Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer
Monica M. Olcina,
Nikolas G. Balanis,
Ryan K. Kim,
B. Arman Aksoy,
Julia Kodysh,
Michael J. Thompson,
Jeff Hammerbacher,
Thomas G. Graeber,
Amato J. Giaccia
Affiliations
Monica M. Olcina
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Corresponding author
Nikolas G. Balanis
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
Ryan K. Kim
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA
B. Arman Aksoy
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Julia Kodysh
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Michael J. Thompson
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Jeff Hammerbacher
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
Thomas G. Graeber
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA; Crump Institute for Molecular Imaging, University of California, Los Angeles, Los Angeles, CA, USA
Amato J. Giaccia
Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Corresponding author
Summary: Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators. We hypothesize that the same selective pressure could lead to complement alterations at the genetic level. We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types. Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer. The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55. The range of strategies employed by tumors to dysregulate the complement system testifies to the importance of this pathway in tumor progression. : Mutations in the complement system are prevalent across cancers. Olcina et al. find that colorectal cancers with complement component mutations are associated with increased hypoxic signaling and poor overall survival outcomes. Hypoxia-induced expression of complement regulator CD55 controls complement-mediated cytotoxicity. Keywords: innate immunity, cancer, mutations, hypoxia, complement system, complement-mediated cytotoxicity
