The landscape of cancer genes and mutational processes in breast cancer

Authors

Stephens PJ

Tarpey PS

Davies H

Van Loo P

Greenman C

Wedge DC

Nik-Zainal S

Martin S

Varela I

Bignell GR

Yates LR

Papaemmanuil E

Campbell PJ

Futreal PA

Stratton MR

Doi

10.1038/nature11017

PMID: 22722201 · DOI: 10.1038/nature11017 · Journal: Nature (2012)

TL;DR

Whole-exome sequencing and copy number analysis of 100 primary breast cancers identified 7,241 somatic mutations and revealed driver mutations in at least 40 cancer genes, including nine newly established cancer genes (AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1, TBX3). The study found 73 different combinations of mutated cancer genes across the 100 tumours and characterized multiple distinct mutational processes, including a TpC-dinucleotide signature present in approximately 10% of cases.

Cohort & data

  • 100 primary breast cancers (79 ER+, 21 ER-) with matched normal DNA from the brca_sanger cohort.
  • Cancer type: BRCA.
  • Whole-exome sequencing (whole-exome-seq) of 21,416 protein-coding genes and 1,664 microRNAs.
  • Copy number analysis using Affymetrix SNP6.0 (affymetrix-snp6) with ASCAT v2.1.
  • Follow-up validation sequencing of selected genes in an additional 250 breast cancers.

Key findings

  • 7,241 somatic point mutations identified: 6,964 single-base substitutions (4,737 missense, 422 nonsense, 158 essential splice site, 8 stop codon read-through, 1,637 silent) and 277 small indels.
  • 1,712 homozygous deletions and 1,751 amplification events detected by copy number analysis.
  • Driver mutations identified in at least 40 cancer genes; seven genes (TP53, PIK3CA, ERBB2, MYC, FGFR1/ZNF703, GATA3, CCND1) were mutated in >10% of cases, collectively contributing 58% of driver mutations (144/250).
  • 73 different combinations of mutated cancer genes observed across 100 tumours; most breast cancers differed from all others.
  • Maximum 6 mutated cancer genes per tumour; 28 cases showed only a single driver.
  • Nine new cancer genes established: AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1, TBX3.
  • Strong positive correlations between total substitution number and mitosis score (P = 0.0002) and tubule score (P = 0.002).
  • A distinctive mutational signature characterized by C mutations at TpC dinucleotides present in ~10% of tumours, with strand bias suggesting transcription-coupled nucleotide excision repair involvement.
  • C>T at CpG substitutions showed strong positive correlation with age at diagnosis in ER- cancers (P = 1.2 x 10^-7) but not in ER+ cancers (P = 0.27).

Genes & alterations

  • MAP3K1: Truncating mutations in 6% of breast cancers, predominantly ER+; inactivates JUN kinase signalling pathway.
  • MAP2K4: Known recessive cancer gene with inactivating mutations; downstream target of MAP3K1.
  • MAP3K13: Truncating and non-synonymous mutations; activates MAP2K7 in JUN kinase pathway.
  • AKT2: Activating Glu17Lys missense mutation identical to recurrent AKT1 E17K; dominantly acting oncogene.
  • AKT1: Known activating mutations in breast cancer.
  • PIK3CA: Mutated in >10% of cases; AKT pathway activation.
  • PTEN: Inactivating mutations leading to AKT activation.
  • NCOR1: Truncating mutations and homozygous deletions; participates in oestrogen receptor alpha transcriptional repression.
  • SMARCD1: Inactivating mutations; SWI/SNF chromatin remodelling complex component.
  • ARID1B: Inactivating mutations; SWI/SNF complex component.
  • CDKN1B: Three truncating mutations and a missense mutation; inhibitor of cyclin E/CDK2 and cyclin D/CDK4.
  • CASP8: Three truncating mutations; predicted to abrogate apoptosis.
  • TBX3: Six tumours with mutations; T-box transcription factor regulating stem cell pluripotency; recurrent in-frame deletions at Thr210 and Asn212.
  • TP53, ERBB2, MYC, FGFR1, GATA3, CCND1: Each mutated in >10% of cases.
  • KRAS, NF1, APC, ARID1A, ARID2, ASXL1, BAP1, SETD2, SF3B1, SMAD4, STK11: Driver mutations from known cancer genes in other tumour types.
  • CDH1, RB1, BRCA1: Previously known breast cancer driver genes confirmed.
  • MDM2: Driver amplifications identified in copy number analysis.

Clinical implications

  • Approximately half of breast cancers may have abrogation of JUN kinase signalling through mutations in MAP3K1, MAP2K4, MAP3K13, or AKT/PIK3CA/PTEN pathway activation, suggesting potential therapeutic vulnerability.
  • The substantial genetic diversity (73 combinations of driver genes in 100 tumours) underscores the challenge of personalized treatment approaches.
  • Three newly identified cancer genes (MAP3K1, CASP8, TBX3) carry inherited common variants conferring small increased risks of breast cancer, linking somatic and germline genetics.
  • The TpC mutational signature in ~10% of tumours may indicate prior exposure to a bulky DNA-damaging agent, potentially relevant for understanding aetiology.

Limitations & open questions

  • Cohort of 100 cases likely underestimates the true number of cancer genes and driver mutations per case.
  • The biological consequences of JUN kinase pathway inactivation remain incompletely understood.
  • The causal relationship between high tumour grade and increased mutation number is unclear (mutations may be consequence rather than cause of aggressive biology).
  • The basis for the pronounced difference in CpG mutation-age correlation between ER+ and ER- cancers is unexplained.
  • The identity of the bulky DNA-damaging agent responsible for the TpC mutational signature remains unknown.
  • No drug response or treatment outcome data were reported.

Citations from this paper used in the wiki

  • “Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3.” (Abstract)
  • “Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes.” (Abstract)
  • “Seven of the 40 cancer genes (TP53, PIK3CA, ERBB2, MYC, FGFR1/ZNF703, GATA3 and CCND1) were mutated in more than 10% of cases. Collectively these contributed 58% of driver mutations (144 of 250).” (Results)
  • “Somatic mutations in MAP3K1 were observed in 6% of breast cancers, predominantly in ER+ cases.” (Results)
  • “Because AKT phosphorylates and inhibits MAP2K4 and mutations in PIK3CA and PTEN can result in AKT activation, about half of breast cancers may have abrogation of JUN kinase signalling.” (Results)

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