The landscape of cancer genes and mutational processes in breast cancer

Abstract

All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.

Figure 1. New cancer genes established in this study and involvement of the JUN kinase signalling pathway

a, Representations of the protein-coding sequences and major domains in cancer genes established in this study. Somatic mutations are shown as circles: truncating (red), essential splice site (blue), missense (green) and in-frame indel (yellow). The red lines indicate the positions of large homozygous deletions. aa, amino acids. b, Pathways regulating the JUN kinases MAP2K7 and MAP2K8, indicating genes with mutations in this series. Genes in green are activated by mutations, whereas genes in red are inactivated.

Figure 2. The landscape of driver mutations in breast cancer

Each of the 40 cancer genes in which a driver mutation or copy number change has been identified is listed down the left-hand side. The number of mutations in each gene in the 100 tumours is shown (rows), as is the number of driver mutations in each breast cancer (columns). Point mutations and copy number changes are coloured red and blue, respectively.

Figure 3. The variation in numbers and types of mutation between individual breast cancers

a, Numbers of small indels and base substitutions in the protein-coding exons of each of the 100 breast cancers studied. The cases are ranked according to the number of base substitutions. *Breast cancer PD4120 (see main text). b, Mutation spectrum of four primary tumours with diverse mutational patterns.

Figure 4. The mutational signature of ER1 breast cancer PD4120

a, The mutational spectrum. b, The sequence context of C → T, C → G and C → A mutations. The central blue bar indicates the position of the mutated cytosine and the bases 5′ and 3′ are numbered on the horizontal axis. c, Strand bias of mutations showing substitutions at C bases and at T bases according to whether they are on the transcribed (T) or untranscribed (U) strands of the genes screened.

Figure 5. The relationship between age at breast cancer diagnosis and all substitutions, and for C → T substitutions at CpG sites

a, b, Data from the 79 ER+ breast cancers. c, d, Data from the 21 ER− breast cancers.