How aneuploidy drives cancer
Stephen J. Elledge, Ph.D.
Gregor Mendel Professor of Genetics
Harvard Medical School
Aneuploidy has been recognized as a hallmark of cancer for more than 100 years, yet no general theory has emerged to explain the recurring patterns of aneuploidy in cancer. Dr. Elledge’s laboratory developed the Tumor Suppressor and Oncogene (TUSON) Explorer, a computational method that analyzes the patterns of mutational signatures in tumors and predicts the likelihood that any individual gene functions as a tumor suppressor gene (TSG) or an oncogene (OG). By analyzing more than 8,200 tumor-normal pairs, his lab has provided statistical evidence suggesting that many more genes possess cancer-driver properties than anticipated, forming a continuum of oncogenic potential. These genes represent the vast majority of cancer drivers, and the genetic networks they drive are a focus of future cancer system-biological approaches to cancer research. By integrating the driver predictions with information on somatic copy-number alterations, his lab has found that the distribution and the potency of TSGs (STOP genes), OGs, and essential genes (GO genes) on chromosomes can predict the complex patterns of aneuploidy and copy-number variation characteristic of cancer genomes. The lab proposes that the cancer genome is shaped through a process of cumulative haploinsufficiency and triplosensitivity. Dr. Elledge and his lab are now assessing how aneuploidy drives cancer and the potency with which it does so. They have found that, in many cases, aneuploidy predicts survival better than do mutational drivers or existing clinical parameters. They have also discovered that different classes of aneuploidy drive transcriptional programs for two hallmarks of cancer. Aneuploidy promotes a cell-proliferation program and inhibits the infiltration of immune cells leading to immune evasion. Melanoma patients with tumors exhibiting high aneuploidy show poorer responses to immunotherapy with anti-CTLA4 antibodies. Dr. Elledge and his lab are now exploring which genes in recurring amplicons drive proliferation.
This page was last updated on Wednesday, August 11, 2021