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Cancer results from alterations at essential genomic sites and is characterized by uncontrolled cell proliferation, invasion and metastasis. Identification of driver genes of metastatic progression is essential, as metastases, not primary tumors, are fatal. To gain insight into the mutational concordance between different steps of malignant progression we performed exome sequencing and validation with targeted deep sequencing of successive steps of malignant progression from pre-invasive stages to asynchronous distant metastases in six breast cancer patients.

Using the ratio of non-synonymous to synonymous mutations, a surprisingly large number of cancer driver genes, ranging between 3 and 145, were estimated to confer a selective advantage in the studied primary tumors. We report a substantial amount of metastasis specific mutations and a number of novel putative metastasis driver genes. Most notable are the DCC, ABCA13, TIAM2, CREBBP, BCL6B and ZNF185 genes, mainly mutated exclusively in metastases and highly likely driver genes of metastatic progression.

We find different genes and pathways to be affected at different steps of malignant progression. The Adherens junction pathway is affected in four of the six studied patients and this pathway most likely plays a vital role in the metastatic process.

Introduction Cancer evolves through the stochastic, cumulative acquisition of driver mutations disrupting key pathways leading to the hallmarks of cancer []. A cancer driver mutation confers a selective advantage, while passenger mutations are coexisting mutations in the successfully expanding clones []. The cancer genome evolves dynamically influenced by the generation of additional mutations and selective forces acting on cancer clones, the latter being time and site dependent. Tyagach voljvo prodazha v bishkeke. The term oncogene addiction [] describes the cancer cell dependence of particular driver genes for maintenance of the malignant phenotype and provides the rationale for targeted therapy. One of the major challenges in cancer genetics is to identify cancer driver genes. Mutations in the coding region can be divided into synonymous, also known as silent mutations, and non-synonymous mutations. Typically, nucleotide substitutions in the third codon position are silent, whereas substitutions in the first and second codon positions result in an amino acid change.

The ratio of non-synonymous to synonymous mutations (NS:S ratio) has been used as a reliable indicator of selection. Sluzhebnaya zapiska o vvedenii novoj shtatnoj edinici obrazec. Two factors influence the NS:S ratio, including the rate of creation and the selective forces acting on them. In the absence of selection, non-synonymous and synonymous mutations are equally likely to persist [] and thus the NS:S ratio can indicate whether or not selection is occurring. The metastatic process is highly complex and not yet fully understood. The main bottleneck for metastasis formation is believed to be colonization at the distant site []. A solid tumor is suggested to infiltrate into the circulatory system one million cancer cells per day [] and tumor cells are found to disseminate systemically even from pre-invasive tissue [].