Post-zygotic structural variants in histologically normal breast tissue may predispose to sporadic breast cancer [SET 13]. Homo sapiens

Sporadic breast cancer (SBC) is a common and heterogeneous disease. There is no reliable way of early prediction of risk for SBC in the general population. We studied 282 females with SBC concentrating on copy number aberrations in tumor-free breast tissue (uninvolved margin, UM) outside the area of primary tumor (PT). Totally 1162 UMs (1-14 per breast) were studied. PT and blood/skin as control was also analyzed. Comparative analysis between genetic profiles for UM(s), PT(s) and blood/skin from the same patient is the core of study design. We identified 108 patients with at least one aberrant UM specimen, representing 38.3% of all cases. Gains were the dominating mutations in microscopically normal breast cells and gain of ERBB2, with overexpression of HER2 protein, was the most common aberration in normal cells. Five additional receptor genes (EGFR, FGFR1, IGF1R, LIFR and NGFR) also showed gains, and these were occasionally present in combination with the gain of ERBB2. Up to 67.6% of patients showed gain of one or more of these genes in normal cells. The aberrations found in normal cells from UMs were previously described in cancer literature, which suggest their causative, driving role in this disease. We demonstrate that analysis of normal cells from cancer-bearing patients leads to identification of genetic signatures that may predispose to SBC. Early detection of signals suggesting a predisposition towards development of SBC, long before detectable tumors are formed, is a key to the anticipated shift into a preventive paradigm of personalized medicine of breast cancer. Overall design: We studied 282 female breast cancer patients that were assessed as affected by sporadic disease at the time of diagnosis and all underwent mastectomy. In total, 1162 UMs (uninvolved margin tissues), ranging from 1 to 14 UMs per patient, taken outside the location of clinically characterized index primary tumor, were analyzed on Illumina arrays. For each subject, DNA from at least one control tissue was also analyzed, which was predominantly blood DNA, alternatively skin-derived DNA. We also studied primary tumor (PT), or up to 3 primary tumor foci from patients with diagnosis of multifocal disease. This GEO project contains the genotyping profiles (processed and normalized data including Log R Ratio and B allele frequency) for these 1162 UMs used in the study. Information on phenotypes (age at diagnosis, tumor focality, tumor grade, tumor molecular phenotype) is also provided, whenever available. 92 experiments runned on platform GPL6984 (Human1M-Duov3_B)

散发性乳腺癌（Sporadic Breast Cancer, SBC）是一类常见且具有高度异质性的疾病，目前在普通人群中尚无可靠的早期风险预测手段。本研究纳入282名散发性乳腺癌女性患者，重点探究原发肿瘤（Primary Tumor, PT）区域外的无瘤乳腺组织（未受累切缘，Uninvolved Margin, UM）中的拷贝数变异。共计分析1162份未受累切缘组织，每位患者可提供1~14份此类样本，同时对原发肿瘤及血液/皮肤对照样本开展检测。本研究的核心设计在于对同一患者的未受累切缘组织、原发肿瘤与血液/皮肤的遗传谱进行比较分析。

本研究共鉴定出108名患者至少携带1份存在遗传变异的未受累切缘组织标本，占全部研究病例的38.3%。拷贝数扩增是镜下外观正常的乳腺细胞中占主导的突变类型，其中ERBB2扩增伴随HER2蛋白过表达，是正常细胞中最常见的遗传变异。另有5种受体基因（EGFR、FGFR1、IGF1R、LIFR及NGFR）同样出现扩增，且此类变异偶尔会与ERBB2扩增同时存在。高达67.6%的患者在其正常乳腺细胞中存在至少1种上述基因的扩增。

既往癌症相关研究文献中已有未受累切缘正常细胞中此类变异的报道，提示其在该疾病发生发展中具有致病驱动作用。本研究证实，对癌症患者的正常体细胞进行分析，可识别出可能赋予散发性乳腺癌易感风险的遗传特征。在可检测到实体肿瘤形成之前，早期发现提示散发性乳腺癌易感的信号，是推动乳腺癌个性化医疗向预防范式转变的核心关键。

研究整体设计：本研究纳入282名确诊时被判定为散发性乳腺癌且均接受乳房切除术的女性患者。共计获取1162份未受累切缘组织，所有样本均取自临床确诊的索引原发肿瘤区域以外，每位患者可获得1~14份此类组织样本，全部样本通过Illumina芯片完成检测。对于每位受试者，我们还至少分析了1份对照组织的DNA，主要为血液DNA，也可选用皮肤来源的DNA。此外，本研究还对原发肿瘤进行了分析，对于确诊为多灶性疾病的患者，最多可分析3处原发肿瘤病灶。

本GEO（Gene Expression Omnibus，基因表达综合数据库）数据集包含本研究中使用的1162份未受累切缘组织的基因分型谱，涵盖经处理与标准化的数据，包括对数比率比（Log R Ratio）与B等位基因频率（B Allele Frequency）。同时还提供了可用的表型信息，包括诊断时年龄、肿瘤多灶性、肿瘤分级、肿瘤分子表型等。本数据集共计92个实验基于平台GPL6984（Human1M-Duov3_B）完成。