The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Abstract

Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers1 and are a tumour type defined by exclusion, for which comprehensive landscapes of somatic mutation have not been determined. Here we show in 104 early TNBC cases, that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some exhibiting only a handful of somatic aberrations in a few pathways, whereas others contain hundreds of somatic events and multiple pathways implicated. Integration with matched whole transcriptome sequence data revealed that only ~36% of mutations are expressed. By examining single nucleotide variant (SNV) allelic abundance derived from deep re-sequencing (median >20,000 fold) measurements in 2414 somatic mutations, we determine for the first time in an epithelial tumour, the relative abundance of clonal genotypes among cases in the population. We show that TNBC vary widely and continuously in their clonal frequencies at the time of diagnosis, with basal subtype TNBC2,3 exhibiting more variation than non-basal TNBC. Although p53 and PIK3CA/PTEN somatic mutations appear clonally dominant compared with other pathways, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal and cell shape/motility proteins occurred at lower clonal frequencies, suggesting they occurred later during tumour progression. Taken together our results show that future attempts to dissect the biology and therapeutic responses of TNBC will require the determination of individual tumour clonal genotypes.

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

“…Triple negative breast cancer (TNBC), which comprises the majority of Basal-like tumors, is characterized by relatively high TMB. 35 The objective response rate in a recently reported phase Ib clinical trial of programmed-cell death protein 1 (PD-1) immune checkpoint inhibition in heavily pre-treated TNBC patients with PD-L1 expressing tumors was only 18.5%. 36 In our study, 36% of Basal-like tumors were classified as TMB-Hi, and 24% of these tumors (9% overall) belonged to the FID subclass, suggesting by extrapolation that only a relatively small fraction of these tumors may be particularly immunogenic.…”

Navigating cancer network attractors for tumor-specific therapy

“…1d). This dynamic nature of signaling networks could, at least in part, explain why all mutant proteins do not seem to be expressed at a given point in time 30 , if a substantial part of the proteome is so dynamic that it is expressed only when the cell senses a specific cue. Moreover, according to a general principle of complex systems introduced in the 1980s 31,32 , dynamic cellular networks can only exist in a finite number of states, owing to the constraints that interactions between nodes impose on one another.…”

Functional screening identifies MCT4 as a key regulator of breast cancer cell metabolism and survival

“…One common feature within the complex genetic landscape of breast cancer is the activation of the PI3K-Akt signalling pathway [9][10][11]. Akt is one of the main drivers of anabolic metabolism and activates glucose MCT4 supports breast cancer cell survival 153 uptake, glycolysis and lipid synthesis [15].…”