METABRIC Breast Cancer (brca_metabric)

Overview

METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) is a large-scale integrative genomic study of primary breast tumours from UK and Canadian tumour banks. The dataset comprises a discovery cohort of 997 tumours and an independent validation cohort of 995 tumours (total n = 1,992). Genomic profiling used Affymetrix SNP 6.0 arrays for copy-number and SNP genotyping; transcriptomic profiling used Illumina HT-12 v3 expression arrays. TP53 mutational status was assessed on a subset. Data are deposited at the European Genome-Phenome Archive (EGAS00000000083).

Composition

  • Discovery cohort: 997 primary breast tumours
  • Validation cohort: 995 primary breast tumours (total n = 1,992)
  • Cancer type: BRCA
  • ER-positive/LN-negative patients did not receive chemotherapy; ER-negative/LN-positive patients did; no HER2+ patients received trastuzumab during this study period

Assays / panels (linked)

Papers using this cohort

  • PMID:22522925
  • PMID:27161491 — Pereira et al. 2016, Nature Communications: targeted sequencing of 173 genes in 2,433 primary METABRIC tumors; primary expanded-driver characterization study.

Notable findings derived from this cohort

  • Joint integrative clustering of CNA and expression data identified 10 integrative clusters (IntClust 1-10) with distinct copy-number profiles and clinical outcomes, validated in the independent 995-tumour cohort PMID:22522925
  • IntClust 5 (ERBB2-amplified, n = 94) showed the worst disease-specific survival at 5 and 15 years (discovery HR 3.899, 95% CI 2.234-6.804) PMID:22522925
  • IntClust 2 (11q13/14 cis-acting, ER-positive, n = 45) was a high-risk subgroup driven by CCND1, EMSY, PAK1, and RSF1 amplifications (discovery HR 3.620, 95% CI 1.905-6.878) PMID:22522925
  • IntClust 4 (CNA-devoid, n = 167) had favourable prognosis and was enriched for lymphocytic infiltration and adaptive immune response signatures PMID:22522925
  • Germline variants and somatic CNAs influenced expression of >39% (11,198/28,609) of expression probes genome-wide PMID:22522925
  • Used as an external reference cohort for cross-species transcriptome comparison; 10.5% TP53/PIK3CA co-mutation rate cited to contextualize rat CRISPR model findings PMID:26437033
  • Served as the validation cohort for the three ILC transcriptional subtypes (reactive-like, immune-related, proliferative); reactive-like ILC had better DSS (HR=0.47, p=0.038) and OS (HR=0.50, p=0.023) than proliferative ILC PMID:26451490
  • Targeted sequencing of 173 genes in 2,433 METABRIC tumors (+ 650 normals) identified 40 Mut-driver genes; PIK3CA (40.1%), TP53 (35.4%), KMT2C (11.4%), GATA3 (11.1%) dominated; 45.2% of all tumours carried an Akt-pathway functional mutation. PMID:27161491
  • PIK3CA mutations carried distinct prognostic value by IntClust background: shorter BCSS specifically in ER+ IntClust1 (17q23-amp), IntClust2 (11q13–14-amp), and IntClust9 (8q24-amp), resolving contradictory prior PIK3CA literature. PMID:27161491
  • 22.6% of all tumours harboured mutations in chromatin-function Mut-drivers (KMT2C, ARID1A, NCOR1, CTCF, KDM6A, PBRM1, TBL1XR1). PMID:27161491
  • High MATH (intra-tumour heterogeneity) scores associated with worse BCSS in ER+ (P=0.003) but not ER-; IntClust2 had paradoxically low MATH despite poor outcome, due to the CCND1/PAK1 11q13–14 co-amplification being a single early clonal event. PMID:27161491

Sources

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