The molecular landscape of breast ductal carcinoma in situ

ABBA MC; GONG T; LU Y; LEE J; ZHONG Y; LACUNZA E; BUTTI M; TAKATA Y; GADDIS S; SHEN J; ESTECIO MR; SAHIN AA; ALDAZ CM

Bariloche

Simposio; 3° South American Spring Symposium in Signal Transduction and Molecular Medicine (SISTAM2015); 2015

Ductal carcinoma in situ (DCIS) is a non-invasive precursor lesion to invasive ductal breast carcinomas (IDC). The recent characterization of the breast cancer molecular landscape achieved by the TCGA project provides key insights of the biological process and pathways operating in each IDC subtypes. Here, we performed full exome, transcriptome and methylome analysis of normal and pure high-grade DCIS samples, providing a comprehensive catalogue of genomics, epigenomics and gene pathway changes occurring at a pre-invasive stage. Mutations affecting cancer driver genes were found in > 50% of DCIS lesions. Significantly, 83% of lesions displayed numerous large chromosomal copy numberalterations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups a High-risk DCIS (HR-DCIS) and a Moderate-risk DCIS (MR-DCIS) group based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The HR-DCIS group displayed signatures characteristic of activated Treg cells and immune complexes indicative of a tumor-associated immune suppressive phenotype. Furthermore, we identified specific coding and non-coding RNA signatures andhypermethylation profiles likely involved in the natural progression of pre-malignant breast lesions.