TCGA Breast Invasive Carcinoma (TCGA, Cell 2015)

Overview

The 2015 TCGA breast cancer dataset (brca_tcga_pub2015) is the comprehensive multi-platform molecular characterization of 817 primary breast tumors published by Ciriello et al. in Cell (2015). It expands on the original 2012 TCGA breast study (brca_tcga_pub) by including a histology-enriched design: 127 invasive lobular carcinoma (ILC), 490 invasive ductal carcinoma (IDC), 88 mixed IDC/ILC, and 112 other histologies. The primary aim was to characterize the molecular landscape of ILC relative to IDC across DNA, RNA, protein, and epigenomic dimensions. Validation of ILC transcriptional subtypes was performed in the brca_metabric cohort.

Composition

• 817 primary breast tumors: 127 ILC, 490 IDC, 88 mixed IDC/ILC, 112 other histologies.
• ILC PAM50 subtype composition: 83% Luminal A, 94% (113/120) ER+ by IHC.
• Platforms: whole-exome sequencing, RNA-seq, miRNA-seq, Affymetrix SNP6 (copy number), HM27 and HM450 methylation arrays, RPPA (reverse-phase protein arrays, n=633). Whole-genome bisulfite sequencing in 5 samples for methylation validation.
• Reference genome: hg19.

Assays / panels (linked)

• whole-exome-seq
• rna-seq
• mirna-seq
• affymetrix-snp6
• hm27-methylation-array
• hm450-methylation-array
• rppa

Papers using this cohort

• PMID:26451490 — Ciriello et al. 2015, Cell — “Comprehensive molecular portraits of invasive lobular breast cancer.”

Notable findings derived from this cohort

• ILC-enriched mutations vs IDC: CDH1 63% vs 2% (q=3.94E-53); TBX3 9% vs 2%; PIK3CA 48% vs 33%; FOXA1 7% vs 2%; TP53 depleted in ILC (8% vs 44%) PMID:26451490.
• CDH1 alterations detected in 120/127 (95%) ILC cases; CDH1 promoter DNA hypermethylation was not observed, contradicting older MSP-based reports PMID:26451490.
• ILC has the highest pAKT activity of any breast cancer subtype — comparable to HER2+ and Basal-like — driven by upstream RTK alterations and PTEN loss rather than PIK3CA mutation per se PMID:26451490.
• Three ILC transcriptional subtypes identified (reactive-like, immune-related, proliferative); validated in brca_metabric; proliferative ILC had worse DSS and OS PMID:26451490.
• Mixed IDC/ILC tumors resolve molecularly into ILC-like or IDC-like classes (not a third hybrid entity); CDH1 status is the dominant classifier PMID:26451490.

Sources

• Ciriello G et al. “Comprehensive molecular portraits of invasive lobular breast cancer.” Cell. 2015;163(2):506-519. PMID:26451490. DOI: 10.1016/j.cell.2015.09.033.

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