Homologous Recombination Deficiency Derived from Whole-genome Sequencing Predicts Platinum Response in Triple-negative Breast Cancers

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Apr 7

PMID 37029129

Authors

Petra Ter Brugge

Sarah C Moser

Ivan Bieche

Petra Kristel

Sabrina Ibadioune

Alexandre Eeckhoutte

Roebi de Bruijn

Eline van der Burg

Catrin Lutz

Stefano Annunziato

Julian de Ruiter

Julien Masliah Planchon

Sophie Vacher

Laura Courtois

Rania El-Botty

Ahmed Dahmani

Elodie Montaudon

Ludivine Morisset

Laura Sourd

Lea Huguet

Heloise Derrien

Fariba Nemati

Sophie Chateau-Joubert

Thibaut Larcher

Anne Salomon

Didier Decaudin

Fabien Reyal

Florence Coussy

Tatiana Popova

Jelle Wesseling

Marc-Henri Stern

Jos Jonkers

Elisabetta Marangoni

Affiliations

Soon will be listed here.

Abstract

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.

Citing Articles

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References

Sondka Z, Bamford S, Cole C, Ward S, Dunham I, Forbes S . The COSMIC Cancer Gene Census: describing genetic dysfunction across all human cancers. Nat Rev Cancer. 2018; 18(11):696-705. PMC: 6450507. DOI: 10.1038/s41568-018-0060-1. View

Kaklamani V, Jeruss J, Hughes E, Siziopikou K, Timms K, Gutin A . Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat. 2015; 151(3):629-38. DOI: 10.1007/s10549-015-3435-y. View

Scheinin I, Sie D, Bengtsson H, van de Wiel M, Olshen A, van Thuijl H . DNA copy number analysis of fresh and formalin-fixed specimens by shallow whole-genome sequencing with identification and exclusion of problematic regions in the genome assembly. Genome Res. 2014; 24(12):2022-32. PMC: 4248318. DOI: 10.1101/gr.175141.114. View

Jamal K, Galbiati A, Armenia J, Illuzzi G, Hall J, Bentouati S . Drug-gene Interaction Screens Coupled to Tumor Data Analyses Identify the Most Clinically Relevant Cancer Vulnerabilities Driving Sensitivity to PARP Inhibition. Cancer Res Commun. 2023; 2(10):1244-1254. PMC: 10035383. DOI: 10.1158/2767-9764.CRC-22-0119. View

Kluin R, Kemper K, Kuilman T, de Ruiter J, Iyer V, Forment J . XenofilteR: computational deconvolution of mouse and human reads in tumor xenograft sequence data. BMC Bioinformatics. 2018; 19(1):366. PMC: 6172735. DOI: 10.1186/s12859-018-2353-5. View

den Brok W, Schrader K, Sun S, Tinker A, Zhao E, Aparicio S . Homologous Recombination Deficiency in Breast Cancer: A Clinical Review. JCO Precis Oncol. 2022; 1:1-13. DOI: 10.1200/PO.16.00031. View

Lord C, Ashworth A . BRCAness revisited. Nat Rev Cancer. 2016; 16(2):110-20. DOI: 10.1038/nrc.2015.21. View

van de Wiel M, Kim K, Vosse S, van Wieringen W, Wilting S, Ylstra B . CGHcall: calling aberrations for array CGH tumor profiles. Bioinformatics. 2007; 23(7):892-4. DOI: 10.1093/bioinformatics/btm030. View

De Luca X, Newell F, Kazakoff S, Hartel G, McCart Reed A, Holmes O . Using whole-genome sequencing data to derive the homologous recombination deficiency scores. NPJ Breast Cancer. 2020; 6:33. PMC: 7414867. DOI: 10.1038/s41523-020-0172-0. View

10.

Forbes S, Bhamra G, Bamford S, Dawson E, Kok C, Clements J . The Catalogue of Somatic Mutations in Cancer (COSMIC). Curr Protoc Hum Genet. 2008; Chapter 10:Unit 10.11. PMC: 2705836. DOI: 10.1002/0471142905.hg1011s57. View

11.

Ibarra A, Schwob E, Mendez J . Excess MCM proteins protect human cells from replicative stress by licensing backup origins of replication. Proc Natl Acad Sci U S A. 2008; 105(26):8956-61. PMC: 2449346. DOI: 10.1073/pnas.0803978105. View

12.

Rondinelli B, Gogola E, Yucel H, Duarte A, van de Ven M, van der Sluijs R . EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation. Nat Cell Biol. 2017; 19(11):1371-1378. DOI: 10.1038/ncb3626. View

13.

Coussy F, El-Botty R, Chateau-Joubert S, Dahmani A, Montaudon E, Leboucher S . BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers. Sci Transl Med. 2020; 12(531). PMC: 8662740. DOI: 10.1126/scitranslmed.aax2625. View

14.

Zhu Y, Hu Y, Tang C, Guan X, Zhang W . Platinum-based systematic therapy in triple-negative breast cancer. Biochim Biophys Acta Rev Cancer. 2022; 1877(1):188678. DOI: 10.1016/j.bbcan.2022.188678. View

15.

Haibe-Kains B, Desmedt C, Loi S, Culhane A, Bontempi G, Quackenbush J . A three-gene model to robustly identify breast cancer molecular subtypes. J Natl Cancer Inst. 2012; 104(4):311-25. PMC: 3283537. DOI: 10.1093/jnci/djr545. View

16.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

17.

Bicknell L, Walker S, Klingseisen A, Stiff T, Leitch A, Kerzendorfer C . Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nat Genet. 2011; 43(4):350-5. DOI: 10.1038/ng.776. View

18.

Narod S, Huzarski T, Gronwald J, Byrski T, Marczyk E, Cybulski C . Predictors of survival for breast cancer patients with a BRCA1 mutation. Breast Cancer Res Treat. 2017; 168(2):513-521. DOI: 10.1007/s10549-017-4605-x. View

19.

Cruz C, Castroviejo-Bermejo M, Gutierrez-Enriquez S, Llop-Guevara A, Ibrahim Y, Gris-Oliver A . RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann Oncol. 2018; 29(5):1203-1210. PMC: 5961353. DOI: 10.1093/annonc/mdy099. View

20.

Haas B, Dobin A, Li B, Stransky N, Pochet N, Regev A . Accuracy assessment of fusion transcript detection via read-mapping and de novo fusion transcript assembly-based methods. Genome Biol. 2019; 20(1):213. PMC: 6802306. DOI: 10.1186/s13059-019-1842-9. View