DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer

Church, David N.; Briggs, Sarah; Palles, Claire; Domingo, Enric; Kearsey, Stephen; Grimes, Jonathan M.; Gorman, Maggie; Martin, Lynn; Howarth, Kimberley; Hodgson, Shirley; Kaur, Kulvinder; Taylor, Jenny C.; Tomlinson, Ian

doi:10.1093/hmg/ddt131

Cited by 332 publications

(322 citation statements)

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“…Importantly, our analyses further support previous studies that showed an association of POLE proofreading mutations with younger age and favorable prognosis. 11,29,30 It is noteworthy that in this cohort, the frequency of POLE proofreading mutation was 15%, consistent with its association with high tumor grade 10,11,29 and higher than the 6% frequency detected in unselected low-and intermediate-risk endometrial cancers. 10,11,29,30 In addition, we found that microsatellite instability was associated with a reduced risk of recurrence and distant metastases.…”

Section: Discussionsupporting

confidence: 82%

“…[6][7][8][9][10][11] These alterations have been fitted in the dualistic model of endometrial carcinogenesis discriminating endometrial cancers in the more indolent endometrioid cancers (type 1) and the more aggressive non-endometrioid cancers (type 2). Recently, comprehensive molecular profiling of 373 endometrial cancers suggested that the traditional dualistic model can be improved upon classification of endometrial cancers into four molecular subgroups with a potential prognostic significance: DNA polymerase epsilon (POLE) ultramutated, microsatellite instable hypermutated, copy-number low and copy-number high (serous-like and mostly TP53 mutant).…”

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confidence: 99%

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Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

et al. 2015

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This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P = 0.014) and distant metastasis rates 23%, 64%, and 50% (P = 0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n = 14) and group 2 (microsatellite instable; n = 19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n = 36) and 39% in group 4 (NSMP; Po 0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; Po 0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment. Modern Pathology (2015) 28, 836-844; doi:10.1038/modpathol.2015 published online 27 February 2015 Risk classification of endometrial carcinomas is based upon a combination of clinical and histopathological factors and is used in guiding adjuvant therapy. High-risk factors are (combinations of) advanced age, high-grade, non-endometrioid histology, extensive lymphovascular space invasion, and

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Section: Discussionsupporting

confidence: 82%

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confidence: 99%

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

et al. 2015

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“…POLE and POLD1 exonuclease domain mutations may occur in the germline, where they cause polymerase proofreading‐associated polyposis – a condition characterized by intestinal polyposis and tumours of the colorectum and uterus, among other organs 7. Somatic POLE exonuclease domain mutations (hereafter simply referred to as POLE mutations) occur in sporadic tumours of the endometrium (7–15% cases) 8, 9, colorectum (1–2%) 10, 11, and, less commonly, in other cancers (although, for reasons that are unclear, somatic POLD1 exonuclease domain mutations are very uncommon). POLE ‐mutant colorectal and endometrial cancers have an excellent prognosis 8, 11, 12, 13, probably owing to a robust antitumour immune response against the multitude of immunogenic neoantigens that they are predicted to harbour 11, 14, 15.…”

Section: Introductionmentioning

confidence: 99%

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Temko

Gool

Rayner

et al. 2018

The Journal of Pathology

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Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non‐malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE‐mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE‐mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T‐cell infiltrate present in POLE‐mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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“…Germline mutations affecting the exonuclease domains of DNA polymerases δ (Polδ) and e (Pole) cause hereditary CRC (19), and somatic changes in the exonuclease domain of Pole were found in sporadic hypermutated CRC and EC (20)(21)(22)(23). Two of these exonuclease domain mutations were modeled in yeast and found to increase mutation rate, supporting their role in the development of hypermutated tumors (19,24).…”

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confidence: 99%

Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity

Mertz

Sharma²,

Chabes

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Defects in DNA polymerases δ (Polδ) and e (Pole) cause hereditary colorectal cancer and have been implicated in the etiology of some sporadic colorectal and endometrial tumors. We previously reported that the yeast pol3-R696W allele mimicking a human cancer-associated variant, POLD1-R689W, causes a catastrophic increase in spontaneous mutagenesis. Here, we describe the mechanism of this extraordinary mutator effect. We found that the mutation rate increased synergistically when the R696W mutation was combined with defects in Polδ proofreading or mismatch repair, indicating that pathways correcting DNA replication errors are not compromised in pol3-R696W mutants. DNA synthesis by purified Polδ-R696W was error-prone, but not to the extent that could account for the unprecedented mutator phenotype of pol3-R696W strains. In a search for cellular factors that augment the mutagenic potential of Polδ-R696W, we discovered that pol3-R696W causes S-phase checkpoint-dependent elevation of dNTP pools. Abrogating this elevation by strategic mutations in dNTP metabolism genes eliminated the mutator effect of pol3-R696W, whereas restoration of high intracellular dNTP levels restored the mutator phenotype. Further, the use of dNTP concentrations present in pol3-R696W cells for in vitro DNA synthesis greatly decreased the fidelity of Polδ-R696W and produced a mutation spectrum strikingly similar to the spectrum observed in vivo. The results support a model in which (i) faulty synthesis by Polδ-R696W leads to a checkpoint-dependent increase in dNTP levels and (ii) this increase mediates the hypermutator effect of Polδ-R696W by facilitating the extension of mismatched primer termini it creates and by promoting further errors that continue to fuel the mutagenic pathway.DNA polymerase δ | colon cancer | dNTP pools | mutagenesis | DNA replication fidelity W hen functioning properly, DNA replication is phenomenally accurate, making ∼10 −10 mutations per base pair during each replication cycle (1). In respect to human biology, it means that, on average, less than one mutation occurs each time the human genome is replicated. This amazing exactitude is contingent upon the serial action of DNA polymerase selectivity, exonucleolytic proofreading, and DNA mismatch repair (MMR). MMR defects increase spontaneous mutagenesis in numerous model systems (2) and give rise to cancer in mice (3). In humans, inherited mutations in MMR genes predispose to colorectal cancer (CRC) in Lynch syndrome (4, 5). Additionally, MMR genes are inactivated via hypermethylation in ∼15% of sporadic CRC, endometrial cancer (EC), and gastric cancer (6).Like defects in MMR, mutations that decrease the base selectivity or proofreading activity of replicative DNA polymerases elevate spontaneous mutagenesis in eukaryotic cells (7-14) and cancer incidence in mice (15)(16)(17)(18). Germline mutations affecting the exonuclease domains of DNA polymerases δ (Polδ) and e (Pole) cause hereditary CRC (19), and somatic changes in the exonuclease domain of Pole were found in sporad...

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DNA polymerase ɛ and δ exonuclease domain mutations in endometrial cancer

Cited by 332 publications

References 33 publications

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

Refining prognosis and identifying targetable pathways for high-risk endometrial cancer; a TransPORTEC initiative

Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response

Colon cancer-associated mutator DNA polymerase δ variant causes expansion of dNTP pools increasing its own infidelity

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