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

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.

Intra-individual Gene Expression Variability of Histologically Normal Breast Tissue

“…Moreover, our study compiled histologically normal breast tissues from women undergoing a variety of procedures. Previous research suggests that cancer-adjacent tissue possesses some differences from benign tissues of disease-free women 9 , 34 – 36 . To test the potential impact of the samples from breast cancer patients, we conducted a series of sensitivity analysis: (1) checking the similarity of gene expression by tissue sources using principle component analysis (Supplementary Figure 1A ); (2) re-evaluating the variabilities across different levels after excluding tissue samples with distance to tumor less than 1 cm (n = 15, Supplementary Figure 1B ); (3) comparing the intra-individual variabilities between the whole samples (n = 57) and the subset (n = 42) (Supplementary Figure 1B ).…”

Multiple Myeloma Exemplifies a Model of Cancer Based on Tissue Disruption as the Initiator Event

“…This view results from numerous studies where tissue disruption can be either the inducer or the repressor of the cancerous state ( 1 ). Nevertheless, the genetic origin of the disease remains widely accepted (the necessary pre-existence of mutated cells and the initiator role of mutations are most of the time not called into question) in spite of new data showing (a) the presence of oncogenic mutations in normal tissues ( 2 – 4 ) and the ability of these tissues to eliminate mutant cells to prevent tumor initiation ( 5 ), (b) the development of pre-cancerous lesions without oncogenic mutations ( 6 ), or (c) the presence of epigenetic ( 7 ), gene expression ( 8 ) or micro-environmental ( 9 ) alterations that might precede the emergence of genetically abnormal cells, that further question the genetic model of cancer initiation. Epigenetic alterations especially are increasingly acknowledged as being able to initiate transformation, as genetic alterations do, by providing the gene expression plasticity necessary to provide stochastic oncogenic epigenetic changes ( 10 ).…”

Differences in mutational processes and intra-tumour heterogeneity between organs

“…In accordance with this hypothesis, numerous studies have now shown that tissue disruption can be either the inducer or the repressor of the cancerous state [44, 74–76]. Therefore, the presence of epigenetic [77], gene expression [78] or micro-environmental [79] alterations that might precede the emergence of genetically abnormal cells further argues for a major role of non-genetic processes in the first steps of oncogenesis.The early increase in gene expression variability allows another type of bet-hedging that can synergize with genetic ITH to allow phenotypic diversification, the transcriptional ITH. When RNA-seq data were used to measure the level of transcriptional ITH, 12 major cancer types showed distinct levels of this type of ITH [7].…”

“…In accordance with this hypothesis, numerous studies have now shown that tissue disruption can be either the inducer or the repressor of the cancerous state [44, 74–76]. Therefore, the presence of epigenetic [77], gene expression [78] or micro-environmental [79] alterations that might precede the emergence of genetically abnormal cells further argues for a major role of non-genetic processes in the first steps of oncogenesis.…”