Sequence analysis of mutations and translocations across breast cancer subtypes

Authors

Banerji S

Cibulskis K

Rangel-Escareno C

Brown KK

Carter SL

Frederick AM

Lawrence MS

Sivachenko AY

Sougnez C

Zou L

Meyerson M

Getz G

Hidalgo-Miranda A

Toker A

Doi

10.1038/nature11154

PMID: 22722202 · DOI: 10.1038/nature11154 · Journal: Nature (2012)

TL;DR

Whole-exome sequencing of 103 and whole-genome sequencing of 22 treatment-naive breast cancers across all major expression subtypes identified six significantly mutated genes including the novel discovery of recurrent inactivating CBFB mutations and RUNX1 deletions. The study also discovered a recurrent MAGI3-AKT3 gene fusion enriched in triple-negative breast cancer that constitutively activates Akt kinase and is sensitive to ATP-competitive Akt inhibitors.

Cohort & data

  • 108 primary, treatment-naive breast carcinoma/normal DNA pairs from patients in Mexico (n=54) and Vietnam (n=49)
  • Cancer type: BRCA (Luminal A, Luminal B, Her2-enriched, basal-like subtypes)
  • Dataset: brca_broad
  • 103 pairs with whole-exome sequencing (33 Mb target, median 85.1% at 30x); 22 pairs with whole-genome sequencing (30x)
  • 235 additional samples screened for MAGI3-AKT3 fusion by RT-PCR
  • Mutation calling with MutSig; copy number with ABSOLUTE/HAPSEG; rearrangements with dRanger

Key findings

  • Overall non-silent mutation rate: 1.27 per Mb (range 0.31-8.05), consistent with prior breast cancer reports
  • Six significantly mutated genes (FDR < 0.1): TP53 (27%), PIK3CA (27%), AKT1 (6%), GATA3 (4%), MAP3K1 (3%), CBFB (4%)
  • CBFB identified as significantly mutated in breast cancer for the first time – 4 ER+ samples with truncating mutations (1 nonsense, 3 frameshift)
  • Two additional cases harbour homozygous deletions of RUNX1, the DNA-binding partner of CBFB
  • AKT1 and PIK3CA mutations were mutually exclusive
  • 21 of 31 TP53 mutations were homozygous; TP53 mutations associated with higher mutation rate (p = 0.0079)
  • ERBB2 harboured activating S310F mutations in 2 samples without ERBB2 amplification
  • Recurrent MAGI3-AKT3 fusion found in 8/235 (3.4%) additional samples, including 5/72 (6.9%) triple-negative cases

Genes & alterations

Gene Alteration Finding
PIK3CA Missense (helical E542/E545 40%, kinase H1047 47%) 27% of samples; activates PI3K pathway
TP53 Missense, nonsense (distributed across gene) 27% of samples; 21/31 homozygous
CBFB Nonsense + frameshift truncations 4% of ER+ samples; first report of significant recurrence
RUNX1 Homozygous deletion 2 cases; partner of CBFB in transcription factor complex
AKT1 E17K (PH domain) 6% of samples; activating, mutually exclusive with PIK3CA
GATA3 Frameshift (3 novel) + splice-site 4% in luminal tumours
MAP3K1 Frameshift, nonsense, missense + homozygous deletion 3% in ER+ disease; pattern consistent with recessive inactivation
ERBB2 S310F activating mutation 2 samples without amplification
AKT3 MAGI3-AKT3 fusion (intron 1 breakpoint) Constitutive Akt activation; enriched in triple-negative
MAGI3 MAGI3-AKT3 fusion + hemizygous deletion Loss of PTEN-binding PDZ domain
PTEN Functional loss via MAGI3 disruption MAGI3 PDZ domain required for PTEN inhibition of PI3K

Clinical implications

  • The MAGI3-AKT3 fusion produces constitutive Akt phosphorylation that is inhibited by ATP-competitive Akt inhibitor GSK-690693 but NOT by allosteric PH-domain inhibitor MK-2206, suggesting fusion-positive triple-negative breast cancers should be treated with ATP-competitive (not allosteric) Akt inhibitors
  • CBFB/RUNX1 inactivation highlights the role of differentiation transcription factors in breast cancer pathogenesis and may represent a therapeutic vulnerability
  • ERBB2 S310F activating mutations occur without amplification, suggesting mutation-based patient selection for anti-HER2 therapy

Limitations & open questions

  • Sample size (n=103 exomes) limits power to detect low-frequency driver genes
  • Only 46% of indels among significantly mutated genes confirmed (vs 94% for point mutations), suggesting indel calling sensitivity was limited
  • MAGI3-AKT3 fusion frequency (6.9% in triple-negative) based on RT-PCR screening of 72 samples; larger cohorts needed to refine prevalence
  • Functional validation of CBFB/RUNX1 loss in breast tumorigenesis not performed
  • No clinical outcome data reported; prognostic significance of findings not assessed
  • Cohort is ethnically specific (Mexican and Vietnamese); generalizability to other populations unclear

Citations from this paper used in the wiki

  • “Six genes were found to be mutated with significant recurrence in the 103 whole exome sequenced samples… One gene, CBFB is identified for the first time as a significantly mutated gene in breast cancer or any other epithelial cancer”
  • “The fusion was present in 8 of the 235 samples, including 5 out of 72 triple negative (ER-/PR-/Her2-) samples”
  • “Phosphorylation of GSK3beta by the MAGI3-AKT3 fusion can be inhibited with an ATP-competitive small molecule Akt inhibitor, GSK-690693, but not with an allosteric Akt inhibitor, MK-2206, that interacts with the PH domain of Akt”
  • “AKT1 and PIK3CA mutations, which activate the phosphatidylinositol-3-kinase (PI3K) pathway, were mutually exclusive in our dataset”

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