Mouse model and human patient data reveal critical roles for Pten and p53 in suppressing POLE mutant tumor development

Abstract

Mutations in the exonuclease domain of POLE are associated with tumors harboring very high mutation burdens. The mechanisms linking this significant mutation accumulation and tumor development remain poorly understood. Pole+/P286R;Trp53+/– mice showed accelerated cancer mortality compared to Pole+/P286R;Trp53+/+ mice. Cells from Pole+/P286R mice showed increased p53 activation, and subsequent loss of p53 permitted rapid growth, implicating canonical p53 loss of heterozygosity in POLE mutant tumor growth. However, p53 status had no effect on tumor mutation burden or single base substitution signatures in POLE mutant tumors from mice or humans. Pten has important roles in maintaining genome stability. We find that PTEN mutations are highly enriched in human POLE mutant tumors, including many in POLE signature contexts. One such signature mutation, PTEN-F341V, was previously shown in a mouse model to specifically decrease nuclear Pten and lead to increased DNA damage. We found tumors in Pole+/P286R mice that spontaneously acquired PtenF341V mutations and were associated with significantly reduced nuclear Pten and elevated DNA damage. Re-analysis of human TCGA (The Cancer Genome Atlas) data showed that all PTEN-F341V mutations occurred in tumors with mutations in POLE. Taken together with recent published work, our results support the idea that development of POLE mutant tumors may involve disabling surveillance of nuclear DNA damage in addition to POLE-mediated hypermutagenesis.

Candidate variants in DNA replication and repair genes in early-onset renal cell carcinoma patients referred for germline testing

“…Pt #2 with a POLE variant also harbored candidate variants in BRCA2, PDGFRA. In other studies, hypermutant ccRCCs also carried mutations in TP53, PTEN, VHL, and UNC5C [ 58 , 59 ]. POLE and POLD1 are currently not considered classical tumor suppressor genes, and LOH is typically not observed in tumors.…”

Signatures of defective DNA repair and replication in early-onset renal cancer patients referred for germline genetic testing

“…Pt#2 with a POLE candidate PGV also harbored candidate PGVs in BRCA2, PDGFRA. In other studies, hypermutant ccRCCs also carried mutations in TP53, PTEN, VHL, and UNC5C (45,46). It is also possible that defects in polymerase genes affect cancer risk by affecting biological processes beyond DNA replication and repair.…”