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Cancers 2019, 11(3), 354; https://doi.org/10.3390/cancers11030354

Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types

1
Northern Institute for Cancer Research, Paul O’Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
2
Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne NE7 7DN, UK
3
Northern Gynecological Oncology Centre, Queen Elizabeth Hospital, Sherriff Hill, Gateshead NE9 6SX, UK
4
Tata Medical Center, 14 MAR (E-W), New Town, Rajarhat, Kolkata 700 160, India
*
Authors to whom correspondence should be addressed.
Received: 22 December 2018 / Revised: 4 March 2019 / Accepted: 5 March 2019 / Published: 13 March 2019
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Abstract

Dysfunctional homologous recombination DNA repair (HRR), frequently due to BRCA mutations, is a determinant of sensitivity to platinum chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi). In cultures of ovarian cancer cells, we have previously shown that HRR function, based upon RAD51 foci quantification, correlated with growth inhibition ex vivo induced by rucaparib (a PARPi) and 12-month survival following platinum chemotherapy. The aim of this study was to determine the feasibility of measuring HRR dysfunction (HRD) in other tumours, in order to estimate the frequency and hence wider potential of PARPi. A total of 24 cultures were established from ascites sampled from 27 patients with colorectal, upper gastrointestinal, pancreatic, hepatobiliary, breast, mesothelioma, and non-epithelial ovarian cancers; 8 were HRD. Cell growth following continuous exposure to 10 μM of rucaparib was lower in HRD cultures compared to HRR-competent (HRC) cultures. Overall survival in the 10 patients who received platinum-based therapy was marginally higher in the 3 with HRD ascites (median overall survival of 17 months, range 10 to 90) compared to the 7 patients with HRC ascites (nine months, range 1 to 55). HRR functional assessment in primary cultures, from several tumour types, revealed that a third are HRD, justifying the further exploration of PARPi therapy in a broader range of tumours. View Full-Text
Keywords: homologous recombination DNA repair; functional biomarker assay; poly(ADP-ribose) polymerase inhibitors (PARPi), primary culture; precision medicine; platinum-based chemotherapy homologous recombination DNA repair; functional biomarker assay; poly(ADP-ribose) polymerase inhibitors (PARPi), primary culture; precision medicine; platinum-based chemotherapy
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Gentles, L.; Goranov, B.; Matheson, E.; Herriott, A.; Kaufmann, A.; Hall, S.; Mukhopadhyay, A.; Drew, Y.; Curtin, N.J.; O’Donnell, R.L. Exploring the Frequency of Homologous Recombination DNA Repair Dysfunction in Multiple Cancer Types. Cancers 2019, 11, 354.

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