title: TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance.
abstract: OBJECTIVE
  In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC).
  
  
  METHODS
  TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method.
  
  
  RESULTS
  TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P < 0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive.
  
  
  CONCLUSIONS
  This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development.
authors.affiliation: K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Laxmi
authors.initials: L
authors.lastname: Silwal-Pandit
authors.affiliation: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; Division of Cancer Medicine, Surgery and Transplantation, Department of Oncology, Oslo University Hospital, Oslo;
authors.forename: Hans Kristian Moen
authors.initials: HK
authors.lastname: Vollan
authors.affiliation: Cancer Research UK, Cambridge Institute; Department of Oncology, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Suet-Feung
authors.initials: SF
authors.lastname: Chin
authors.affiliation: Cancer Research UK, Cambridge Institute; Department of Oncology, University of Cambridge, Cambridge, United Kingdom;
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Rueda
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia; and Molecular Oncology, British Colombia Cancer Research Center, Vancouver, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: McKinney
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia; and Molecular Oncology, British Colombia Cancer Research Center, Vancouver, Canada.
authors.forename: Tomo
authors.initials: T
authors.lastname: Osako
authors.affiliation: Authors' Affiliations: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California;
authors.forename: David A
authors.initials: DA
authors.lastname: Quigley
authors.affiliation: Authors' Affiliations: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; Division of Medicine, Department of Clinical Molecular Oncology, Akershus University Hospital, Lørenskog, Norway;
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Colombia; and Molecular Oncology, British Colombia Cancer Research Center, Vancouver, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Aparicio
authors.affiliation: Authors' Affiliations: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; anita.langerod@rr-research.no a.l.borresen-dale@medisin.uio.no Carlos.Caldas@cruk.cam.ac.uk.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Cancer Research UK, Cambridge Institute; Cambridge Experimental Cancer Medicine Centre; Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS Foundation Trust and NIHR Cambridge Biomedical Research Centre; Department of Oncology, University of Cambridge, Cambridge, United Kingdom; anita.langerod@rr-research.no a.l.borresen-dale@medisin.uio.no Carlos.Caldas@cruk.cam.ac.uk.
authors.forename: Carlos
authors.initials: C
authors.lastname: Caldas
authors.affiliation: Authors' Affiliations: Department of Genetics, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine; anita.langerod@rr-research.no a.l.borresen-dale@medisin.uio.no Carlos.Caldas@cruk.cam.ac.uk.
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000628:therapy; D015331:Cohort Studies; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D005260:Female; D005500:Follow-Up Studies; D042822:Genomic Instability; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D011379:Prognosis; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53