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Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes

  • Epidemiology
  • Published:
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Abstract

Distinct subtypes of triple negative (TN) breast cancer have been identified by tumor expression profiling. However, little is known about the relationship between histopathologic features of TN tumors, which reflect aspects of both tumor behavior and tumor microenvironment, and molecular TN subtypes. The histopathologic features of TN tumors were assessed by central review and 593 TN tumors were subjected to whole genome expression profiling using the Illumina Whole Genome DASL array. TN molecular subtypes were defined based on gene expression data associated with histopathologic features of TN tumors. Gene expression analysis yielded signatures for four TN subtypes (basal-like, androgen receptor positive, immune, and stromal) consistent with previous studies. Expression analysis also identified genes significantly associated with the 12 histological features of TN tumors. Development of signatures using these markers of histopathological features resulted in six distinct TN subtype signatures, including an additional basal-like and stromal signature. The additional basal-like subtype was distinguished by elevated expression of cell motility and glucose metabolism genes and reduced expression of immune signaling genes, whereas the additional stromal subtype was distinguished by elevated expression of immunomodulatory pathway genes. Histopathologic features that reflect heterogeneity in tumor architecture, cell structure, and tumor microenvironment are related to TN subtype. Accounting for histopathologic features in the development of gene expression signatures, six major subtypes of TN breast cancer were identified.

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Acknowledgments

HEBCS: Dario Greco, Tuomas Heikkinen, Kristiina Aittomäki. KBCP thanks Eija Myöhänen, Helena Kemiläinen, and Aija Parkkinen for their skillful technical assistance. We thank all study participants, clinicians, family doctors, researchers, and technicians for their contributions and commitment to this study. SBCS would like to thank Sue Higham, Helen Cramp, Ian Brock, Sabapathy Balasubramanian, Malcolm W.R. Reed, and Dan Connley. NBHS thanks study participants and research staff for their contributions and commitment to this study. POSH thanks Linda Haywood for her technical support.

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The TNBCC and this tumor study was supported by the Breast Cancer Research Foundation, NIH Grants CA116167, CA192393, and an NIH specialized program of research excellence (SPORE) (P50 CA116201) in breast cancer to Mayo Clinic. K. Purrington completed this work partially as a Mayo Cancer Genetic Epidemiology Training Program (CA92049-03) fellow. The Australian Breast Cancer Tissue Bank is generously supported by the National Health and Medical Research Council of Australia, The Cancer Institute NSW, and the National Breast Cancer Foundation. MCCS cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC Grants 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR). HeCOG research has been co‐financed by the European Union (European Social Fund) and Greek national funds through the operational program Education and Lifelong Learning of the National Strategic Reference Framework Research Funding Program: Thales—investing in knowledge society through the European Social Fund. The HEBCS was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society, and the Sigrid Juselius Foundation. KBCPstudy was funded by grants from the Finnish Cancer Society, the special Governmental EVO Research Fund of Kuopio University Hospital (grants 53125, 53127, and 53132), and strategic funding of the University of Eastern Finland. SKKDKFZS is supported by the DKFZ. The SBCS was supported by Yorkshire Cancer Research S295, S299, S305PA, and Sheffield Experimental Cancer Medicine Centre. The Nashville Breast Health Study (NBHS) was supported by National Institutes of Health (Grant R01CA100374). POSH is supported by C1275/A11699, C1275/A9896, and C22524.

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Purrington, K.S., Visscher, D.W., Wang, C. et al. Genes associated with histopathologic features of triple negative breast tumors predict molecular subtypes. Breast Cancer Res Treat 157, 117–131 (2016). https://doi.org/10.1007/s10549-016-3775-2

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