CB 399: Genomic Instability and Cancer Fall 2015

Genomic Instability and Cancer

Course Director: Dr. Andrew Murray

Curriculum Fellow:  Megan Mittelstadt (megan_mittelstadt@hms.harvard.edu)

High fidelity DNA replication, coupled with effective DNA-maintenance machinery, is fundamental to cell growth and division. Inherent to many human cancer cells, when this process becomes dysregulated, genetic alterations ranging from nucleotide-level changes to chromosomal translocations and aneuploidy can occur. This nanocourse will begin by exploring the history of two lines of research and the intersection between them that informs modern cancer biology. The first are studies of genetic instability in model organisms, starting with the work of Boveri and ending with the discovery and analysis of DNA repair pathways and cell cycle checkpoints. The second is the gradual appreciation that genetic instability plays a major role in cancer, beginning with the realization that cancer required multiple mutations, moving on to Nowell’s seminal work on cancer progression, and finishing with a description of the biology of tumor suppressor genes. We will continue with a discussion of the mechanisms leading to the evolution of karyotypes with implications for cancer, congenital disease, and likely organismal evolution. The focus will be on newly discovered mutational processes that can generate massive chromosome rearrangements “all-at-once” and are curiously localized to one or occasionally a few chromosomes. A review of recent technical progress in combining cellular imaging with single cell genomics, enabling mechanistic studies of these phenomena, will be included. Finally, we will explore the interplay between evolutionary and spatial dynamics at the surfaces of evolving three-dimensional cell masses, such as tumors. A crucial aspect is the effect of “inflation” on gene fixation at the frontier of expanding tumors. Key dimensionless parameters controlling the survival probability in the limit of small selective advantage will be identified, showing that inflating spherical cell masses can enhance mutant survival probabilities by factors of 100 or more, compared to cell masses which are merely “treadmilling”, i.e. those where the radius remains constant in time.


Andrew Murray, Harvard University Herchel Smith Professor of Molecular Genetics, HHMI Professor, Director of the FAS Center for Systems Biology

David Pellman, DFCI Margaret M. Dyson Professor of Pediatric Oncology, HHMI Investigator, HMS Professor of Cell Biology

David Nelson, Harvard University Arthur K. Solomon Professor of Biophysics, Professor of Physics and Applied Physics


First Session (open to all without prior registration): Tuesday, November 10, 3 – 6 PM
Location: Emerson Hall, Room 210 (Cambridge campus)

Second Session (limited to registered students): Thursday, November 12, 3 – 5 PM
Location: Memorial Hall, Room 28 (Cambridge campus)


DROP DEADLINE: Tuesday, November 3, 2015


Day 2 Student Assignment

Part I: Discussion Prompt

How can we identify and target drivers of genomic instability in clinical samples and in tumor models? Be prepared to discuss your viewpoints at the start of the second session. (No written submission required.)

Part II: Student-driven discussion (three papers have been provided for background reading - must be logged in to view)

Enrolled students will be asked to prepare three questions related to the material presented. These questions can be based on what you heard in the lectures on Day 1 or from your readings, and should be thoughtful and aimed at stimulating and insightful discussion. You may also choose to prepare an experimental design question for how you might approach answering a current research question in the field. Please submit questions via email to megan_mittelstadt@hms.harvard.edu by 5pm on 11/11.