Mapping genomic and transcriptomic alterations spatially in epithelial cells adjacent to human breast carcinoma

Moustafa Abdalla, Danh Tran-Thanh, Juan Moreno, Vladimir Iakovlev, Ranju Nair, Nisha Kanwar, Mohamed Abdalla, Jennifer P. Y. Lee, Jennifer Yin Yee Kwan, Thomas R. Cawthorn, Keisha Warren, Nona Arneson, Dong-Yu Wang, Natalie S. Fox, Bruce J. Youngson, Naomi A. Miller, Alexandra M. Easson, David McCready, Wey L. Leong, Paul C. Boutros and Susan J. Done ()
Additional contact information
Moustafa Abdalla: Princess Margaret Cancer Centre, University Health Network
Danh Tran-Thanh: University of Toronto
Juan Moreno: University of Toronto
Vladimir Iakovlev: University of Toronto
Ranju Nair: Princess Margaret Cancer Centre, University Health Network
Nisha Kanwar: Princess Margaret Cancer Centre, University Health Network
Mohamed Abdalla: University of Toronto
Jennifer P. Y. Lee: University of Toronto
Jennifer Yin Yee Kwan: University of Toronto
Thomas R. Cawthorn: Princess Margaret Cancer Centre, University Health Network
Keisha Warren: Princess Margaret Cancer Centre, University Health Network
Nona Arneson: Princess Margaret Cancer Centre, University Health Network
Dong-Yu Wang: Princess Margaret Cancer Centre, University Health Network
Natalie S. Fox: University of Toronto
Bruce J. Youngson: University of Toronto
Naomi A. Miller: University of Toronto
Alexandra M. Easson: Princess Margaret Cancer Center and University of Toronto
David McCready: Princess Margaret Cancer Center and University of Toronto
Wey L. Leong: Princess Margaret Cancer Center and University of Toronto
Paul C. Boutros: University of Toronto
Susan J. Done: Princess Margaret Cancer Centre, University Health Network

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract Almost all genomic studies of breast cancer have focused on well-established tumours because it is technically challenging to study the earliest mutational events occurring in human breast epithelial cells. To address this we created a unique dataset of epithelial samples ductoscopically obtained from ducts leading to breast carcinomas and matched samples from ducts on the opposite side of the nipple. Here, we demonstrate that perturbations in mRNA abundance, with increasing proximity to tumour, cannot be explained by copy number aberrations. Rather, we find a possibility of field cancerization surrounding the primary tumour by constructing a classifier that evaluates where epithelial samples were obtained relative to a tumour (cross-validated micro-averaged AUC = 0.74). We implement a spectral co-clustering algorithm to define biclusters. Relating to over-represented bicluster pathways, we further validate two genes with tissue microarrays and in vitro experiments. We highlight evidence suggesting that bicluster perturbation occurs early in tumour development.

Date: 2017
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DOI: 10.1038/s41467-017-01357-y

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