Chromosomal Instability and Aneuploidy

Angelika
Amon
,
PhD
Massachusetts Institute of Technology
David
Pellman
,
MD
Dana-Farber Cancer Institute

Forum Description

Large-scale sequencing efforts have provided unprecedented insight into the genomic changes that occur during tumorigenesis. We now understand that structural and numerical chromosomal aberrations are an almost universal feature of cancer and that tumors are karyotypically heterogeneous, constantly evolving ecosystems. The challenges we are faced with now is to explain what drives this genetic plasticity and to find ways to exploit this hallmark of cancer for therapeutic intervention. The development of new single cell analysis tools and the development of ever more sophisticated cell and animal models of genome instability have opened up new ways to tackle these longstanding questions.

The Forbeck Foundation meeting will bring together the leading researchers studying cancer genomes and their evolution with scientists who seek to understand the mechanisms underlying genome instability. By bringing researchers together from these diverse fields we are hoping to develop hypotheses and approaches to describe in molecular detail how genome instability mechanisms shape the cancer genome and how the condition fuels tumor evolution.

The 2016 Forum on Chromosome Instability and Aneuploidy will be chaired by Dr. Angelika Amon of the Koch Institute for Integrative Cancer Research at MIT and Dr. David Pellman of the Dana Farber Cancer Institute at Harvard Medical School. The goal is to bring together leaders from cancer genome and chromosome instability fields to discuss the state of their respective fields and ways forward to translate this information to the clinic.

Forum Summary

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.

Venue & Travel Information

Travel Forms

TRAVEL FORMS DUE:
October 10, 2016
submit travel form

Travel Policy

Please familiarize yourself with our policies and procedures for travel. We truly appreciate you taking the time to participate in this meeting. As you make your plans, please remember that we are a nonprofit organization dependent on donations and volunteers. We do NOT pay for upgrades, change fees, incurred costs resulting from a flight change, transportation to or from your local (home side) airport, meals or other incidentals.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.
  • Spouses are welcome to come with you at their own cost but are not allowed to attend the meeting. Please no children.

What the Foundation Pays

Accommodations and meals are provided by the foundation during the meeting. Airfare will be covered only if booked through our travel agent. The Foundation will also cover airport transportation on the meeting side at the designated shuttle times. You can select not to utilize Foundation arranged transportation at your own expense when completing the travel form. Once your travel form is received your accommodations and airport transfer will be confirmed. Please let us know of any food allergies or other information we should be aware of on the travel forms.

  • If you would like your airfare covered by the Foundation, you must book with our travel agent. Note we do not cover upgrades, changes, late bookings, etc.
  • Flights must be booked at least 30 days prior to the meeting to confirm your accommodations and airport transfer.
  • As a nonprofit we utilize volunteers and other methods to maximize our efforts (or our donor support) when making accommodations and arranging ground transportation. Ground transportation will be provided upon your arrival either by a foundation volunteer or arranged shuttle. You will be provided airport transportation information the week of the meeting. We do not reimburse for home side airport transfer or incidentals while traveling.

Abstracts

Abstracts are due 30 days prior to the start of the meeting to allow enough time to prepare the meeting book.

The abstracts should be only one or two paragraphs outlining the theme of your presentation and should reflect the objective and spirit of the meeting (see above). Abstracts will be circulated about one week before the meeting. The meeting organizer will start requesting them a month before the meeting.

abstracts DUE:
October 10, 2016
submit abstract

Meeting Structure

The meeting structure has been developed over years of experience.

  • Participants have approximately 45 minutes, depending on the number of participants, for their presentation and discussion. The presentation is meant as a conversation start and should last about twenty minutes briefly covering background information and areas that are new or need further input. This should be structured in such a way as to lead to a lively discussion. Participants are encouraged to interrupt to ask questions or start discussions.
  • A MAXIMUM of 5 slide equivalents per presentation is allowed (Power point slides should not contain more than one graph or gel per slide and no more than 5 bullet points to stress the points being made by the presenter.) We appreciate cooperation with the spirit of this guideline. Handouts are welcome but should be distributed before sessions.
  • Everyone is expected to actively participate in every session and discussions.
  • The time spent at the meeting is relatively short, so please be familiar with papers received prior to the meeting.
  • It is very important that you commit to all sessions of the 2 days of meetings.

Forbeck Scholars Participation

Scholars are selected for each Forbeck Forum. These are outstanding junior clinical or post-doctoral fellows selected based on the quality and relevance of science.

  • Scholars present for 30-45 minutes, depending on the number of participants
  • The same presentation rules apply for scholars
  • After the Forum you are selected to attend, you will attend three years of Scholar Retreats held in Lake Geneva, WI. If you attend a Fall Forum, you will attend the Spring Retreat. If you attend a Spring Forum you will attend a Fall Retreat.
  • Scholars are selected by the Foundation Scientific Advisory Board and peer reviewers selected from past Forbeck Scholars.

General Program

The outline below illustrates a typical program schedule. You will receive a complete schedule, including speaking times, the Thursday the meeting starts.

Arrival Day
1:00 PM Arrivals
6:00 PM Cocktails (opt'l)
7:00 PM Dinner
Meeting Day 1
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Meeting Day 2
7:00 AM Breakfast
8:00 AM Scientific Sessions
12:00 PM Lunch
1:30 PM Scientific Sessions
6:00 PM Cocktails & Dinner
Departure Day
7:00 AM Breakfast
8:00 AM Departures

Frequently Asked Questions

Below are some of our most Frequently Asked Questions. If you have something new to ask, please feel free to contact us.

  • Travel Confirmation will be sent out within 1 week of the meeting. This will include a hotel confirmation number, if there is one, and airport transfer details. We have to wait until we receive almost everyone’s travel to book airport transfer. Due to frequent airline changes, we wait until the week of the meeting to send this out.
  • Airport transfer is provided by Foundation staff, volunteers or arranged shuttle at specific times. If you opt to utilize Foundation airport transportation on your travel form, please be patient in receiving this information. We will send it to the week of the meeting.
  • Speaker agenda is not sent out prior to the meeting. It will be provided upon arrival in the meeting packet. We do not tell people when they are speaking because we expect everyone to attend all sessions. Sessions are all day Friday and Saturday.
  • Frequently airport transfer is provided by volunteers. Please be patient on receiving this information. Airport transfer will be sent out prior to arrival.
  • REMINDER: We do not reimburse for home side airport transfer or incidentals while traveling. We will not honor miscellaneous receipts sent for these expenses.

Forum Participants

Peter
Campbell
,
PhD
Wellcome Sanger Institute
Lucia
Carbone
,
PhD
Oregon Health & Science University
Daniela
Cimini
,
PhD
Virginia Tech
Luca
Comai
,
PhD
University of California
Evan
Eichler
,
PhD
University of Washington
Gerrard
Evan
,
PhD
University of California San Francisco
Emily
Hatch
,
PhD
Fred Hutchinson Cancer Center
Michael
Lampson
,
PhD
University of Pennsylvania
Laura
Landweber
,
Columbia University
Harmit
Malik
,
PhD
Fred Hutchinson Cancer Center
Cynthia
Morton
,
PhD
Harvard University
David
Pellman
,
MD
Dana-Farber Cancer Institute
Zuzana
Storchova
,
Max-Planck Institute
Neil
Umbreit
,
PhD
Dana-Farber Cancer Institute
Jan
Van Deursen
,
PhD
Mayo Clinic
Beth
Weaver
,
PhD
University of Wisconsin

Forum Scholars

Uri Ben-David, PhD
Broad Institute
Lilian Kabeche, PhD
Massachusetts General Hospital
Mia Levine, PhD
University of Pennsylvania
Stefano Santaguida, PhD
Massachusetts Institute of Technology
Jason Sheltzer, PhD
Cold Spring Harbor Laboratory