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2024
article
BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
Ksenija Nešić, John J. Krais, Yifan Wang, Cassandra J. Vandenberg, Pooja Patel, Kathy Q. Cai, Tanya T. Kwan, Elizabeth Lieschke, Gwo‐Yaw Ho, Holly E. Barker, Justin Bedő, Silvia Casadei, Andrew Farrell, Marc R. Radke, Kristy Shield‐Artin, Jocelyn Sietsma Penington, Franziska Geissler, Elizabeth L. Kyran, Robert Betsch, Lijun Xu, Fan Zhang, Alexander Dobrovic, Inger Olesen, Rebecca Kristeleit, Amit M. Oza, Iain A. McNeish, Gayanie Ratnayake, Nadia Traficante, Georgia Chenevix‐Trench, A Green, Penelope M. Webb, Dorota M. Gertig, Sián Fereday, Suzanne Moore, Jillian A. Hung, K.R. Harrap, T. Sadkowsky, Nirmala Pandeya, M. Malt, A. Mellon, R. Paul Robertson, T. Vanden Bergh, Milissa U. Jones, P. Mackenzie, J. Maidens, K. Nattress, Yoke-Eng Chiew, Annie Stenlake, Harold C. Sullivan, Brian M. Alexander, P. Ashover, Stephen M. Brown, T. Corrish, L. Green, L. M. Jackman, Kaltin Ferguson, Karla Martin, A. Martyn, B. Ranieri, J. White, V. Jayde, Pam Mamers, Leanne Bowes, Laura Galletta, Daniel A. Giles, Joy Hendley, Thomas Schmidt, H. Shirley, C. Ball, Christian D. Young, S. Viduka, Hang Tran, Sanela Bilic, Lydia Glavinas, Julia Brooks, R. Stuart‐Harris, Fred Kirsten, J Rutovitz, P. Clingan, Akisha Glasgow, Anthony Proietto, Stephen Braye, Geoffrey Otton, Jenny Shannon, Tony Bonaventura, James Stewart, Stephen Begbie, Michael Friedländer, Debra Bell, Sally Baron‐Hay, A. Ferrier, G. Gard, David Nevell, Nick Pavlakis, Susan Valmadre, Bruce Young, C. Camaris, R. Crouch, L. Edwards, Neville F. Hacker, Donald E. Marsden, Greg Robertson, Philip Beale, Jane Beith, Jonathan Carter, C. Dalrymple, R. Houghton, Prudence A. Russell, Matthew Links, John J. Grygiel, Jane Hill, Alison H. Brand, Karen Byth, Richard Jaworski, Paul R. Harnett, R. Sharma, Gerard Wain, B. Ward, D. Papadimos, A. Crandon, Michael P. Cummings, K. Horwood, Andreas Obermair, Lewis Perrin, David Wyld, James Nicklin, Marcus Davy, Martin K. Oehler, Cathrine Hall, Tom Dodd, Timothy M. Healy, Keir Pittman, Deborah J. Henderson, Jessica A. Miller, J. Pierdes, Penny Blomfield, D. Challis, Rachel McIntosh, Alyssa Parker, Robert Brown, Robert Rome, D. Allen, Peter Grant, Simon Hyde, R. Laurie, Melissa Robbie, David Healy, Tom Jobling, T. Manolitsas, J. McNealage, Peter A. W. Rogers, B. Susil, E. Sumithran, Ian Simpson, Kelly‐Anne Phillips, Danny Rischin, Stephen B. Fox, Debi Johnson, Stephen Lade, Maurice B. Loughrey, N. O’Callaghan, William K. Murray, Paul Waring, Virginia Billson, Jan Pyman, Deborah Neesham, Michael Quinn, Craig Underhill, Rachel Bell, L. F. Ng, Robert Blum, Vinod Ganju, Ian Hammond, Yee Leung, Anthony J. McCartney, Martin Buck, I. Haviv, D. Purdie, David C. Whiteman, Nikolajs Zeps, Anna DeFazio, David D.L. Bowtell, Thomas C. Harding, Kevin Lin, Elizabeth M. Swisher, Olga Kondrashova, Clare L. Scott, Neil Johnson, Matthew J. Wakefield
28Citations signalées, ce qui n’est pas une note de qualité
24Institutions déclarées
4Pays d’affiliation déclarés
Rattachement africain : au, us, gb, ca.
Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
PARP inhibitor (PARPi) therapy has transformed outcomes for patients with homologous recombination DNA repair (HRR) deficient ovarian cancers, for example those with BRCA1 or BRCA2 gene defects. Unfortunately, PARPi resistance is common. Multiple resistance mechanisms have been described, including secondary mutations that restore the HR gene reading frame. BRCA1 splice isoforms △11 and △11q can contribute to PARPi resistance by splicing out the mutation-containing exon, producing truncated, partially functional proteins. However, the clinical impacts and underlying drivers of BRCA1 exon skipping are not fully understood.We analyzed nine ovarian and breast cancer patient derived xenografts (PDX) with BRCA1 exon 11 frameshift mutations for exon skipping and therapy response, including a matched PDX pair derived from a patient pre- and post-chemotherapy/PARPi. BRCA1 exon 11 skipping was elevated in PARPi resistant PDX tumors. Two independent PDX models acquired secondary BRCA1 splice site mutations (SSMs) that drive exon skipping, confirmed using qRT-PCR, RNA sequencing, immunoblotting and minigene modelling. CRISPR/Cas9-mediated disruption of splicing functionally validated exon skipping as a mechanism of PARPi resistance. SSMs were also enriched in post-PARPi ovarian cancer patient cohorts from the ARIEL2 and ARIEL4 clinical trials.Few PARPi resistance mechanisms have been confirmed in the clinical setting. While secondary/reversion mutations typically restore a gene's reading frame, we have identified secondary mutations in patient cohorts that hijack splice sites to enhance mutation-containing exon skipping, resulting in the overexpression of BRCA1 hypomorphs, which in turn promote PARPi resistance. Thus, BRCA1 SSMs can and should be clinically monitored, along with frame-restoring secondary mutations.
Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.
Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- BRCA1 secondary splice-site mutations drive exon-skipping and PARP inhibitor resistance
- Date Crossref
- 05/08/2024
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Les institutions déclarées
Une affiliation ne permet pas de déduire la nationalité d’un auteur.
Les sujets associés
CRISPR and Genetic EngineeringPARP inhibition in cancer therapyDNA Repair Mechanisms