Deletions linked to TP53 loss drive cancer through p53-independent mechanisms

Abstract

Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a ‘loss of heterozygosity’ deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.

Lung tumors with distinct p53 mutations respond similarly to p53 targeted therapy but exhibit genotype-specific statin sensitivity

“…S1D). Hence, wild-type p53 is able to retain a significant part of its transcriptional activity in mutant Targeting p53 mutant lung tumors p53 lung tumor cells, including the induction of some of its key targets, providing a potential explanation for the high frequency of p53 LOH in mutant tumors (Baker et al 1990;Mitsudomi et al 2000;Zienolddiny et al 2001;Liu et al 2016). …”

“…Despite this, its potential impact on mutant p53 lung tumors has not yet been addressed. Interestingly, p53 mutant tumors, including lung adenocarcinomas, often display loss of heterozygosity (LOH) (Baker et al 1990;Mitsudomi et al 2000;Zienolddiny et al 2001;Liu et al 2016), suggesting that wild-type p53 activity may be counterselected even in the presence of the mutant. Hence, the extent of DN effects of mutant p53 in vivo and, conversely, those of wildtype p53 in mutant lung tumors remain unclear.…”

Imaging Cobalamin Uptake within Malignant Breast Tumors In Vivo

“…Finally, on the cytogenetic bands encoding the Cbl receptor protein genes: TC-R (CD320) on 19p13.2, MEG (LRP2) on 2q31.1, cubilin (CUBN) on 10p13, amnionless (AMN) on 14q32.32, and ASGP-R (ASGR1 and ASGR2) on 17p13.1, are foci of gene amplification or mutations that support breast tumor progression, for example, the amplification of DNMT1 on 19p13.2 [47], PDK1 on 2q31.1 [48], CAMK1D on 10p13 [49], and AKT1 on 14q32.32 [50] and mutations of TP53 on 17p13.1 [51]. Intriguingly, with the concentration of sCD320 increasing in urine and serum during pregnancy, it suggests that the protein fragment may be a biomarker for cellular proliferation [52].…”

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…2,59 The detrimental effect of 17p 2 is implicated to reflect a joined impact of TP53 loss and the reduced dosage of linked tumor suppressor genes. 60 Notably, biallelic loss of TP53 is a rare event in AML that might be addressed by gene transfer therapy, which is currently under preclinical evaluation. 13 …”