Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, M5G 2M9.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada, M5S 1A1.
Nat Commun. 2017 Nov 1;8(1):1245. doi: 10.1038/s41467-017-01357-y.
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.
几乎所有关于乳腺癌的基因组研究都集中在已确立的肿瘤上，因为研究人类乳腺上皮细胞中最早发生的突变事件在技术上具有挑战性。为了解决这个问题，我们创建了一个独特的数据集，其中包括从通向乳腺癌的导管中获得的上皮样本，以及来自乳头对侧导管的匹配样本。在这里，我们证明了随着与肿瘤的接近，mRNA 丰度的波动不能用拷贝数异常来解释。相反，我们通过构建一个评估上皮样本相对于肿瘤位置的分类器来发现围绕原发性肿瘤的局部癌变的可能性（交叉验证微平均 AUC=0.74）。我们实施了一种光谱共聚类算法来定义双聚类。与过度表达的双聚类途径相关，我们进一步使用组织微阵列和体外实验验证了两个基因。我们强调了表明双聚类扰动发生在肿瘤发展早期的证据。
