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

被引:24
作者
Abdalla, Moustafa [1 ,2 ,3 ,4 ]
Danh Tran-Thanh [2 ]
Moreno, Juan [2 ]
Iakovlev, Vladimir [2 ]
Nair, Ranju [1 ]
Kanwar, Nisha [1 ,2 ]
Abdalla, Mohamed [2 ]
Lee, Jennifer P. Y. [2 ]
Kwan, Jennifer Yin Yee [2 ]
Cawthorn, Thomas R. [1 ,2 ]
Warren, Keisha [1 ]
Arneson, Nona [1 ]
Wang, Dong-Yu [1 ]
Fox, Natalie S. [5 ,6 ]
Youngson, Bruce J. [2 ,7 ]
Miller, Naomi A. [2 ,7 ]
Easson, Alexandra M. [8 ,9 ]
McCready, David [8 ,9 ]
Leong, Wey L. [8 ,9 ]
Boutros, Paul C. [5 ,6 ,10 ]
Done, Susan J. [1 ,2 ,5 ,7 ]
机构
[1] Univ Hlth Network, Campbell Family Inst Breast Canc Res, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada
[2] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A1, Canada
[3] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada
[4] Univ Toronto, Dept Physiol, Toronto, ON M5S 1A8, Canada
[5] Univ Toronto, Dept Med Biophys, Toronto, ON M5S 1L7, Canada
[6] Ontario Inst Canc Res, Informat & Biocomp Program, Toronto, ON M5G 0A3, Canada
[7] Univ Hlth Network, Lab Med Program, Toronto, ON M5G 2C4, Canada
[8] Princess Margaret Canc Ctr, Dept Surg Oncol, Toronto, ON M5G 2M9, Canada
[9] Univ Toronto, Toronto, ON M5G 2M9, Canada
[10] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5S 1A8, Canada
关键词
NORMAL TISSUE ADJACENT; COMPREHENSIVE MOLECULAR PORTRAITS; DEMONSTRATE FIELD CANCERIZATION; IN-SITU; CANCER; HETEROZYGOSITY; TUMORS; AMPLIFICATION; MUTATIONS; IMBALANCE;
D O I
10.1038/s41467-017-01357-y
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页数:11
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