The POLD1R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors

Job, Albert; Tatura, Marina; Schäfer, Cora; Lutz, Veronika; Schneider, Hanna; Lankat–Buttgereit, Brigitte; Zielinski, Alexandra; Borgmann, Kerstin; Bauer, Christian; Gress, Thomas M.; Buchholz, Malte; Gallmeier, Eike

doi:10.1038/s41598-020-76033-1

Cited by 9 publications

(4 citation statements)

References 43 publications

(63 reference statements)

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“…The CRISPR/Cas9 technique offers a new approach to potentially edit any desired genome region. Nevertheless, the engineering of POLE and POLD1 in mammalian cells has been scarce and mainly performed in MMRd cell lines ( Hodel et al, 2020 ; Job et al, 2020 ). In our case, the CRISPR-driven POLD1 editing was a major challenge in the MMR-proficient SW837 cell line and could not be accomplished for POLD1 p.(Lys648fs*46).…”

Section: Discussionmentioning

confidence: 99%

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Bonjoch

Lima²,

Díaz‐Gay³

et al. 2023

Front. Mol. Biosci.

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Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1-Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies.

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Section: Discussionmentioning

confidence: 99%

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Bonjoch

Lima²,

Díaz‐Gay³

et al. 2023

Front. Mol. Biosci.

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“…The relationship between two genes, in which single mutations alone are compatible with cell survival, but mutation of both leads to death, is defined as synthetic lethality [ 31 ]. Based on this concept, multiple studies demonstrated that colorectal cancer with deficient POLD1 activity possessed the increased sensitivity to ATR and CHK1 inhibitors in preclinical models [ 32 , 33 ]. However, the effect and underlying mechanisms of POLD1 in HCC are not well-understood.…”

Section: Discussionmentioning

confidence: 99%

A Comprehensive Prognostic Analysis of POLD1 in Hepatocellular Carcinoma

et al. 2022

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Background DNA polymerase delta 1 catalytic subunit (POLD1) plays a key role in DNA replication and damage repair. A defective DNA proofreading function caused by POLD1 mutation contributes to carcinogenesis, while POLD1 overexpression predicts poor prognosis in cancers. However, the effect of POLD1 in hepatocellular carcinoma (HCC) is not well-understood. Methods Expression patterns of POLD1 were evaluated in TCGA and the HPA databases. Kaplan-Meier curves and Cox regression were used to examine the prognostic value of POLD1. The prognostic and predictive value of POLD1 was further validated by another independent cohort from ICGC database. The influences of DNA copy number variation, methylation and miRNA on POLD1 mRNA expression were examined. The correlation between infiltrating immune cells and POLD1 expression was analyzed. GO and KEGG enrichment analyses were performed to detect biological pathways associated with POLD1 expression in HCC. Results POLD1 was overexpressed in HCC (n = 369) compared with adjacent normal liver (n = 50). POLD1 upregulation was significantly correlated with positive serum AFP and advanced TNM stage. Kaplan–Meier and multivariate analyses suggested that POLD1 overexpression predicts poor prognosis in HCC. DNA copy gain, low POLD1 methylation, and miR‑139-3p downregulation were associated with POLD1 overexpression. Besides, POLD1 expression was associated with the infiltration levels of dendritic cell, macrophage, B cell, and CD4 + T cell in HCC. Functional enrichment analysis suggested “DNA replication”, “mismatch repair” and “cell cycle” pathways might be involved in the effect of POLD1 on HCC pathogenesis. Additionally, POLD1 mRNA expression was significantly associated with tumor mutation burden, microsatellite instability, and prognosis in various tumors. Conclusions POLD1 may be a potential prognostic marker and promising therapeutic target in HCC.

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“…We start our analysis by aggregating a list of known and agreed driver variants in the POLE/D1 genes, based on information in ClinVar 12 , as well as literature review 4,9,[15][16][17][18][19][20] (Table S2, Methods). We then classified tumors as PPD based on having a high number of SNVs and high activity of PPD related signatures.…”

Section: Classifying Samples With Ppdmentioning

confidence: 99%

From Subtle to Severe: Multiple Mechanisms Impair POLE and POLD1 Function leading to Distinct Effects on Mutation Rates

Dayan,

Ladany,

Glaser

et al. 2024

Preprint

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Background POLE and POLD1 are DNA polymerase proteins crucial for maintaining genome integrity during replication. While several drivers leading to POLE and POLD1 proofreading deficiency (PPD) have been identified, the complete set of variants causing PPD is not fully established. This study aims to identify new variants that contribute to PPD by analyzing a large dataset of sequenced tumors. Methods We analyzed 204,453 tumors to identify variants associated with POLE and POLD1 proofreading deficiency after extensive filtering and normalizing of the different datasets. Using the support vector machine algorithm, we classified variants as either drivers or non-drivers of PPD based on the number of mutations and mutational signature activity. A saturation analysis was performed to determine the completeness of the identified variants. Results We identified 46 somatic driver variants, compared to only 17 known driver variants, thus more than doubling the current catalog of mutations linked to PPD. This extensive dataset enabled us to characterize the clinical features of PPD tumors, noting a male bias and younger age at diagnosis compared to non-PPD tumors. Different driver variants led to distinct phenotypes in mutational patterns and subsequent mutated genes.

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The POLD1R689W variant increases the sensitivity of colorectal cancer cells to ATR and CHK1 inhibitors

Cited by 9 publications

References 43 publications

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome

A Comprehensive Prognostic Analysis of POLD1 in Hepatocellular Carcinoma

From Subtle to Severe: Multiple Mechanisms Impair POLE and POLD1 Function leading to Distinct Effects on Mutation Rates

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