Targeting DNA repair: the genome as a potential biomarker

Abstract

Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used as both prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next-generation sequencing and improved bioinformatic analyses are revealing mutational signatures, i.e. broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalized treatment decisions. In this review, we use ovarian high-grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but that lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Combination Immune Checkpoint Blockade Strategies to Maximize Immune Response in Gynecological Cancers

“…DNA damage and genomic instability may drive immune response, and several studies are investigating combining checkpoint inhibitors with agents targeting DNA damage pathways in hopes of improving response rates [ 25 , 26 ].…”

<p>Further Understanding of High-Grade Serous Ovarian Carcinogenesis: Potential Therapeutic Targets</p>

“…In contrast, HGSOC possess widespread copy number alterations (CNAs) that lead to an extremely complex genomic landscape. 6 This landscape stems from a defective homologous recombination DNA repair machinery in more than half of HGSOC. 6 Underlying defects include genomic or somatic mutations of BRCA1 and BRCA2 genes or other genes involved in homologous recombination.…”

“…6 This landscape stems from a defective homologous recombination DNA repair machinery in more than half of HGSOC. 6 Underlying defects include genomic or somatic mutations of BRCA1 and BRCA2 genes or other genes involved in homologous recombination. 7 As a result, therapeutic opportunities may arise in HGSOC from targeting vulnerabilities stemming from the defective repair machinery, which have already been exploited with the clinical development and introduction of PARP (polyadenosine diphosphate ribose polymerase) inhibitors.…”

Abstract P4-03-07: Analysis of hereditary cancer syndromes by using a panel of genes: Novel and multiple pathogenic mutations

“…PARPi are currently FDA approved for metastatic breast, ovarian and related cancers, mainly in patients with pathogenic variants in the BRCA1 & BRCA2 genes [61]. In addition to BRCA1/ 2, many other genes encoding HR enzymes are involved in both inherited and acquired cancers and have been associated with PARP inhibitor sensitivity when deficient in vitro or in vivo [62]. In this respect, variants in ATM, CHEK2, PALB2, RAD51C, RAD51D and NBN have shown the most consistent evidence [60,[63][64][65][66][67][68].…”