Decoding the genetics of cancer

The body is made up of trillions of cells that continuously grow and divide to replace old or damaged tissue.  This process is controlled by genes. Cancers develop due to genetic changes or mutations which change the way these genes work. These mutations mean there is nothing to stop cells from growing and dividing uncontrollably, leading to cancer. DNA sequencing of tumours means that hundreds of the mutations associated with cancer have now been identified by scientists. However, it can be difficult to identify which mutations are actually having any effect or driving the cancer and how all these genetic changes work together.  Another challenge is that by the time cancers have become late-stage and resistant to drugs, they have acquired so many mutations that it’s difficult to discern which of these changes helped the tumour to become aggressive and which were what we call “bystanders.”

Transposon and CRISPR screens are two tools which researchers are using to understand and decode the underlying genetics of cancer. By editing and mutating certain genes, researchers can observe the effect that this has on the development or progression of cancer. This will enable them to identify the mutations that are important in driving cancer.

Figure 3 shows the applications of CRISPR and transposon mutagenesis for in vivo cancer screens. “T” = transposon mutagenesis; “C” = CRISPR

From: Noorani, I., Bradley, A. & de la Rosa, J. CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets. Genome Biol 21, 204 (2020). https://doi.org/10.1186/s13059-020-02118-9

Cancers can be very different, even within the same tumour, making it difficult to identify the genes that are driving the cancer and to develop effective targeted treatments. As a result, researchers try to identify and target ‘truncal drivers’, the ancestral mutations that occur early on in a cancer’s family tree and so are likely to be present in many cancer cell types in the tumour. Transposon and CRISPR cancer screens have been developed and used to successfully identify truncal drivers of cancer. In particular, transposon screens have identified new tumour suppressor genes that cooperate with the gene Pten and act as drivers of prostate cancer.

Metastasis, when cancer cells break away from the original site and settle in other parts of the body, is one of the leading causes of cancer-related deaths. Metastatic or advanced prostate cancer is responsible for almost all deaths from prostate cancer. The spread of cancer is dependent on a complex network of genes which are not fully understood. Transposon and CRISPR cancer screens have been used to explore the genetic interactions that lead to the metastasis of multiple cancer types. Dr Jorge de la Rosa’s PCRC project will investigate the growth and spread of prostate cancer using CRISPR-Cas9.

Transposon and CRISPR screens have also been used to explore the genetics behind therapy resistance. Unfortunately, many cancers can develop resistance to treatment caused by new mutations in the cancer cells which enable them to survive in the presence of that treatment. One well-known example is the development of resistance to hormone therapy in prostate cancer cells. The genome of advanced cancers is usually very complex as they have acquired lots of genetic changes during their lifetime. This can make it difficult to identify the genes that drive resistance to treatment.

Most potentially cancerous cells are recognised and destroyed by the immune system at early stages, preventing them from developing into cancer. However, some cancers are able to avoid detection or shut down immune system components this is known as immune escape. Genetic cancer screens can be used to identify the genes that are important for the immune response which could then be used as new drug targets for immunotherapy.

DNA transposons or ‘jumping genes’ are short sections of DNA that can move and change positions within a genome- a person’s genetic material. Researchers have engineered transposons that can be used to create mutations in mice. The transposon can also be used as a tag to identify the genes that have been mutated. For cancer screens, genetic elements have been added to the transposons which enable it to activate or inactivate certain genes. This technique has been used to identify groups of genes that work together in several cancer types. Understanding the network of genes involved in the growth and spread of tumours, allows researchers to determine the best way to target and treat the cancer.

CRISPR is a family of DNA sequences that is found in single-celled organisms, like bacteria. It has been adapted by scientists to use as a gene-editing tool. One example is the CRISPR-Cas9 system which has two parts: a small RNA sequence and Cas9. The RNA sequence guides the Cas9 to a specific part of the genome. Cas9 then acts as ‘molecular scissors’ and cuts the DNA so that that part of the sequence can be changed.

CRISPR has been used successfully in the lab to explore the underlying genetics of many cancers. However, it is really important to study cancer in living organisms. The cells and tissue which surround cancer are known as the tumour microenvironment. Tumours and their microenvironment interact and influence each other so it is important that this is taken into account when we explore the mechanisms behind cancer. Researchers have now developed a variety of ways to use CRISPR to edit genes in living organisms, like mice, which has enabled them to study many aspects of cancer genetics.

Scientific publications, commonly referred to as papers, are how scientists share their own work or review the work done by others. In order to be accepted for publication in a journal, they must first be approved by experts in the field (“peer-reviewed”). As such, they are a testament to a scientific team’s credibility and the quality and reliability of their work. Both the stamp of approval given by a publication and the ability for other scientists to learn about and build upon a team’s research are important steps to take lab science closer to real-life benefits for humans.

This publication is a review article, in which a team of scientists explore and give an overview of the current knowledge on a particular subject. Review articles may also highlight areas for future research or draw new conclusions from existing research. Review articles are a good way for a team of scientists to help other scientists work more quickly by compiling and sharing important areas of expertise. When scientists are planning future studies, review articles can also help them to decide on the most appropriate methods to use for their research.

This paper, under the full title “CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets” was published in the journal Genome Biology. The publication is open access, meaning the information is available to readers at no cost, and the journal’s Impact Factor (a measure of a journal’s influence in academic research circles) is 10.8. The top 2% of journals have an Impact Factor above 10.

The researchers who contributed to this paper are Jorge de la Rosa, Imran Noorani, and Allan Bradley. They are based at the University of Cambridge. During the coronavirus lockdown, Jorge was unable to access his lab to carry out his PCRC research project but he took the opportunity to spend time writing this review to benefit the wider scientific community, in addition to helping the research effort against COVID-19.