Comprehensive molecular portraits of human breast tumours

Abstract

Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

“…Basal-like and Human Epidermal Growth Factor Receptor 2-Enriched (HER2E) breast cancers had the highest TMB (TMB-Hi fraction, 37% and 38%, respectively) while Luminal A (LumA) tumors had the lowest TMB, with only 11.5% in the TMB-Hi fraction (Figure 3A) consistent with previous findings. 22 Among all tumors designated TMB-Hi, the FID subclass represented 44 women who exhibited a high OS rate of 100% at 10 years (Figure 1C); 66% of this excellent-outcome subclass was comprised of the more clinically aggressive subtypes: Basal-like, HER2E and Luminal B (LumB) (Figure 3B). Among the four major subtypes, LumA tumors comprised the majority of the TCGA cohort (53%; n = 495), with 88.5% of LumA tumors classifying with the TMB-Lo group.…”

“…22,23 We hypothesized that TMB, as a quantifier of tumor antigenicity, may influence the prognostic power of the immune subclasses. We posited that a better understanding of the relationship between TMB and the prognostic potential of the immune subclasses could allow one to distinguish tumors inherently vulnerable to immune rejection from those that escape immune recognition by exclusion of immune cells and/or failure to elicit a protective immune response.…”

Basal‐like breast cancer engages tumor‐supportive macrophages via secreted factors induced by extracellular S100A4

“…We used TCGA's BC cohort (Cancer Genome Atlas Network, 2012), n  = 1052, to assess the expression pattern of genes of interest in different subtypes of BC. Gene expression was assayed by RNA sequencing, RSEM (RNAseq by Expectation‐Maximization; Li et al ., 2010) normalized per gene.…”

SNMDA: A novel method for predicting microRNA‐disease associations based on sparse neighbourhood

“…Breast neoplasms is a common disease in women and also a serious threat to the health of women 49, 50. In the early years, the mortality of breast neoplasms is just inferior to lung neoplasms.…”