The human genome is an astonishing system; a self-regulating repository of all the information required to build and maintain the body and its functions in the form of DNA. Every time a cell divides, an exact replica of its DNA is created in each of the two new daughter cells. This process does not always go smoothly. Sometimes, errors in the process of ‘transcribing’ the genetic code can take place.

These are called mutations. Unchecked, mutations can lead to cell malfunctions, and - over time - sufficient accumulated mutations can lead to cancer. Fortunately, our genome also contains genes whose role is to protect the process of cell division, repairing any errors in the DNA to prevent them being reproduced. These genes, known as ‘tumour suppressor genes’, are vital in stopping cancer cells from growing and reproducing. However, when these genes are faulty, this protective function cannot take place, and as a result cancer is more likely to occur. People who inherit a faulty tumour suppressor gene are at greater risk of a range of cancers than the general population.

BRCA1 and BRCA2 are two such genes. A small proportion of the population possess inherited errors in one or both of these genes; around 1 in 400 in the US, and up to 1 in 40 in the Ashkenazi Jewish population . For those affected, there is a greatly increased risk of developing breast and ovarian cancer which for some may result in the choice to undergo elective surgery - double mastectomy and oophorectomy, as in the case of actor Angelina Jolie - to remove the organs at risk of developing cancer in the future. BRCA1 is also implicated in cancers of the prostate, and to a lesser extent, the pancreas. 

Found in the nucleus of every human cell, the role of BRCA1 is to repair damaged DNA, and thus preserve the stability of the genome. Professor Jo Morris at the Institute of Cancer and Genomic Sciences at the University of Birmingham, who undertakes research into cancer predisposition, believes that by understanding how BRCA1 works we can gain important insights into how cancer develops. By examining in detail specific mutations in the BRCA1 gene she hopes that we will be able to make more accurate estimates of the real risk of developing cancer. Not everybody with a BRCA1 mutation carries the same absolute risk of developing cancer.

Jo’s research is deepening our understanding of how this crucial gene actually operates in the body; a paper in 2016 outlined a mechanism by which BRCA1 enables the body to ‘reset’ a DNA strand if it detects an error, what is known as ‘homologous repair’. It is thought that the ability to carry out this kind of repair is essential in preventing cancer, but the precise mechanism has until recently been unconfirmed. Her more recent research seeks to address this uncertainty, and new insights into the repair process has shown that the BRCA1 protein plays a vital role in protecting the fragile ends of the DNA strands during the repair of errors, a process known as ‘fork protection’ People with certain cancers appear to have variants of BRCA1 in which this activity is impaired. This suggests that losing fork protection is a key stage in the development of cancer. The team are currently investigating this in mouse models. If this mechanism is found to be disrupted in cells with mutated BRCA1, this will be a vital step on the journey to understanding cancer, and for informing treatment choice. 

Understanding these pathways may help us know why some tumours show high resistance to chemotherapy, which in turn could inform treatment choices. “If a tumour has developed the ability to grow around the homologous recombination problems, you may still be deficient in this separate pathway”. By studying the enzymes that attach and remove the DNA proteins it may be possible to identify new targets for treatment. It is vital not just to understand the machinery of DNA repair but to look at how the cell recognises that it needs repair - this too is an area for potential drug targets.

Get Quest updates directly into your inbox

Subscribe to Quest to receive email updates

Jo explains how in the future these insights may enhance informed systemic cancer treatments.  A key development in the fight against cancer lies in targeted chemotherapies that induce ‘synthetic lethality’., known as ‘PARP inhibitors’. These treatments aim to weaken cancer cells by causing further mutations. Since all cancer cells by definition are already genetically abnormal, and cells only have a limited number of ways to cope with mutations, by causing additional damage these cells can be killed. Synthetic lethality inhibits the activity of another protective protein called ADP-ase, whose normal function is to help damaged cells repair themselves. Cancer cells thereby are deficient in two ways; their BRCA1 mutation means that their DNA cannot repair errors, and the blocked ADP-ase further prevents self-repair.  Through acquiring this second dysfunction, cancer cells are more likely to die. Among women with BRCA1/2 mutations, the introduction of PARP inhibitors as a maintenance therapy has seen a four-fold prolongation of disease-free survival.

Improvements in cancer survival in recent years can be attributed to a number of ‘gamechanger’ innovations such as immunotherapy. Although the role of immunotherapy in BRCA1 positive cancers is not yet clear , Professor Morris believes that “in the next 2-5 years we think we will have a handle on how to combine the current DNA damaging chemotherapies with immunotherapies to get the best outcomes”. There will still be resistance problems and patients who respond badly, but I think we are going to see changes. It might look incremental but it will be impressive”.

Read more about Professor Morris’s research at the University, and about the broader work of the Institute of Cancer and Genomic Studies

Banner image: Electron micrograph of a breast cancer cell. Credit: Alamy.


Discover more stories about our work and insights from our leading researchers.