Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas

Kuick, Chik Hong; Wong, Wai Loong; Tham, Jill M.; Mansor, Sorsiah; Loh, Eva; Jain, Sudhanshi; Vikas, Nadkarni N.; Tan, Sze Huey; Chan, Sock Hoai; Li, Shao Tzu; Chew, Sung Hock; Hong, Wanjin; Ngeow, Joanne

doi:10.1016/j.ygyno.2015.12.031

Cited by 37 publications

(34 citation statements)

References 24 publications

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“…Patients with hypermutated POLE -mutant endometrial cancers have an excellent prognosis with nearly 100% progression-free survival after surgery [22,28,31,34,38,41,88–91]. A significantly better survival has also been noted for POLE -mutant CRC [44].…”

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

“…A significantly better survival has also been noted for POLE -mutant CRC [44]. Recent studies suggest this could be due to the high immunogenicity of the tumors [31,34,38,41,89,90], which likely results from the hypermutation increasing the number of neoepitopes that can be recognized by the immune system [37,40–42,44,92,93]. The improved survival suggests that, while the hypermutated POLE tumors are often of higher grade, they should be classified separately and could be treated less aggressively [36,94].…”

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

“…Only variants identified in studies where the entire coding sequence of POLE or POLD1 was analyzed [21,22,24,25,27,29,35,41–43,45–51,61–64] are included to show an unbiased distribution. The height of each lollipop corresponds to the number of times the mutation has been reported.…”

Section: Figurementioning

confidence: 99%

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Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Barbari

Shcherbakova

2017

DNA Repair

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The fidelity of DNA replication relies on three error avoidance mechanisms acting in series: nucleotide selectivity of replicative DNA polymerases, exonucleolytic proofreading, and post-replicative DNA mismatch repair (MMR). MMR defects are well known to be associated with increased cancer incidence. Due to advances in DNA sequencing technologies, the past several years have witnessed a long-predicted discovery of replicative DNA polymerase defects in sporadic and hereditary human cancers. The polymerase mutations preferentially affect conserved amino acid residues in the exonuclease domain and occur in tumors with an extremely high mutation load. Thus, a concept has formed that defective proofreading of replication errors triggers the development of these tumors. Recent studies of the most common DNA polymerase variants, however, suggested that their pathogenicity may be determined by functional alterations other than loss of proofreading. In this review, we summarize our current understanding of the consequences of DNA polymerase mutations in cancers and the mechanisms of their mutator effects. We also discuss likely explanations for a high recurrence of some but not other polymerase variants and new ideas for therapeutic interventions emerging from the mechanistic studies.

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Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

Section: Therapeutic Implications Of Dna Polymerase Deficiencymentioning

confidence: 99%

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Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Barbari

Shcherbakova

2017

DNA Repair

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“…Somatic POLD1 mutations have also been observed in up to 5% of sporadic colorectal and endometrial tumors, 8–11,16,17 as well as in other cancers (http://www.cbioportal.org/; http://cancer.sanger.ac.uk/cosmic). In contrast to the POLE variants that have garnered much interest, the majority of POLD1 mutations are found in MMR-deficient tumors and do not show a noticeable concentration in the exonuclease domain.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells

et al. 2017

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Mutations in the POLD1 and POLE genes encoding DNA polymerases δ (Polδ) and ε (Polε) cause hereditary colorectal cancer (CRC) and have been found in many sporadic colorectal and endometrial tumors. Much attention has been focused on POLE exonuclease domain mutations, which occur frequently in hypermutated DNA mismatch repair (MMR)-proficient tumors and appear to be responsible for the bulk of genomic instability in these tumors. In contrast, somatic POLD1 mutations are seen less frequently and typically occur in MMR-deficient tumors. Their functional significance is often unclear. Here we demonstrate that expression of the cancerassociated POLD1-R689W allele is strongly mutagenic in human cells. The mutation rate increased synergistically when the POLD1-R689W expression was combined with a MMR defect, indicating that the mutator effect of POLD1-R689W results from a high rate of replication errors.Purified human Polδ-R689W has normal exonuclease activity, but the nucleotide selectivity of the enzyme is severely impaired, providing a mechanistic explanation for the increased mutation rate in the POLD1-R689W-expressing cells. The vast majority of mutations induced by the POLD1-R689W are GC→TA transversions and GC→AT transitions, with transversions showing a strong strand bias and a remarkable preference for polypurine/polypyrimidine sequences. The mutational specificity of the Polδ variant matches that of the hypermutated CRC cell line, HCT15, in which this variant was first identified. The results provide compelling evidence for the pathogenic role of the POLD1-R689W mutation in the development of the human tumor and emphasize the need to experimentally determine the significance of Polδ variants present in sporadic tumors. KeywordsDNA polymerase δ; colorectal cancer; POLD1; mutator; nucleotide selectivity; mutational spectrum Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

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“…In this regard, in previous study by our group, one patient with a Lynch-like phenotype, negative for mutations in MMR genes, showed a germline mutation in PTEN [24], which was associated with disease in the family. Sometimes, also tumors with MSI-H status have shown germline genetic variants in genes, such as POLE and POLD1 [25], MYH [26] and also in PTEN [27], beyond MMR variants.…”

Section: Discussionmentioning

confidence: 99%

Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome

Liccardo

Rosa

Rossi

et al. 2017

IJMS

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Lynch syndrome (LS), the most frequent form of hereditary colorectal cancer, involves mutations in mismatch repair genes. The aim of this study was to identify mutations in MSH6 from 97 subjects negative for mutations in MLH1 and MSH2. By direct sequencing, we identified 27 MSH6 variants, of which, nine were novel. To verify the pathogenicity of these novel variants, we performed in silico and segregation analyses. Three novel variants were predicted by in silico analysis as damaging mutations and segregated with the disease phenotype; while a novel frameshift deletion variant that was predicted to yield a premature stop codon did not segregate with the LS phenotype in three of four cases in the family. Interestingly, another frame-shift variant identified in this study, already described in the literature, also did not segregate with the LS phenotype in one of two affected subjects in the family. In all affected subjects of both families, no mutation was detected in other MMR genes. Therefore, it is expected that within these families, other genetic factors contribute to the disease either alone or in combination with MSH6 variants. We conclude that caution should be exercised in counseling for MSH6-associated LS family members.

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Mutation spectrum of POLE and POLD1 mutations in South East Asian women presenting with grade 3 endometrioid endometrial carcinomas

Cited by 37 publications

References 24 publications

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Replicative DNA polymerase defects in human cancers: Consequences, mechanisms, and implications for therapy

Nucleotide selectivity defect and mutator phenotype conferred by a colon cancer-associated DNA polymerase δ mutation in human cells

Incomplete Segregation of MSH6 Frameshift Variants with Phenotype of Lynch Syndrome

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