by Institute of Cancer Research

Study design and number of samples per tumor type included in the analysis. Credit: Nature Genetics (2024). DOI: 10.1038/s41588-024-01785-9

Researchers have carried out an in-depth analysis of 10,478 cancer genomes across 35 different cancer types, identifying 330 potential cancer-driving genes, 74 of which are newly associated with cancer. The findings highlight the potential to develop new, more targeted treatment options for cancer patients.

The research, led by scientists at The Institute of Cancer Research, London, revealed that more than 55% of the participants’ tumors may have clinically relevant mutations. These could predict the patients’ sensitivity or resistance to certain treatments or determine their eligibility for clinical trials. The research is published in Nature Genetics.

Identification and actionability of new driver genes

The team analyzed genetic data from the UK 100,000 Genomes Project to identify DNA changes that cause cells to become cancerous—known as driver mutations—across a broad spectrum of cancer types, including colorectal, breast, lung and uterine cancers.

They looked at the whole-genome sequences of people who had their DNA read as part of the project. Whole-genome sequencing is increasingly viewed as an essential tool in precision cancer treatment, allowing for a comprehensive analysis of mutations that may not be captured by standard cancer testing methods.

By using the largest whole-genome sequencing data set of human tumors—10,478 to be exact—the researchers were able to detect driver mutations that have not been reported in earlier studies.

The data revealed that among the 330 driver genes identified, 74 had not previously been linked to any cancer type, creating the potential for new treatment targets for various cancers. Overall, ovarian, bladder and bowel cancer had the highest numbers of newly identified driver genes. Notably, genes such as MAP3K21, USP17L22 and TPTE emerged as potentially important genes in the development of bowel, breast and lung cancer, respectively.

The researchers also evaluated which of the newly identified driver genes could help guide treatment decisions in the future. They discovered that 55% of all samples studied possessed at least one actionable or biologically relevant alteration that could guide the use of approved therapies.

Patients whose tumors had mutational profiles related to DNA repair deficiencies, such as homologous recombination deficiency, could benefit from a type of targeted cancer drug called PARP inhibitors—with some already in use for certain breast and ovarian cancers.

For the main cancer types, the samples were all derived from the U.K. population. In addition, they came from people who tended to be younger than the average U.K. patient and who had earlier stage tumors. Therefore, the study authors note, further exploration of the data is imperative.

Enabling more patients to access targeted therapies

This fresh understanding of mutational landscapes provides hope that existing cancer treatments, such as PARP inhibitors, could be extended to thousands more patients.

In addition, the study emphasizes the importance of using whole-genome sequencing to expand the sequencing panels currently used in clinical settings. Adding more genes to sequencing panels could facilitate the development of new treatments targeting a smaller subset of molecularly-defined patients.

Dr. Amit Sud, Academic Clinical Lecturer in Genetics and Epidemiology at the ICR at the time of the study and now Wellcome Trust Early Career Fellow at the Dana-Farber Cancer Institute, Boston, U.S., said, “This comprehensive analysis of cancer genomes offers insight into the genetic foundations of cancer and opens potential avenues for treatment. We hope to see these findings translate into studies that advance our understanding of cancer as well as the design and testing of new targeted approaches.

“While whole-genome sequencing is not yet widely adopted, its future use in clinical practice could improve patient outcomes by offering more personalized treatment plans. Our findings could extend the reach of precision therapies to patients who are not candidates for local or systemic therapies.”

A new era for precision oncology

As the cost of whole-genome sequencing continues to fall, the study underscores the need to integrate this simple, all-encompassing test into routine cancer care to assist in identifying cancer drivers and other genomic features that may not be captured by standard testing.

Professor Richard Houlston, Professor of Molecular and Population Genetics at the ICR and senior author of the study, said, “Precision oncology first entered our realm 25 years ago and is now well-established in cancer treatment, but our research suggests it could benefit many more patients. Whole-genome sequencing may soon play a central role in guiding personalized cancer treatments, improving survival rates and the quality of life for patients worldwide.

“Importantly, we hope this study encourages further research to understand the biological consequences of these mutations and to determine how to target the genes we’ve identified to treat cancer. The continued sharing of data is vital for accelerating discovery and further informing precision oncology.”

More information: Ben Kinnersley et al, Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology, Nature Genetics (2024). DOI: 10.1038/s41588-024-01785-9

Journal information:Nature Genetics

Provided by Institute of Cancer Research

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