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

Abstract

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.