    • Together with its partners and supporters, Cancer Research UK’s vision is to bring forward the day when all cancers are cured.

    For further information about Cancer Research UK’s work or to find out how to support the charity, please call 0300 123 1022 or visit www.cancerresearchuk.org. Follow us on Twitter and Facebook.

  • University of Cambridge

    The mission of the University of Cambridge is to contribute to society through the pursuit of education, learning and research at the highest international levels of excellence. To date, 98 affiliates of the University have won the Nobel Prize. Founded in 1209, the University comprises 31 autonomous Colleges, which admit undergraduates and provide small-group tuition, and 150 departments, faculties and institutions. Cambridge is a global university. Its 19,000 student body includes 3,700 international students from 120 countries. Cambridge researchers collaborate with colleagues worldwide, and the University has established larger-scale partnerships in Asia, Africa and America. The University sits at the heart of one of the world’s largest technology clusters. The ‘Cambridge Phenomenon’ has created 1,500 hi-tech companies, 14 of them valued at over US$1 billion and two at over US$10 billion. Cambridge promotes the interface between academia and business, and has a global reputation for innovation.

  • The Wellcome Sanger Institute

    The Wellcome Sanger Institute is one of the world’s leading genome centres. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower medical science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease. To celebrate its 25th year in 2018, the Institute is sequencing 25 new genomes of species in the UK. Find out more at www.sanger.ac.uk or follow @sangerinstitute

  • Wellcome

    Wellcome exists to improve health for everyone by helping great ideas to thrive. We’re a global charitable foundation, both politically and financially independent. We support scientists and researchers, take on big problems, fuel imaginations and spark debate. wellcome.org