title: Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer.
abstract: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer.
  
  
  
  A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined. In tumors that acquired therapy resistance, BRCA1 expression was investigated using quantitative real-time polymerase chain reaction and immunoblotting. Next-generation sequencing, methylation-specific multiplex ligation-dependent probe amplification (MLPA) and Target Locus Amplification (TLA)-based sequencing were used to determine mechanisms of BRCA1 re-expression in therapy-resistant tumors.
  
  
  
  BRCA1 protein was not detected in therapy-sensitive tumors but was found in 31 out of 42 resistant cases. Apart from previously described mechanisms involving BRCA1-intragenic deletions and loss of BRCA1 promoter hypermethylation, a novel resistance mechanism was identified in four out of seven BRCA1-methylated PDX tumors that re-expressed BRCA1 but retained BRCA1 promoter hypermethylation. In these tumors, we found de novo gene fusions that placed BRCA1 under the transcriptional control of a heterologous promoter, resulting in re-expression of BRCA1 and acquisition of therapy resistance.
  
  
  
  In addition to previously described clinically relevant resistance mechanisms in BRCA1-deficient tumors, we describe a novel resistance mechanism in BRCA1-methylated PDX tumors involving de novo rearrangements at the BRCA1 locus, demonstrating that BRCA1-methylated breast cancers may acquire therapy resistance via both epigenetic and genetic mechanisms.
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Petra
authors.initials: P
authors.lastname: Ter Brugge
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Petra
authors.initials: P
authors.lastname: Kristel
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Eline
authors.initials: E
authors.lastname: van der Burg
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Ute
authors.initials: U
authors.lastname: Boon
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Michiel
authors.initials: M
authors.lastname: de Maaker
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Esther
authors.initials: E
authors.lastname: Lips
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Lennart
authors.initials: L
authors.lastname: Mulder
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Julian
authors.initials: J
authors.lastname: de Ruiter
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Catia
authors.initials: C
authors.lastname: Moutinho
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Heidrun
authors.initials: H
authors.lastname: Gevensleben
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Ian
authors.initials: I
authors.lastname: Majewski
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Józwiak
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Wigard
authors.initials: W
authors.lastname: Kloosterman
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Markus
authors.initials: M
authors.lastname: van Roosmalen
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Frans
authors.initials: F
authors.lastname: Hogervorst
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Nick
authors.initials: N
authors.lastname: Turner
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Jelle
authors.initials: J
authors.lastname: Wesseling
authors.affiliation: Affiliations of authors: Division of Molecular Pathology and Cancer Genomics Centre Netherlands (PtB, PK, EvdB, UB, MdM, EL, LM, JdR, JW, JJ), Division of Molecular Carcinogenesis (IM), Department of Epidemiology and Biostatistics (KJ), and Family Cancer Clinic and Department of Pathology (FH), The Netherlands Cancer Institute, Amsterdam, the Netherlands; Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain (CM, ME); The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK (HG, NT); Laboratory of Preclinical Investigation, Translational Research Department, Curie Institute, Paris, France (EM); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (WK, MvR, KD, EC); Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Catalonia, Spain (ME); Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain (ME).
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000172:deficiency; D002945:Cisplatin / Q000627:therapeutic use; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D050939:Gene Fusion; D019398:Genes, BRCA1; D006801:Humans; D008558:Melphalan / Q000627:therapeutic use; D051379:Mice; D009154:Mutation; D009368:Neoplasm Transplantation; D015376:Nimustine / Q000627:therapeutic use; D010793:Phthalazines / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; D010793:Phthalazines; D010879:Piperazines; D015376:Nimustine; D002945:Cisplatin; D008558:Melphalan; C531550:olaparib