TY - JOUR
T1 - Identification of metastasis driver genes by massive parallel sequencing of successive steps of breast cancer progression
AU - Krøigård, Anne Bruun
AU - Larsen, Martin Jakob
AU - Lænkholm, Anne-Vibeke
AU - Knoop, Ann S
AU - Jensen, Jeanette Dupont
AU - Bak, Martin
AU - Mollenhauer, Jan
AU - Thomassen, Mads
AU - Kruse, Torben A
PY - 2018/1
Y1 - 2018/1
N2 - 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.
AB - 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.
KW - Breast Neoplasms/genetics
KW - Female
KW - High-Throughput Nucleotide Sequencing/methods
KW - Humans
KW - Neoplasm Metastasis/genetics
U2 - 10.1371/journal.pone.0189887
DO - 10.1371/journal.pone.0189887
M3 - Journal article
C2 - 29293529
SN - 1932-6203
VL - 13
JO - PLoS Computational Biology
JF - PLoS Computational Biology
IS - 1
M1 - e0189887
ER -
