Metastatic Breast Cancer (France/IGR, 2016)

Overview

The brca_igr_2015 dataset (published 2016, cBioPortal identifier brca_igr_2015) comprises whole-exome sequencing of 216 tumor-normal pairs from metastatic breast cancer (mBC) patients enrolled in four prospective French trials: SAFIR01 (NCT01414933, n=86), SAFIR02 (NCT02299999, n=80), SHIVA (NCT01771458, n=35), and MOSCATO (NCT01566019, n=15). The dataset was deposited at EGA (EGAS00001001695) and at cBioPortal. It serves as the primary discovery resource for the Lefebvre et al. 2016 study identifying metastasis-specific driver genes in breast cancer, including ESR1 and RB1, and elevated APOBEC-mediated mutagenesis in HR+/HER2− metastatic disease.

Composition

  • 216 tumor-normal pairs from metastatic breast cancer patients.
  • Subtype distribution: 143 (66%) HR+/HER2−, 51 (24%) triple-negative (HR−/HER2−), 14 (6%) HER2+; 8 unclassified.
  • Median patient age 54 (range 26–82); 94% had received prior chemotherapy; 84% of HR+/HER2− patients had prior endocrine therapy.
  • Cancer type: BRCA (metastatic; bone metastases excluded due to DNA-extraction difficulty).
  • Sample sites: visceral and soft-tissue metastases (bone excluded).

Assays / panels (linked)

  • whole-exome sequencing — Illumina HiSeq 2500/4000 or NextSeq 500 with Agilent SureSelect All Exon V5 or Clinical Research Exome capture; mean coverage 83±18× (normal) and 122±15× (tumor).
  • Mutation calling: BWA-MEM alignment → GATK base recalibration → Mutect v1.1.7 (substitutions) + Scalpel v0.5.2 (indels); annotated with snpEff/snpSift.
  • Copy number: ExomeCNV + DNAcopy + GISTIC2 (amp >0.3, del <−0.3 log2 ratio).
  • Driver detection: MutSig, MuSiC, drGAP (FDR<0.1).
  • Mutational signatures: WTSI/Sanger framework + deconstructSigs over 13 COSMIC breast cancer signatures.
  • Cancer cell fraction: Sequenza tumor purity → ABSOLUTE-style framework.

Papers using this cohort

  • PMID:28027327 — Lefebvre et al. 2016. WES of 216 metastatic breast cancers from four prospective French trials; identified 12 significantly mutated drivers, ESR1 and RB1 as mBC-specific drivers, and 8 genes enriched in metastasis (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, AGRN) conferring 2-fold higher death hazard.

Notable findings derived from this cohort

  • Twelve significantly mutated driver genes in mBC by MutSig (FDR<0.1): TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, CDKN2A PMID:28027327.
  • ESR1 identified as a metastasis-specific driver (OR=29, 95% CI 9–155, p=1.2e-12); 22 mutations in hormone-receptor domain across 20/143 HR+/HER2− mBCs (14%), all in patients with prior endocrine therapy; 9 additional focal amplifications; combined 19% of HR+/HER2− mBC PMID:28027327.
  • RB1 loss-of-function in 5% of HR+/HER2− mBC vs <1% in HR+/HER2− early breast cancer; implies subset with primary resistance to CDK4/6 inhibitors PMID:28027327.
  • PALB2 somatic mutations enriched in mBC (4%) vs early breast cancer (0.1%; FDR=0.006); candidate population for PARP inhibitor trials PMID:28027327.
  • TSC1/TSC2 combined mutation rate 6.3% in HR+/HER2− mBC vs 0.7% in HR+/HER2− early breast cancer (p=0.0004); potential outlier responders to everolimus PMID:28027327.
  • APOBEC-mediated mutagenesis (signatures 2+13) nearly doubled in HR+/HER2− mBC vs primary TCGA samples (58.8% vs 31.9%, p<2e-16), linked to subclonal mutation acquisition under therapy PMID:28027327.
  • Eight-gene metastasis-enrichment signature (ESR1, FSIP2, AGRN, FRAS1, IGFN1, EDC4, OSBPL3, PALB2) associated with 2-fold higher death hazard on multivariate analysis (HR=1.97, 95% CI 1.34–2.89, p=0.001) PMID:28027327.

Sources

  • cBioPortal study: brca_igr_2015
  • EGA accession: EGAS00001001695

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