DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Castellucci, Enrico; He, Tianfang; Goldstein, D. Yitzchak; Halmos, Balázs; Chuy, Jennifer

doi:10.1634/theoncologist.2017-0034

Cited by 26 publications

(27 citation statements)

References 21 publications

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“…32,33 Previous studies have also found that hypermutated MSS tumors harbored POLE mutations. 34,35 Four cases with hypermutated MSS tumors harboring POLE mutations were also observed in the present study. In a population-based cohort study on MSS CRC, POLE mutations were associated with lower risk of recurrence.…”

Section: Discussionsupporting

confidence: 72%

Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing

Kim

Chun

Hong

et al. 2019

The Journal of Molecular Diagnostics

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Next-generation sequencing (NGS) panels are widely used for defining tumor mutation profiles and determining treatment approaches. We performed targeted NGS with 382 colorectal cancer genes with known microsatellite instability (MSI). After exclusion of germline alterations, the load of somatic mutations and small insertion/deletion (indel) alterations were determined. In the test set, 79 patients with 41 microsatellite-stable (MSS) and 38 MSI tumors were included. There were 120 MSS and eight MSI-high tumors in the validation set. The number of somatic mutations of whole samples were distinguished into three groups: mutant functional polymerase epsilon catalytic subunit, MSI, and MSS tumors. The median numbers of somatic and indel mutations in MSI tumors were higher. The indel mutation to whole mutation ratio (I index) was higher in MSI tumors. Hypermutation and low I index of polymerase epsilon catalytic subunit mutant tumors, a somatic mutation load cutoff of 40, and an I index of 9% were selected as the criteria for detecting MSI tumors with high sensitivity and specificity. With the analysis of alteration patterns of homopolymer genes, a higher median number of homopolymer mutations in MSI tumors was observed. Mutated homopolymer 5 was selected as the criterion for detecting MSI tumors. MSI in colorectal cancer can be detected by targeted NGS panels with high sensitivity and specificity using somatic mutation load and I index.

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Section: Discussionsupporting

confidence: 72%

Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing

Kim

Chun

Hong

et al. 2019

The Journal of Molecular Diagnostics

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“…In support of this, we observed a trend of higher somatic mutation burden in OC patients with germline ANKRD11 and POLE ‐mutations. This finding is consistent with what has been observed in endometrial and colorectal tumors with somatic POLE ‐mutations . In addition, it might also raise the beneficial potential of including POLE in gene panel testing of OC patients and their family members in order to optimize the prevention strategies to decrease their risk of OC and colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Our finding is consistent with recent findings that POLE mutations can contribute to susceptibility to a broad cancer spectrum including OC. 34,35 Furthermore, it has also been reported that POLEmutant endometrial and colorectal tumors had a high somatic mutation burden, elevated expression of immune checkpoint genes and increased lymphocytic infiltration, [36][37][38][39][40][41][42][43] and therefore immune checkpoint inhibitors was recommended for treating cancers with POLE-mutations. 41,44 Similar recommendation was also demonstrated in mismatch repair (MMR) deficient cancers regardless of the cancers' tissue of origin.…”

Section: Discussionmentioning

confidence: 99%

“…This finding is consistent with what has been observed in endometrial and colorectal tumors with somatic POLE-mutations. 40,42,43 In addition, it might also raise the beneficial potential of including POLE in gene panel testing of OC patients and their family members in order to optimize the prevention strategies to decrease their risk of OC and colorectal cancer. We noticed POLE variants were more prevalent in the TCGA OC cohort than in our discovery cohort (4.34% vs. 2.53% in Table 2).…”

Section: Discussionmentioning

confidence: 99%

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Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Zhu

Zhang

Chen

et al. 2019

Intl Journal of Cancer

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Despite the identification of several ovarian cancer (OC) predisposition genes, a large proportion of familial OC risk remains unexplained. We adopted a two‐stage design to identify new OC predisposition genes. We first carried out a large germline whole‐exome sequencing study on 158 patients from 140 families with significant OC history, but without evidence of genetic predisposition due to BRCA1/2. We then evaluated the potential candidate genes in a large case–control association study involving 381 OC cases in the Cancer Genome Atlas project and 27,173 population controls from the Exome Aggregation Consortium. Two new putative OC risk genes were identified, namely, ANKRD11, a putative tumor suppressor, and POLE, an enzyme involved in DNA repair and replication. These two genes likely confer moderate OC risk. We performed in vitro experiments and showed an ANKRD11 mutation identified in our patients markedly lowered the protein expression by compromising protein stability. Upon future validation and functional characterization, these genes may shed light on cancer etiology along with improving ascertainment power and preventive care of individuals at high risk of OC.

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“…POLE ‐mutant microsatellite stable (MSS) and MSI‐H endometrial adenocarcinomas have been linked with increased immunogenic mutations . Both POLE ‐mutant and MSI‐H endometrial cancers demonstrate enhanced antitumor immune activity with infiltration of T lymphocytes . The histologic appearance of the endometrial tumor is not a reliable predictor of the underlying molecular defect, especially for the POLE ‐mutant subgroup, which has been previously reported to show low‐grade or high‐grade endometrioid, serous, or mixed histology.…”

Section: Molecular Tumor Boardmentioning

confidence: 99%

Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma

et al. 2018

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Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ () mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.

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DNA Polymerase ε Deficiency Leading to an Ultramutator Phenotype: A Novel Clinically Relevant Entity

Cited by 26 publications

References 21 publications

Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing

Mutation Burden and I Index for Detection of Microsatellite Instability in Colorectal Cancer by Targeted Next-Generation Sequencing

Whole‐exome sequencing of ovarian cancer families uncovers putative predisposition genes

Tumor Mutational Burden Guides Therapy in a Treatment Refractory POLE-Mutant Uterine Carcinosarcoma

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