Multi-omics analyses provide novel biological insights to distinguish lobular ductal types of invasive breast cancers

CDH1 浸润性小叶癌 生物 表观遗传学 小RNA 乳腺癌 DNA甲基化 癌症研究 浸润性导管癌 计算生物学 基因 生物信息学 癌症 基因表达 遗传学 钙粘蛋白 细胞
作者
Ambily Sivadas,Victor C. Kok,Ka‐Lok Ng
出处
期刊:Breast Cancer Research and Treatment [Springer Science+Business Media]
卷期号:193 (2): 361-379 被引量:14
标识
DOI:10.1007/s10549-022-06567-7
摘要

BackgroundInvasive 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.MethodsA 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.ResultsApproximately 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.ConclusionsOur findings identify novel molecular candidates that potentially drive and modify the disease differentially among these histotypes.
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