Homologous recombination deficiency in ovarian cancer: a review of its epidemiology and management. Prevalence of Homologous Recombination–Related Gene Mutations Across Multiple Cancer Types. Targeting the DNA Damage Response in Cancer. DNA-damage repair the good, the bad, and the ugly. The DNA Damage Response: Making it Safe to Play with Knives. European Journal of Cancer, 60, pp.49-58.Ģ. Homologous recombination deficiency and ovarian cancer. These are commonly referred to as ‘HRR gene panel’ and ‘HRD Genomic Instability’ tests.ġ. Recent clinical studies have explored the use of diagnostics that go ‘beyond BRCA’. Pathogenic mutations in the BRCA genes are the archetypal cause of homologous recombination deficiency and BRCA testing has proved an effective diagnostic tool. 1,7Ĭlinical utility has been demonstrated with PARP inhibitors in four tumour types (ovarian, prostate, breast, and pancreatic) where patients were selected for tumours displaying homologous recombination deficiency. In HRD tumours, for example, those with breast cancer susceptibility gene 1/2 (BRCA1/2) loss of function mutations, PARP inhibitor therapy can result in an unsupportable level of genomic instability and cancer cell death. In replicating cells this can lead to DNA double-strand breaks that would normally be repaired through the HRR pathway. Poly ADP-ribose polymerase ( PARP) inhibitors can exploit HRD in cancer cells by blocking PARP enzyme activity 6, preventing DNA single-strand break repair and trapping PARP onto the DNA. 5,6 Exploiting HRD and genetic mutations in cancers This phenotype of loss of HRR capability and the associated genomic instability is called Homologous Recombination Deficiency, or HRD. Such aberrations can be loss or rearrangement of sections of DNA, including entire genes. Using the second copy of the gene as a DNA template these proteins work in a coordinated way to repair the break and restore genome integrity.Ĭells with mal-functioning HRR rely on error-prone pathways such as Non-Homologous End-Joining to repair DSBs, leading to the accumulation of genetic aberrations and genomic instability. Healthy cells can effectively fix DSBs via Homologous Recombination Repair (HRR), which is an efficient, mostly error-free pathway for DSB repair. 1-2,4 The Value of HRR and HRDĭNA double-strand breaks, or DSBs, are the most genotoxic form of DNA damage. This provides a targeted approach to cancer treatment with the potential to improve patient outcomes across multiple tumour types. 3 By understanding and identifying these dependencies, we can use precision medicine approaches and targeted DDR inhibitors to maximise DNA damage and selectively kill cancer cells. Importantly, most cancers have a greater dependency on the DDR, due to the loss of one or more DDR capabilities during the development of cancer. In this scenario, pathways are activated to pause cell division and allow time for repair. 2 While some types of DNA damage are repaired quickly, complex DNA damage takes longer to repair. Two key factors influence the DDR – the type of DNA damage, and when the damage occurs during the cell division. 1ĭamage to DNA occurs on a daily basis, and the DDR describes the multiple ways in which DNA damage is detected and repaired. Our understanding of DNA Damage Response (DDR), one of our key scientific platforms, and the role it plays in cancer is enabling us to push our research further to target a broad range of cancers including difficult to treat or aggressive cancers. Precision medicine connects the right patient to the right therapy and is bringing significant improvements in cancer patient care. Partnerships, alliances and recognition.
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