Genomic, Transcriptomic, Epigenetic, and Immune Profiling of Mucinous Breast Cancer

: While invasive ductal breast cancer (IDC) represents the most common histological type of breast cancer, minor subtypes exist such as mucinous breast cancer (MuBC). MuBC patients are generally older and have an excellent prognosis while at the pathological level, these tumors present with cells floating in extracellular mucin. To unravel the molecular architecture of MuBC, we applied low pass whole genome sequencing and microscopic evaluation of stromal tumor infiltrating lymphocytes (TIL) to 30 MuBC from a retrospective institutional cohort. We further analyzed two independent datasets from the International Cancer Genomics Consortium (ICGC) and The Cancer Genome Atlas (TCGA). Genomic data (n = 26 MuBC, n = 535 estrogen-receptor (ER) positive/HER2-negative IDC), methylation data (n = 28 MuBC, n = 529 ER-positive/HER2-negative IDC) and transcriptomic data (n = 27 MuBC, n = 467 ER-positive/HER2-negative IDC) were analyzed. MuBC was characterized by low TIL levels (median = 0.0%, average = 3.4%, 95% CI = 1.9-4.9%). Compared to IDC, MuBC had a lower genomic instability (P = .01, two-sided Mann-Whitney U test), and a decreased prevalence of PIK3CA mutations (39.7% in IDC vs. 6.7% in MuBC, P = .01 in ICGC; and 34.8% vs 0.0%, P = .02 in TCGA, two-sided Fisher's exact test). Finally, our report identifies aberrant DNA methylation of MUC2 as a possible cause of extracellular production of mucin in MuBC.