<p>Supplementary Table S1: Overview of the TNBC616 cohort. Supplementary Table S2: Overview of all cohorts, including the number of TNBCs, doi and accessions. Supplementary Table S3: List of gene sets identified by CONEXIC in Guy's TNBC. Supplementary Table S4: List of gene sets identified by CONEXIC in METABRIC TNBC. Supplementary Table S5: Table of modulatory genes identified by CONEXIC in Guy's TNBC. Supplementary Table S6: Table of modulatory genes identified by CONEXIC in METABRIC TNBC. Supplementary Table S7: List of significantly enriched GO biological processes in Guy's-set 33. Supplementary Table S8: List of significantly enriched GO biological processes in METABRIC-set 15. Supplementary Table S9: List of significantly enriched GO biological processes in Guy's-set 27.</p>
ARTICLE ABSTRACT
The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1, and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors (∼50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.
