Dicentric chromosomes in cancer

Most cancer cells acquire changes in the number and content of their chromosomes. For example, many cancer cells have more than the normal 46 chromosomes (termed “aneuploidy”), and others have rearranged chromosomes that are combined with large parts of other chromosomes, or a scrambled order of chromosome segments. Such changes can drive cancer development, and so it is critical to understand how they come about and how they drive cancer. This will facilitate the future prevention and treatment of disease. Here, we will study particular types of rearranged chromosomes, termed “dicentric” chromosomes. These chromosomes are commonly formed in cancer cells and they are clearly implicated in driving cancer development and patient response to treatment, but they are surprisingly understudied. Indeed, they are also almost certainly under-identified because they are not easily recognised using traditional laboratory methods, so many cancer types are not screened for their presence. Additionally, a substantial number of people carry dicentric chromosomes from birth. For example, about 1/800 individuals carry a type of dicentric chromosome called a ‘Robertsonian’ chromosome (ROB). While the day-to-day health impact of possessing a ROB is usually minor, and most carriers are unaware, they have high rates of reproductive problems. Notably, we have found that carriers of a particular type of ROB (rob(15;21)c), are at hugely increased risk of developing a specific form of leukaemia. It is therefore vital to develop techniques to identify and study dicentric chromosomes and to understand how they contribute to cancer development. Normal chromosomes have a single region (termed a “centromere”) that allows them to be sorted and inherited correctly when cells divide. Dicentric chromosomes are formed by the abnormal breaking and joining of two normal chromosomes, creating one abnormal chromosome with two centromeres. Exactly how this happens remains unclear. Importantly, chromosomes with two centromeres are unstable in cells because they are likely to be sorted incorrectly and damaged during cell division. We hypothesise that dicentric chromosomes can contribute to cancer development in at least three ways. First, abnormal sorting of dicentric chromosomes may lead to the breaking and scrambled ordering of DNA segments which can drive cancer development. Second, dicentric chromosomes can cause defective sorting of other chromosomes in the cell, leading to aneuploidy. Third, the abnormal structure of the dicentric chromosome itself causes changes that drive cancer. We aim to understand the causes and consequences of dicentric chromosomes in human cancer patients. This work will complement prior work on dicentric chromosomes that were created in the laboratory. These studies indicated the possible causes, but do not tell us which are actually responsible for disease development. Previously, centromeres have been hard to study because of their complicated DNA sequence, but technological innovations now mean the time is right to tackle this important problem. We will combine the expertise of the Ryan and Higgins groups, and use groundbreaking “long-read” DNA sequencing approaches that can determine the sequence and structure of dicentric chromosomes in cancer patients for the first time, integrated with novel laboratory approaches that track the fate of these chromosomes in cells. Our work will benefit patients by improving methods to identify dicentric chromosomes for cancer screening and diagnosis, help identify factors that promote formation of dicentric chromosomes and cancer, and provide insight into prognosis for more tailored treatment and potentially for the development of novel treatments.