The landscape of cancer genes and mutational processes in breast cancer

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.

[1]  Daniel G. Miller.  On the nature of susceptibility to cancer. The presidential address , 1980, Cancer.

[2]  Thorsten Heinzel,et al.  Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor , 1995, Nature.

[3]  H. Koeffler,et al.  p27/Kip1 mutation found in breast cancer. , 1996, Cancer research.

[4]  J. Seidman,et al.  Mutations in human TBX3 alter limb, apocrine and genital development in ulnar-mammary syndrome , 1997, Nature Genetics.

[5]  R. Hruban,et al.  Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. , 1998, Cancer research.

[6]  Eric R. Ziegel,et al.  Generalized Linear Models , 2002, Technometrics.

[7]  Mi-Sung Kim,et al.  Akt (Protein Kinase B) Negatively Regulates SEK1 by Means of Protein Phosphorylation* , 2002, The Journal of Biological Chemistry.

[8]  T. Hubbard,et al.  A census of human cancer genes , 2004, Nature Reviews Cancer.

[9]  Gen Sheng Wu.  The functional Interactions Between the MAPK and p53 Signaling Pathways , 2004, Cancer biology & therapy.

[10]  M. Stratton,et al.  Statistical Analysis of Pathogenicity of Somatic Mutations in Cancer , 2006, Genetics.

[11]  A. Ashworth,et al.  Signalling Pathways Implicated in Early Mammary Gland Morphogenesis and Breast Cancer , 2006, PLoS genetics.

[12]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[13]  Spyro Mousses,et al.  A transforming mutation in the pleckstrin homology domain of AKT1 in cancer , 2007, Nature.

[14]  L. Mullenders,et al.  Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects , 2008, Cell Research.

[15]  William C Hahn,et al.  Oncogenic transformation and experimental models of human cancer. , 2008, Frontiers in bioscience : a journal and virtual library.

[16]  Wolfgang Link,et al.  The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. , 2008, Current cancer drug targets.

[17]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[18]  J. Turchi,et al.  Eukaryotic nucleotide excision repair: from understanding mechanisms to influencing biology , 2008, Cell Research.

[19]  Ludger Hengst,et al.  The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy , 2008, Nature Reviews Cancer.

[20]  D. Reisman,et al.  The SWI/SNF complex and cancer , 2009, Oncogene.

[21]  M. Stratton,et al.  The cancer genome , 2009, Nature.

[22]  Richard Durbin,et al.  Sequence analysis Fast and accurate short read alignment with Burrows – Wheeler transform , 2009 .

[23]  Kai Ye,et al.  Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads , 2009, Bioinform..

[24]  E. Lander,et al.  Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling , 2010, Proceedings of the National Academy of Sciences.

[25]  Yuriy L. Orlov,et al.  Tbx3 improves the germ-line competency of induced pluripotent stem cells , 2010, Nature.

[26]  Rony Seger,et al.  The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. , 2010, Methods in molecular biology.

[27]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[28]  Tian-Li Wang,et al.  Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma , 2010, Science.

[29]  Douglas F Easton,et al.  Genome-wide association studies in common cancers--what have we learnt? , 2010, Current opinion in genetics & development.

[30]  Richard Durbin,et al.  Fast and accurate long-read alignment with Burrows–Wheeler transform , 2010, Bioinform..

[31]  C. Perou,et al.  Allele-specific copy number analysis of tumors , 2010, Proceedings of the National Academy of Sciences.

[32]  Richard A. Moore,et al.  ARID1A mutations in endometriosis-associated ovarian carcinomas. , 2010, The New England journal of medicine.

[33]  P. A. Futreal,et al.  Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma , 2010, Nature.

[34]  K. Merrell,et al.  Differential recruitment of nuclear receptor coregulators in ligand-dependent transcriptional repression by estrogen receptor-α , 2011, Oncogene.

[35]  N. Dalay,et al.  Molecular Analysis of the P27/Kip1 Gene in Breast Cancer , 2012, Molecular Diagnosis.

[36]  Michael Jones,et al.  Genome-wide association analysis identifies three new breast cancer susceptibility loci , 2012, Nature Genetics.