Meta-analysis of the prognostic value of CpG island methylator phenotype in rectal cancer

Kokelaar, Rory; Jones, H; Beynon, J.; Evans, Martyn; Harris, Dean

doi:10.1007/s00384-018-3108-5

Cited by 7 publications

(5 citation statements)

References 37 publications

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“…With regard to the heterogeneity in the BRAF and p53 analyses, it is noteworthy that the rate of BRAF mutations was higher in the mucinous groups in all included studies, and the rate of p53 alterations was lower in the mucinous groups in all but one study. Heterogeneity may have been underestimated in the CIMP analysis, given the difficulties reported in determining and assigning CIMP status owing to the variety of markers currently used. The majority of studies included in the analysis were retrospective, which may increase the risk of sampling bias and data collection bias.…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of the molecular associations of mucinous colorectal cancer

Reynolds

Furney

Kay

et al. 2019

British Journal of Surgery

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Background: Mucinous differentiation occurs in 5-15 per cent of colorectal adenocarcinomas. This subtype of colorectal cancer responds poorly to chemoradiotherapy and has a worse prognosis. The genetic aetiology underpinning this cancer subtype lacks consensus. The aim of this study was to use meta-analytical techniques to clarify the molecular associations of mucinous colorectal cancer.Methods: This study adhered to MOOSE guidelines. Databases were searched for studies comparing KRAS, BRAF, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), p53 and p27 status between patients with mucinous and non-mucinous colorectal adenocarcinoma. A random-effects model was used for analysis.Results: Data from 46 studies describing 17 746 patients were included. Mucinous colorectal adenocarcinoma was associated positively with KRAS (odds ratio (OR) 1⋅46, 95 per cent c.i. 1⋅08 to 2⋅00, P = 0⋅014) and BRAF (OR 3⋅49, 2⋅50 to 4⋅87; P < 0⋅001) mutation, MSI (OR 3⋅98, 3⋅30 to 4⋅79; P < 0⋅001) and CIMP (OR 3⋅56, 2⋅85 to 4⋅43; P < 0⋅001), and negatively with altered p53 expression (OR 0⋅46, 0⋅31 to 0⋅67; P < 0⋅001). Conclusion:The genetic origins of mucinous colorectal adenocarcinoma are predominantly associated with BRAF, MSI and CIMP pathways. This pattern of molecular alterations may in part explain the resistance to standard chemotherapy regimens seen in mucinous adenocarcinoma.

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Section: Discussionmentioning

confidence: 99%

Meta-analysis of the molecular associations of mucinous colorectal cancer

Reynolds

Furney

Kay

et al. 2019

British Journal of Surgery

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“…Interestingly, assessing the methylation status of specific genes could be useful in clinical practice. Indeed, it could represent a biomarker for the detection or monitoring of specific diseases such as CRC, and more particularly of the serrated lesions that are associated with a CIMP signature [58,59,60]. For instance, a recent study reported on a positive correlation between CIMP and older age in SSA/Ps, indicating a lower risk of developing a malignancy in young patients [61].…”

Section: Cpg Island Methylator Phenotype An Epigenetic Signature mentioning

confidence: 99%

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

Palma

D’Argenio

Pol

et al. 2019

Cancers

145

102

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Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.

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“…The primary findings of Chapter 3 were that a clear association was demonstrated between the presence of pEMVI and male sex, T and N stage, AJCC classification, and the requirement for adjuvant chemotherapy 258 . This study confirms the association of EMVI with worse clinicopathological features and that these translated into a statistically significant survival disadvantage, in keeping with the findings of other authors 280 In order to gain a fuller understanding of the role of CIMP in EMVI in rectal cancer, a metaanalysis including the data gathered in Chapter 3 was undertaken 721 . Briefly, a systematic search was performed of PubMed, Embase, MEDLINE, PubMed Central, and Cochrane electronic databases for articles pertaining to CIMP and rectal cancer.…”

Section: The Cpg Methylator Phenotype and Extramural Vascular Invasionsupporting

confidence: 88%

A Mechanistic Investigation of the Relationship Between Extramural Vascular Invasion (EMVI) and CpG Island Methylator Phenotype (CIMP) in Rectal Cancer

Rory¹

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Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer death worldwide. Each year, one million people will develop CRC, and 40-50% will die within five years. Furthermore, rectal and distal sigmoid cancers are known to present at a later stage and have a poorer prognosis than other colonic cancers. Rectal cancers that demonstrate pathological extramural vascular invasion (EMVI-positive) are known to have a poorer prognosis than those that do not (EMIV-negative), and EMVI has is acknowledged as an important risk factor for systemic recurrence, local recurrence and death. Additionally, EMVI status influences the need for pre- and post-operative chemoradiation (CRT); which may influence survival outcomes. Aberrant DNA methylation is emerging as a carcinogenic mechanism and potential biomarker in colorectal cancer. This study investigates the association between hypermethylation and EMVI in vivo and in vitro. Firstly, the in vivo associations between hypermethylation, EMVI, and clinical and histopathological outcomes are examined. Secondly, an investigation of the effects of demethylation on invasive colorectal cell lines in vitro aims to illuminate the genetic and cellular mechanisms that underlie methylation-dependent pathological cellular behaviour. Finally, highlighted biologic mechanisms are investigated in vivo to discover if there is an association with EMVI and survival outcomes. By these means the axis of association between hypermethylation, EMVI, and clinical outcomes is investigated. The investigation is conducted within the framework of consensus molecular subtyping in colorectal cancer, and in concordance with current methodologies of assessing DNA methylation status. The primary findings demonstrate that EMVI is associated with hypermethylation in vivo, but that there is no direct correlation between hypermethylation and disease-free (DFS) or overall survival (OS). In vitro, demethylation of hypermethylated colorectal cancer cells, by means of established demethylating agent 5-azacytidine and putative demethylator RRx-001, reduces their propensity to migrate and invade. Demethylation in vitro is also associated with changes in the expression of the metalloproteinases involved in the metabolism of the basement membrane and the epithelial-to-mesenchymal transition and tumour metastasis, notably MMP2 and TIMP2. Changes in expression were confirmed at transcriptomal and proteomic levels in response to demethylation. In vivo, MMP2 expression was shown to be statistically significantly associated with EMVI, DFS, and OS, and was also independently predictive of EMVI, raising the possibility that it could act as a diagnostic and predictive biomarker in rectal cancers. These findings indicate a mechanistic association between hypermethylation and EMVI, mediated by methylation-dependent expression of metalloproteinases. Metalloproteinase expression, specifically MMP2, may act as a potential biomarker for EMVI and correlates to survival outcomes in rectal cancer.

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Meta-analysis of the prognostic value of CpG island methylator phenotype in rectal cancer

Cited by 7 publications

References 37 publications

Meta-analysis of the molecular associations of mucinous colorectal cancer

Meta-analysis of the molecular associations of mucinous colorectal cancer

The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer

A Mechanistic Investigation of the Relationship Between Extramural Vascular Invasion (EMVI) and CpG Island Methylator Phenotype (CIMP) in Rectal Cancer

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