DCIS genomic signatures define biology and clinical outcome: Human Tumor Atlas Network (HTAN) analysis of TBCRC 038 and RAHBT cohorts

Abstract

Ductal carcinoma in situ (DCIS) is the most common precursor of invasive breast cancer (IBC), with variable propensity for progression. We have performed the first multiscale, integrated profiling of DCIS with clinical outcomes by analyzing 677 DCIS samples from 481 patients with 7.1 years median follow-up from the Translational Breast Cancer Research Consortium (TBCRC) 038 study and the Resource of Archival Breast Tissue (RAHBT) cohorts. We made observations on DNA, RNA, and protein expression, and generated a de novo clustering scheme for DCIS that represents a fundamental transcriptomic organization at this early stage of breast neoplasia. Distinct stromal expression patterns and immune cell compositions were identified. We found RNA expression patterns that correlate with later events. Our multiscale approach employed in situ methods to generate a spatially resolved atlas of breast precancers, where complementary modalities can be directly compared and correlated with conventional pathology findings, disease states, and clinical outcome.

Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma

“…To analyze ECM components by gene expression, an ECM gene signature (GO ECM structural constituent, GO:0030021) was downloaded from the GSEA website ( www.gsea-msigdb.org ) and used to compare MIBI-identified samples with the top and bottom quartiles of cancer-associated fibroblast density in the stroma. Stromal LCM-RNaseq samples were used for this analysis from a paired transcriptomic study of the RAHBT cohort ( Strand et al, 2021 ). Raw reads were normalized with DESeq2 R package (version 1.30.0, Anders and Huber, 2010 ) and a paired t test was compared to the log2 ratio of group means to generate the volcano plot ( Table S3 ).…”

Accurate genome-wide genotyping from archival tissue to explore the contribution of common genetic variants to pre-cancer outcomes

“…The modest cost and relative experimental simplicity of our approach, accompanied by a state-of-the-art imputation strategy can likely be scaled up provided diagnostic sections or left-over specimens can be found. Several large DCIS cohorts are generating mutational profiles, including some with lc-WGS and associated with clinical outcomes, which would be particularly suitable for validation in the future [17,43].…”

Molecular subtyping reveals uniqueness of prognosis in breast ductal carcinoma in situ patients with lumpectomy

“…The different gene expression profiles between DCIS and IBC reflect the need to classify DCIS by its own features [ 23 , 24 ]. However, attempts on classify DCIS by genomic signatures still need more studies for verification [ 25 ]. Although IHC-based subtyping of DCIS is derived from IBC, this kind of subtyping also provides insights into the nature of DCIS.…”