Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer

Grainne M O'Kane; Ashton A Connor; Steven Gallinger

doi:10.1016/j.molmed.2017.10.007

Characterization, Detection, and Treatment Approaches for Homologous Recombination Deficiency in Cancer

Trends Mol Med. 2017 Dec;23(12):1121-1137. doi: 10.1016/j.molmed.2017.10.007. Epub 2017 Nov 10.

Authors

Grainne M O'Kane¹, Ashton A Connor², Steven Gallinger³

Affiliations

¹ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada; Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada.
² PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada.
³ PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada. Electronic address: steven.gallinger@uhn.ca.

PMID: 29133135
DOI: 10.1016/j.molmed.2017.10.007

Abstract

Investigations of carcinogenesis have evolved from the identification of clonal driver mutations in candidate genes to the integration of large volumes of genomic and transcriptomic data revealing recurrently altered pathways and signatures of mutational processes. Inactivation of BRCA1, BRCA2, or PALB2 impairs efficient double-strand break repair (DSBR), giving rise to a spectrum of homologous recombination deficiency (HRD) cancer phenotypes. Harnessing HRD therapeutically has been promising in a number of tumors; these approaches include leveraging synthetic lethality by targeting alternative repair pathways via PARP inhibition, inducing HRD to modulate potential tumor vulnerabilities, and preventing mechanisms of drug resistance. It is therefore crucial to develop assays for accurate HRD detection and to broaden the patient population who can avail of novel treatment options.

Keywords: cancer; detection; double-strand DNA break repair; homologous recombination deficiency; treatment.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Animals
DNA Breaks, Double-Stranded
DNA Repair / genetics
Homologous Recombination / genetics*
Humans
Neoplasms / genetics*
Nuclear Proteins / genetics

Substances

Nuclear Proteins