<i><scp>POLE</scp></i> somatic mutations in advanced colorectal cancer

Guerra, Joana; Pinto, Carla; Pinto, Daniel; Pinheiro, Manuela; Silva, Romina; Peixoto, Ana; Rocha, Patrícia; Veiga, Isabel; Santos, Catarina; Santos, Rui; Cabreira, Verónica; Lopes, Paula; Henrique, Rui; Teixeira, Manuel R.

doi:10.1002/cam4.1245

Cited by 41 publications

(29 citation statements)

References 25 publications

(40 reference statements)

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“…Germline and somatic POLE mutations are associated with hypermutated CRC and endometrial cancer. 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.…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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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“…Interestingly, some CRC patients (2-3%) harbor MSS tumors with DNA polymerase epsilon or delta (POLE, POLD) mutations. It has been reported that in a subset of MSS tumors, mutations in the genes encoding these enzymes responsible for DNA synthesis and repair (92,93) are associated with an ultramutated phenotype defined by a high number of frameshift mutations. Indeed, predicted neoantigen load is 3-4 times higher in MSS tumors carrying POLE mutations than in MSI CRCs (13,79).…”

Section: Immune Checkpoint Blockade In Crcmentioning

confidence: 99%

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

et al. 2020

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Colorectal cancer (CRC) is highly heterogeneous at the genetic and molecular level, which has major repercussions on the efficacy of immunotherapy. A small subset of CRCs exhibit microsatellite instability (MSI), a molecular indicator of defective DNA mismatch repair (MMR), but the majority are microsatellite-stable (MSS). The high tumor mutational burden (TMB) and neoantigen load in MSI tumors favors the infiltration of immune effector cells, and antitumor immune responses within these tumors are strong relative to their MSS counterparts. MSI has emerged as a major predictive marker for the efficacy of immune checkpoint blockade over the last few years and nivolumab or pembrolizumab targeting PD-1 has been approved for patients with MSI refractory or metastatic CRC. However, some MSS tumors show DNA polymerase epsilon (POLE) mutations that also confer a very high TMB and may also be heavily infiltrated by immune cells making them amenable to respond to immune checkpoint inhibitors (ICI). In this review we discuss the role of the different immune landscapes in CRC and their relationships with defined CRC genetic subtypes. We discuss potential reasons why immune checkpoint blockade has met with limited success for the majority of CRC patients, despite the finding that immune cell infiltration of primary non-metastatic tumors is a strong predictive, and prognostic factor for relapse and survival. We then consider in which ways CRC cells develop mechanisms to resist ICI. Finally, we address the latest advances in CRC vaccination and how a personalized neoantigen vaccine strategy might overcome the resistance of MSI and MSS tumors in patients for whom immune checkpoint blockade is not a treatment option.

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“…Interestingly, BRAF V600E mutations were commonly observed with MLH1 mutations in sporadic cases and with CIMP [ 60 , 61 ]. DNA polymerase epsilon ( POLE ) mutations have been observed in a small subset of microsatellite-stable and hypermutated CRCs that affects the proofreading activity of the enzyme, leading to the misincorporation of the bases during DNA replication [ 62 ]. According to the TCGA study, ACVR2A , APC , TGFβ-R2 , MSH3 , MSH6 , SLC9A9 , TCF7L2 , and BRAFV600E are the most frequently mutated genes in these hypermutated tumors [ 44 ].…”

Section: Molecular Biology and Genetic Perspectivementioning

confidence: 99%

Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature

et al. 2018

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Colorectal cancer is the third most common cancer worldwide with a high mortality rate at the advanced stages. However, colorectal cancer is not a single type of tumor; its pathogenesis depends on the anatomical location of the tumor and differs between right side and left side of the colon. Tumors in the proximal colon (right side) and distal colon (left side) exhibit different molecular characteristics and histology. In the right-sided tumors, mutations in the DNA mismatch repair pathway are commonly observed; and these tumors generally have a flat histology. In the left-sided tumors, chromosomal instability pathway-related mutations, such as KRAS, APC, PIK3CA, p53 mutations are observed and these tumors demonstrate polypoid-like morphology. Therapy responses are totally different between these tumor entities. Left-sided colorectal cancer (LCRC) patients benefit more from adjuvant chemotherapies such as 5-fluorouracil (5-FU)-based regimes, and targeted therapies such as anti- epidermal growth factor receptor (EGFR) therapy, and have a better prognosis. Right-sided colorectal cancer (RCRC) patients do not respond well to conventional chemotherapies, but demonstrate more promising results with immunotherapies because these tumors have high antigenic load. For the development of effective therapy regimes and better treatment options, it is essential to evaluate right-sided and left-sided tumors as separate entities, and design the therapy regime considering the differences between these tumors.

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POLE somatic mutations in advanced colorectal cancer

Cited by 41 publications

References 25 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

Relationships Between Immune Landscapes, Genetic Subtypes and Responses to Immunotherapy in Colorectal Cancer

Difference Between Left-Sided and Right-Sided Colorectal Cancer: A Focused Review of Literature

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