Publications

@article{Dionellis2021-py,

title = {Genomic instability profiles at the single cell level in mouse 

 colorectal cancers of defined genotypes},

author = {Vasilis S Dionellis and Maxim Norkin and Angeliki Karamichali and Giacomo G Rossetti and Joerg Huelsken and Paloma Ordonez-Moran and Thanos D Halazonetis},

year  = {2021},

date = {2021-03-01},

journal = {Cancers (Basel)},

volume = {13},

number = {6},

pages = {1267},

publisher = {MDPI AG},

abstract = {The genomes of many human CRCs have been sequenced, revealing a 

 large number of genetic alterations. However, the molecular 

 mechanisms underlying the accumulation of these alterations are 

 still being debated. In this study, we examined colorectal 

 tumours that developed in mice with Apclox/lox, LSL-KrasG12D, 

 and Tp53lox/lox targetable alleles. Organoids were derived from 

 single cells and the spectrum of mutations was determined by 

 exome sequencing. The number of single nucleotide substitutions 

 (SNSs) correlated with the age of the tumour, but was unaffected 

 by the number of targeted cancer-driver genes. Thus, tumours 

 that expressed mutant Apc, Kras, and Tp53 alleles had as many 

 SNSs as tumours that expressed only mutant Apc. In contrast, the 

 presence of large-scale (\>10 Mb) copy number alterations (CNAs) 

 correlated strongly with Tp53 inactivation. Comparison of the 

 SNSs and CNAs present in organoids derived from the same tumour 

 revealed intratumoural heterogeneity consistent with genomic 

 lesions accumulating at significantly higher rates in tumour 

 cells compared to normal cells. The rate of acquisition of SNSs 

 increased from the early stages of cancer development, whereas 

 large-scale CNAs accumulated later, after Tp53 inactivation. 

 Thus, a significant fraction of the genomic instability present 

 in cancer cells cannot be explained by aging processes occurring 

 in normal cells before oncogenic transformation.},

keywords = {cancer drivers, colorectal cancer, copy number alterations, exome sequencing, genomic instability, mouse models, mutational   signature, Organoids, single cell, single nucleotide variants},

pubstate = {published},

tppubtype = {article}

}