Abstract
Abstract
KRAS
and
TP53
are frequently mutated in non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide. The most common event at the
TP53
locus is mutation/loss of one allele and retention of a wild-type allele, which confers better survival outcomes than complete
TP53
loss. To study the contribution of
TP53
heterozygosity, we generated a murine lung tumor model with a
KrasG12D
mutation and intact (
K
) or single-allele loss (
KP+/
-) of
Trp53 and
compared it with publicly available complete loss (
KP
) data. K and KP+/− mice lived longer than KP mice, paralleling clinical survival data. Single-cell transcriptomic analysis of tumor-burdened lungs indicated that
Trp53
heterozygosity expanded transcriptional plasticity that was not present in K and KP tumors. Genomic instability was also higher in KP+/− mice relative to the KP genotype.
Trp53
gene dosage, thus, regulates phenotypic plasticity and evolutionary trajectories of tumor states across K, KP+/−, and KP tumors. Murine KP+/− tumor signatures and copy-number profiles were present in human NSCLC datasets. Two of these signatures correlated with better and worse patient survival outcomes, respectively.
TP53
heterozygosity in
KRAS
-mutant lung cancers presents a distinct genomic landscape that should be taken into account in the development of novel therapeutic strategies.