The 2016 Forbeck Foundation meeting provided an exciting venue for researchers in different fields to come together, for the first time, to discuss new advances in understanding the structure of cancer genomes, with potentially important implications for novel therapeutic strategies in cancer.

Much like the evolution of a new organism, cancer genomes evolve from normal ones by a series of DNA alterations, enabling all of the manifestations of the disease to develop. It is common to quote Shakespeare’s Tempest for the insight that “What’s past is prologue”; this insight was the theme of the 2016 Forbeck meeting. Knowing the past history of a cancer genome can help us identify the “drivers” of uncontrolled cancer cell division. Such drivers are important drug targets. Knowledge of the evolutionary history can also tell us about trade-offs made during cancer evolution, trade-offs that could lead vulnerabilities that might also be “druggable”.

The problem with cancer is that we don’t see the entire evolutionary history but only the final product of this evolution—the genome of the mature tumor. We therefore have to infer the evolutionary history of the cancer based on the DNA sequence of the cancer cell at the time of diagnosis and our knowledge of the “ways” that genomes can change. This is a very similar challenge faced by evolutionary biologists who track the development of new species. Despite the conceptual similarities, these communities of scientists rarely interact. In this meeting, cancer geneticists and evolutionary biologists were able to discuss cutting edged new methods for defining the evolutionary history of complex genomes, with the specific goal of achieving a better understanding of cancer. An important focus was on strategies to identify DNA “signatures” of events that altered the genome. These signatures can be thought of as being similar to the fossil record that gives us insight into organismal evolution. To better define these signatures, the meeting also included molecular geneticists trying to recreate and better define these signatures in the laboratory.

Our chromosomes define who we are –Like all living beings, humans are built from cells – approximately 37 trillion. Each of these 37 trillion cells harbors the same 23 pairs of chromosomes (46 total), that are unique to us humans. Contained on these chromosomes, collectively called our genome, is all the information necessary to build a human from a fertilized egg.

The making of a human from a fertilized egg requires cell division during which each cell’s chromosomes are duplicated and then evenly divided between the two daughter cells together with the cell’s other content. The process of chromosome duplication and division is incredibly accurate. Cells make a mistake, incorrectly dividing up a chromosome pair, only once every 1000 - 10,000 divisions! The chromosome copying process is even less error prone. However, given that humans are made up of 37 trillion cells, even with such a low error rate, some cells in our bodies do end up with an incorrect chromosome number or errors in the information contained on chromosomes. The condition where a cell carries too few or too many chromosomes is called aneuploidy. Perhaps the most famous aneuploidy is Down Syndrome (also known as Trisomy 21). Individuals with Down Syndrome carry three copies of chromosome 21 instead of the normal two in each of their cells.

Chromosome number and structure change in cancer – Aneuploidy is not only the cause of Down Syndrome, it is also a hallmark of cancer. More than 90 percent of solid tumors and 75 percent of blood cancers such as Leukemia and Lymphoma harbor too many, often twice to four times the normal number, and in rare cases too few chromosomes. We are all aware how dramatic the effects of Down Syndrome are on a person’s intellectual abilities, health, and life expectancy - Changing the chromosome number by only a little, 47 instead of 46 chromosomes, has a dramatic impact on human health. How would gaining dozens of chromosomes and changing their makeup affect cancer cells? The goal of the 2016 Forbeck meeting was to understand how cancer cells end up with the wrong number and make-up of chromosomes and how these changes affect cancer formation, development and response to treatment.

New technologies, known as high throughput DNA sequencing technologies, have provided unprecedented insight into how the cancer cell’s genome changes as cancers develop. We now understand that not only chromosome structures and number are altered in cancer, we also know that within a tumor not all cancer cells are alike. Cells within the same tumor differ in their chromosomal make-up and are said to be heterogeneous and constantly evolving. The challenges we are faced with now is to explain what drives this plasticity and to find ways to exploit this hallmark of cancer for therapeutic intervention. Another major goal of the meeting was to gain insight into how cancer genomes develop by considering what is known about how the genomes of new organisms evolve. Evolutionary biologists Evan Eichler, Lucia Carbone, Lucca Comai, Harmit Malik, and Laura Landweber described how humans, apes, fruit flies, plants and single celled animals known as protozoa use unusual strategies to shape their chromosomes and genomes. Much discussion occurred around the topic of whether cancer genome evolution occurs one-step-at-a-time or rather in sudden bursts. This has important implications for how fast cancer develops and could have therapeutic implications if fast and slow evolving tumors have different properties. Dr. Comai’s talk revealed an example of sudden genome evolution in plants that is strikingly similar to a mechanism of cancer genome evolution discovered by Peter Campbell called “chromothripsis”. Plants provide unique tools for studying this phenomenon. Significant discussion and cross-fertilization also occurred about methodology. Dr. Eichler emphasized the value of technical approaches that could “read” long sequences of DNA continuously to detect complex alterations of chromosomes. Peter Campbell presented a new method to define DNA sequence “signatures” that would indicate that the genome had been altered in specific ways.

Lively discussions and the development of new hypotheses were formulated surrounding questions as to what types of mechanisms are at play that facilitate the generation of abnormal cancer genomes. Jan van Deursen discussed the importance of centrosomes, key components of the chromosome division machinery in cancer evolution. Michael Lampson described that chromosome shape and structure can affect how chromosomes are divided during cell division, with specific alterations such as fusion between two chromosomes making them more susceptible to faulty partitioning. Emily Hatch and David Pellman discussed how chromosomes that find themselves isolated from the rest of the chromosomes can become damaged because their duplication becomes less efficient and accurate. David Pellman also discussed new work on abnormal duplication of the DNA and advanced a hypothesis that might explain some of the “signatures” described by Peter Campbell.

Another focus of the discussions was how cells react to having the wrong number of chromosomes. Daniela Cimini, Jason Sheltzer, Zuzanna Storchova and Angelika Amon discussed the wide-reaching effects that aneuploidy has on the state and function of normal cells and cancer cells. They proposed that an incorrect chromosome copy number can lead to further damage of chromosomes and changes in chromosome structure and number. Input from Dr. Eichler and others with expertise on genome evolution lead to ideas about how to test the contribution of this further damage to cancer genome structure. A major topic of discussion was whether altered number of whole chromosomes could promote or inhibit tumor growth. Uri-Ben David presented data supporting the hypothesis that specific aneuploidies promote tumor development. Angelika Amon and Jason Sheltzer highlighted countervailing examples where chromosome number changes were not advantageous, arguing that the majority of chromosome abnormalities decrease cancer cell fitness but that some specific rare karyotypes do promote tumorigenesis.

An unexpected, yet exciting outcome of the meeting was the realization that not only did cancer biologists learn from evolutionary biologists but the reverse was also true. Lively discussions surrounded questions critical to both disciplines such as - How can we best infer evolutionary history from genome analysis data? Is the evolution of new species and of cancer a gradual process or a sequence of defined, punctuated catastrophic events? And To what extent do errors in the chromosome division process shape the architecture of cancer genomes and define the development of new species? At the end of this meeting it was clear that the evolutionary processes shaping new species have much in common with the development of cancer and that if we understand one process we will likely understand the other.

Conclusions and Outlook
The 2016 William Guy Forbeck Research Foundation meeting on Chromosomal Instability and Aneuploidy was unique in that, for the first time, it brought together evolutionary biologist and scientists who seek to understand how our genomes change during the process of cancer development. Cross-fertilization as facilitated by the 2016 Forbeck meeting are critical to push the field forward. They generate new ideas and approaches that would have otherwise not occurred.

The success of the 2016 meeting is perhaps best illustrated by the fact that it, already, has led to collaborations. David Pellman and Nabeel Bardeesy will work together to understand the complex processes that pancreatic cancer cells undergo to reshuffle their genomes. Uri Ben-David and Angelika Amon have initiated a collaboration to understand why certain chromosome gains and losses are highly prevalent in specific cancers. While this first meeting between new groups of scientists was highly successful it was only a beginning. Clearly, much work needs to be done to fully understand how normal cells begin to reshuffle their chromosomes to facilitate cancer development. Important next questions also include how, once we obtained this knowledge, we can apply it to the clinic to develop new strategies to combat this devastating disease.

Collaboration Update–2021
A paper entitled Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition which was co-authored by Uri Ben-David, Stefano Santaguida, and Zuzana Storchova was just recently published. This is one of the many examples of how fruitful the Forbeck Forums are.

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