Division of Nutrition, St. John's Research Institute, St. John's National Academy of Health Sciences, Bangalore, India.
Division of Medical Oncology, Kuang Tien General Hospital Cancer Center, 117 Shatien Rd Shalu Dist, Taichung, 43303, Taiwan.
Breast Cancer Res Treat. 2022 Jun;193(2):361-379. doi: 10.1007/s10549-022-06567-7. Epub 2022 Mar 29.
Invasive lobular carcinoma (ILC) treatment is similar to invasive ductal carcinoma (IDC; now invasive carcinoma-no special type, IBC-NST), based on its intrinsic subtype. However, further investigation is required for an integrative understanding of differentially perturbed molecular patterns and pathways in these histotypes.
A dataset of 780 IDC and 201 ILC samples from the TCGA-BRCA project for cross-platform multi-omics was analyzed. We leveraged a consensus approach integrating different bioinformatic algorithms to analyze mutations, CNAs, mRNA, miRNA abundance, methylation, and protein abundance to understand the complex crosstalks that distinguish ILC and IDC samples. A histotype-matched comparison was performed. We performed Cox survival analyses for prognosis based on our identified 53 histotype-specific and four discordant genes.
Approximately 90% of ILC cases were of the luminal subtype. Somatic mutations in CDH1 were higher in ILC than in IDC (FDR-adjusted p < 0.01). Fifty-three significant oncogenic or tumor-suppressive DEGs were identified in a single histotype. PPAR signaling and lipolysis regulation in adipocytes were significantly enriched in ILC tumors. CDH1 protein had the highest differential abundance (AUC: 0.85). Moreover, BTG2, GSTA2, GPR37L1, and PGBD5 amplification was associated with poorer OS in ILC compared with no alteration. RIMS2, NACA4P, MYC, ZFPM2, and POU5F1B amplification showed a lower overall survival in patients with IDC. miR-195 showed an IDC-specific downregulation, causing overexpression of CCNE1. Integrative multi-omics supervised analysis identified 296 differentially expressed genes that successfully distinguished IDC and ILC histotypes.
Our findings identify novel molecular candidates that potentially drive and modify the disease differentially among these histotypes.
浸润性小叶癌（ILC）的治疗方法与浸润性导管癌（IDC；现为非特殊型浸润性癌，IBC-NST）相似，这是基于其固有亚型。然而，为了全面了解这些组织类型中差异失调的分子模式和途径，还需要进一步研究。
我们分析了 TCGA-BRCA 项目中 780 例 IDC 和 201 例 ILC 样本的数据集，用于跨平台多组学的综合分析。我们利用共识方法整合不同的生物信息学算法来分析突变、CNA、mRNA、miRNA 丰度、甲基化和蛋白质丰度，以了解区分 ILC 和 IDC 样本的复杂串扰。我们进行了组织类型匹配的比较。根据我们鉴定的 53 个组织类型特异性和 4 个不一致基因，进行 Cox 生存分析以预测预后。
约 90%的 ILC 病例为 luminal 亚型。与 IDC 相比，ILC 中 CDH1 的体细胞突变更高（经 FDR 调整的 p<0.01）。在单个组织类型中鉴定出 53 个显著的致癌或肿瘤抑制 DEGs。PPAR 信号和脂肪细胞中的脂肪分解调节在 ILC 肿瘤中显著富集。CDH1 蛋白的差异丰度最高（AUC：0.85）。此外，与无改变相比，BTG2、GSTA2、GPR37L1 和 PGBD5 的扩增与 ILC 的较差 OS 相关。RIMS2、NACA4P、MYC、ZFPM2 和 POU5F1B 的扩增在 IDC 患者中显示出较低的总生存期。miR-195 在 IDC 中特异性下调，导致 CCNE1 过表达。基于多组学的综合分析确定了 296 个差异表达基因，可成功区分 IDC 和 ILC 组织类型。
我们的研究结果确定了潜在的新分子候选物，这些候选物可能在这些组织类型中驱动和改变疾病的发生。
