Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

被引：137

作者：

de Jonge, Marthe M. ^{[1
]}

Auguste, Aurelie ^{[2
]}

van Wijk, Lise M. ^{[3
]}

Schouten, Philip C. ^{[1
]}

Meijers, Matty ^{[3
]}

ter Haar, Natalja T. ^{[1
]}

Smit, Vincent T. H. B. M. ^{[1
]}

Nout, Remi A. ^{[4
]}

Glaire, Mark A. ^{[5
]}

Church, David N. ^{[5
,6
]}

Vrieling, Harry ^{[3
]}

Job, Bastien ^{[7
]}

Boursin, Yannick ^{[2
]}

de Kroon, Cor D. ^{[8
]}

Rouleau, Etienne ^{[9
]}

Leary, Alexandra ^{[2
,10
]}

Vreeswijk, Maaike P. G. ^{[3
]}

Bosse, Tjalling ^{[1
]}

机构：

[1] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands

[2] Gustave Roussy Canc Ctr, INSERM, U981, Villejuif, France

[3] Leiden Univ, Dept Human Genet, Med Ctr, Leiden, Netherlands

[4] Leiden Univ, Dept Radiotherapy, Med Ctr, Leiden, Netherlands

[5] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England

[6] Oxford Univ Hosp NHS Fdn Trust, Oxford Biomed Res Ctr, John Radcliffe Hosp, NIHR, Oxford, England

[7] UMS AMMICA, Gustave Roussy Canc Ctr, Plateforme Bioinformat, Villejuif, France

[8] Leiden Univ, Dept Gynecol, Med Ctr, Leiden, Netherlands

[9] Gustave Roussy Canc Ctr, Dept Genet, Villejuif, France

[10] Gustave Roussy Canc Ctr, Dept Med Oncol, Villejuif, France

来源：

CLINICAL CANCER RESEARCH | 2019年 / 25卷 / 03期

基金：

英国惠康基金;

关键词：

CLEAR-CELL; MAINTENANCE THERAPY; SOMATIC MUTATIONS; OPEN-LABEL; CANCER; OVARIAN; PLATINUM; PREDICT; CHEMOTHERAPY; SURVIVAL;

D O I：

10.1158/1078-0432.CCR-18-1443

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics. Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort. Results: Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24%(n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001). Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.

引用

页码：1087 / 1097

页数：11

共 54 条

[1] Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer [J].

Abkevich, V. ;

Timms, K. M. ;

Hennessy, B. T. ;

Potter, J. ;

Carey, M. S. ;

Meyer, L. A. ;

Smith-McCune, K. ;

Broaddus, R. ;

Lu, K. H. ;

Chen, J. ;

Tran, T. V. ;

Williams, D. ;

Iliev, D. ;

Jammulapati, S. ;

FitzGerald, L. M. ;

Krivak, T. ;

DeLoia, J. A. ;

Gutin, A. ;

Mills, G. B. ;

Lanchbury, J. S. .

BRITISH JOURNAL OF CANCER, 2012, 107 (10) :1776-1782

[2] Signatures of mutational processes in human cancer [J].

Alexandrov, Ludmil B. ;

Nik-Zainal, Serena ;

Wedge, David C. ;

Aparicio, Samuel A. J. R. ;

Behjati, Sam ;

Biankin, Andrew V. ;

Bignell, Graham R. ;

Bolli, Niccolo ;

Borg, Ake ;

Borresen-Dale, Anne-Lise ;

Boyault, Sandrine ;

Burkhardt, Birgit ;

Butler, Adam P. ;

Caldas, Carlos ;

Davies, Helen R. ;

Desmedt, Christine ;

Eils, Roland ;

Eyfjord, Jorunn Erla ;

Foekens, John A. ;

Greaves, Mel ;

Hosoda, Fumie ;

Hutter, Barbara ;

Ilicic, Tomislav ;

Imbeaud, Sandrine ;

Imielinsk, Marcin ;

Jaeger, Natalie ;

Jones, David T. W. ;

Jones, David ;

Knappskog, Stian ;

Kool, Marcel ;

Lakhani, Sunil R. ;

Lopez-Otin, Carlos ;

Martin, Sancha ;

Munshi, Nikhil C. ;

Nakamura, Hiromi ;

Northcott, Paul A. ;

Pajic, Marina ;

Papaemmanuil, Elli ;

Paradiso, Angelo ;

Pearson, John V. ;

Puente, Xose S. ;

Raine, Keiran ;

Ramakrishna, Manasa ;

Richardson, Andrea L. ;

Richter, Julia ;

Rosenstiel, Philip ;

Schlesner, Matthias ;

Schumacher, Ton N. ;

Span, Paul N. ;

Teague, Jon W. .

NATURE, 2013, 500 (7463) :415-+

[3]

[Anonymous], 2016, FIR 2016 01 28 RUN

[4]

[Anonymous], GENETIC MECH CARCINO

[5] Just how accurate are the major risk stratification systems for early-stage endometrial cancer? [J].

Bendifallah, S. ;

Canlorbe, G. ;

Collinet, P. ;

Arsene, E. ;

Huguet, F. ;

Coutant, C. ;

Hudry, D. ;

Graesslin, O. ;

Raimond, E. ;

Touboul, C. ;

Darai, E. ;

Ballester, M. .

BRITISH JOURNAL OF CANCER, 2015, 112 (05) :793-801

[6] PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy [J].

Bian, X. ;

Gao, J. ;

Luo, F. ;

Rui, C. ;

Zheng, T. ;

Wang, D. ;

Wang, Y. ;

Roberts, T. M. ;

Liu, P. ;

Zhao, J. J. ;

Cheng, H. .

ONCOGENE, 2018, 37 (03) :341-351

[7] Detection of S-phase cell cycle progression using 5-ethynyl-2′-deoxyuridine incorporation with click chemistry an alternative to using 5-bromo-2′-deoxyuridine antibodies [J].

Buck, Suzanne B. ;

Bradford, Jolene ;

Gee, Kyle R. ;

Agnew, Brian J. ;

Clarke, Scott T. ;

Salic, Adrian .

BIOTECHNIQUES, 2008, 44 (07) :927-929

[8] Integrated Molecular Characterization of Uterine Carcinosarcoma [J].

Cherniack, Andrew D. ;

Shen, Hui ;

Walter, Vonn ;

Stewart, Chip ;

Murray, Bradley A. ;

Bowlby, Reanne ;

Hu, Xin ;

Ling, Shiyun ;

Soslow, Robert A. ;

Broaddus, Russell R. ;

Zuna, Rosemary E. ;

Robertson, Gordon ;

Laird, Peter W. ;

Kucherlapati, Raju ;

Mills, Gordon B. ;

Weinstein, John N. ;

Zhang, Jiashan ;

Akbani, Rehan ;

Levine, Douglas A. .

CANCER CELL, 2017, 31 (03) :411-423

[9] Prognostic Significance of POLE Proofreading Mutations in Endometrial Cancer [J].

Church, David N. ;

Stelloo, Ellen ;

Nout, Remi A. ;

Valtcheva, Nadejda ;

Depreeuw, Jeroen ;

ter Haar, Natalja ;

Noske, Aurelia ;

Amant, Frederic ;

Tomlinson, Ian P. M. ;

Wild, Peter J. ;

Lambrechts, Diether ;

Jurgenliemk-Schulz, Ina M. ;

Jobsen, Jan J. ;

Smit, Vincent T. H. B. M. ;

Creutzberg, Carien L. ;

Bosse, Tjalling .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2015, 107 (01)

[10] Appendix 5: Endometrial cancer: eUpdate published online 8 June 2017 (www.esmo.org/Guidelines/Gynaecological-Cancers) [J].

Colombo, N. ;

Creutzberg, C. ;

Querleu, D. ;

Barahona, M. ;

Sessa, C. .

ANNALS OF ONCOLOGY, 2017, 28 :153-156

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