TY - JOUR
T1 - Subclonal mutation selection in mouse lymphomagenesis identifies known cancer loci and suggests novel candidates
AU - Webster, Philip
AU - Dawes, Joanna
AU - Dewchand, Hamlata
AU - Takacs, Katalin
AU - Iadarola, Barbara
AU - Bolt, Bruce
AU - Caceres Silva, Juan
AU - Kaczor, Jakub
AU - Dharmalingam, Gopuraja
AU - Dore, Marian
AU - Game, Laurence
AU - Adejumo, Thomas
AU - Elliott, James
AU - Naresh, Kikkeri
AU - Karimi, Mohammad
AU - Rekopoulou, Katerina
AU - Tan, Ge
AU - Paccanaro, Alberto
AU - Uren, Anthony
PY - 2018/7/9
Y1 - 2018/7/9
N2 - Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of retrovirus driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel, novel statistical approaches for identifying driver mutations and yields a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening two BCL2 transgenic models confirms known drivers of human B-cell non- Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features also gives robust identification of known cancer genes independently of local variance in mutation density. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.
AB - Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of retrovirus driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This scale of data allows novel, novel statistical approaches for identifying driver mutations and yields a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. We also demonstrate negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Screening two BCL2 transgenic models confirms known drivers of human B-cell non- Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance and MHC loci. Correlating mutations with genotypic and phenotypic features also gives robust identification of known cancer genes independently of local variance in mutation density. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.
U2 - 10.1038/s41467-018-05069-9
DO - 10.1038/s41467-018-05069-9
M3 - Article
SN - 2041-1723
VL - 9
SP - 1
EP - 14
JO - Nature Communications
JF - Nature Communications
M1 - 2649
ER -