Abstract：
Mutations are abundantly present in tissues of healthy individuals, including the breast epithelium. Yet it remains unknown whether mutant cells directly induce lesion formation or first spread, leading to a field of mutant cells that is predisposed towards lesion formation. To study the clonal and spatial relationships between morphologically normal breast epithelium adjacent to pre-cancerous lesions, we developed a three-dimensional (3D) imaging pipeline combined with spatially resolved genomics on archival, formalin-fixed breast tissue with the non-obligate breast cancer precursor ductal carcinoma in situ (DCIS). Using this 3D image-guided characterization method, we built high-resolution spatial maps of DNA copy number aberration (CNA) profiles within the DCIS lesion and the surrounding normal mammary ducts. We show that the local heterogeneity within a DCIS lesion is limited. However, by mapping the CNA profiles back onto the 3D reconstructed ductal subtree, we find that in eight out of 16 cases the healthy epithelium adjacent to the DCIS lesions has overlapping structural variations with the CNA profile of the DCIS. Together, our study indicates that pre-malignant breast transformations frequently develop within mutant clonal fields of morphologically normal-looking ducts. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
摘要：
突变在健康个体的组织中大量存在，包括乳腺上皮.然而，目前尚不清楚突变细胞是否直接诱导病变形成或首次扩散，导致突变细胞的领域倾向于病变形成。研究癌前病变附近形态正常的乳腺上皮之间的克隆和空间关系，我们开发了一个三维（3D）成像管道与空间分辨基因组学相结合的档案，福尔马林固定的乳腺组织与非专性乳腺癌前体导管原位癌（DCIS）。使用这种3D图像引导的表征方法，我们建立了DCIS病变和周围正常乳腺导管内DNA拷贝数畸变(CNA)谱的高分辨率空间图.我们表明DCIS病变内的局部异质性是有限的。然而,通过将CNA轮廓映射回3D重建的导管子树，我们发现16例中有8例与DCIS病变相邻的健康上皮与DCIS的CNA谱有重叠的结构变异.一起,我们的研究表明，在形态正常的导管的突变克隆区域内，癌前乳腺转化经常发生。©2024作者由JohnWiley＆SonsLtd代表英国和爱尔兰病理学会出版的病理学杂志。
