Epigenetics and Field Cancerization the Caveats of Carcinogenesis and Recurrence of Gastrointestinal Malignancies – A Systematic Review and Meta-analysis Protocol

doi:10.21203/rs.3.rs-2508201/v1

Download PDF

Systematic Review

Epigenetics and Field Cancerization the Caveats of Carcinogenesis and Recurrence of Gastrointestinal Malignancies – A Systematic Review and Meta-analysis Protocol

https://doi.org/10.21203/rs.3.rs-2508201/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background

Gastrointestinal malignancies constitute the most common neoplasms with increasing prevalence worldwide, which portend a dismal morbidity and higher mortality rate. Epigenetic phenotypes and field cancerization impute a cutting edge for precursor of several gastrointestinal malignancies, this genetic aberration have been critically implicated in tumorigenesis and recurrence of gastrointestinal malignancies. There has been a paucity of knowledge about the interface effect between epigenetic signatures, epigenetic phenotype and field cancerization for carcinogenesis and recurrence of disease, a comprehensive analysis on the interplay of these biomarkers would streamline the strategy for epigenetic screening and chemoprevention therapy of gastrointestinal malignancy. This systematic review aims at assessing the effect of epigenetics and field cancerization on carcinogenesis and recurrence of gastrointestinal malignancies.

Methods and Analysis

This Systematic review and Meta-analysis will administer the provisions of Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 guideline and the review protocol will be submitted to PROSPERO review registry for registration. The literature search will be executed through several electronic databases including EMBASE, PubMed, Scopus, Web of Science, Cochraine , Global index medicus , semantic scholar and google scholar . All original research articles reporting on the effect of epigenetic signatures, epigenetics and field cancerization on the carcinogenesis and recurrence of gastrointestinal cancers in adults will be included. Only articles with NOS score above 4 and Low ROB based on D1-D5 for RCTs will be included for a Meta-analysis.

Ethical Consideration and Dissemination

There is no involvement of human subject participation in this review thus giving no effect to ethical implication .The evidence report of this review will be disseminated on scientific conferences and will be published to a reputable journal of gastroenterology oncology. This review has been registered at PROSPERO registry ID CRD 42023391339

Epigenetics & Genomics

Molecular Genetics

Cancer Biology

Surgery

Gastrointestinal Surgery

Oncology

Epigenetics

Genomic Signatures

Field Cancerization

Gastrointestinal Malignancies

Rationale

Gastrointestinal malignancy including esophageal cancer, gastric cancer, colorectal cancer and hepatobiliary cancers constitute the most common neoplasms with increasing prevalence worldwide, which result into a dismal morbidity and high mortality rate portending a dramatic burden on the socio-economic index especially in low and middle-income countries (1,2). Field cancerization imputes a cutting edge for precursor of tumorigenesis of several epithelial tumors including gastrointestinal malignancies; the nascence of cancerization field is instigated by the caveats of epigenetic phenotype (3). The field cancerization also known as field defect is a region of normal tissue, which comprises of cells with aggregate of DNA alterations collectively termed as epigenetics that has been instigated the pathway of genomic transformation and progression of normal epithelial tissue into malignancy(4,5). In contrary to classical mutations epigenetics can affect the gene expression in normal tissue without any remarkable alteration of DNA sequence. Epigenetic modifications encompass the DNA Methylation, histone modification, chromatin remodeling and non-coding RNAs (6–9).

Several genetic signatures have been incriminated to potentiate the precursors for development of aberrant epigenetics such as DNA methylation that are implicated in tumorigenesis, metachronous status and recurrence of gastrointestinal malignancies. Despite the fact that the recent pharmacogenomic studies have revealed a potential efficacy of demethylating agents such as 5-azacitidine , 5-azadeoxycytidine and many others which could streamline the panacea of chemopreventive therapy strategy, still there is more opacity on clinical implication of this evidence (7,10–14) .

There has been a paucity of knowledge about the interface effect between epigenetic signatures, epigenetic phenotype and field cancerization for carcinogenesis and recurrence of the disease, a comprehensive analysis on the interplay of these biomarkers is needed in order to bridge the gap and streamline the strategy for epigenetic screening and chemoprevention therapy of gastrointestinal malignancies. This review will gleam more light for clinical imperative of epigenetic diagnostics and strategy optimization for chemoprevention and control of cancer recurrence.

Objectives

The research question to be addressed in this review shall be described based on the PICOS protocol

Participants: The articles reporting on the epigenetic effect of epigenetic signatures, epigenetic phenotype and field cancerization for tumorigenesis and recurrence of gastrointestinal malignancies including esophageal cancer, gastric cancer, colonic and colorectal cancers, and hepatobiliary cancers in human adults will be recruited.

Intervention/Exposure: Epigenetic Signatures, Epigenetic phenotypes and Field Cancerization status

Comparators: Different types of epigenetic signatures, high aberrant epigenetics versus low aberrant epigenetics, site of field cancerization adjacent to tumor site versus distant field cancerization.

Outcome: Genetic mutation, carcinogenesis, metachronous cancers and cancer recurrence

Study Design: Systematic review and Meta-analysis

Broad objective

To assess the effect of epigenetics and field cancerization for carcinogenesis and recurrence of gastrointestinal malignancies.

Specific objectives

To describe the epidemiological characteristics gastrointestinal malignancies for participants included in this review
To evaluate the type of epigenetic signature pathways for development gastrointestinal cancers
To evaluate the epigenetic phenotype and field cancerization status in gastrointestinal tract tissue
To determine the correlation between epigenetic signatures, epigenetic phenotype and field cancerization for carcinogenesis and recurrence of gastrointestinal malignancy.

Protocol and registration

Herein the protocol will be developed with adherence to Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) 2020 guideline and the review protocol will be submitted to PROSPERO review registry for registration

Eligibility Criteria

Inclusion

All original research articles reporting on the effect of epigenetic signatures, epigenetics and field cancerization on the carcinogenesis and recurrence of gastrointestinal cancers (esophageal cancer, gastric cancer, colonic cancer, colorectal cancer and hepatobiliary cancer) in adults will be included. All cross sectional observational studies, cohort studies, case-control studies and randomized clinical trials published from January 2013 to December 2022 without language limitation will be included.

Exclusion

All articles reporting on animal subjects and pediatric population will be excluded; all articles with missing data will be excluded.

Information Sources

The literature search will be executed through several electronic databases including EMBASE, PubMed, Scopus, Web of Science, Cochraine, Global index medicus , semantic scholar and google scholar .

Search and search strategy

The following key strings will be used in various permutations in combination with Boolean operators and Filters “Epigenetic” [MeSH Terms], “Epigenetics”[MeSH Terms], “Epigenetic process”[MeSH Terms] , “Gene Expression signature”[MeSH Terms], “Field defect”, “Field cancerization” , “Carcinogenesis”, “Tumorigenesis”[MeSH Terms], “Locoregional neoplasm recurrence”[MeSH Terms], “Cancer of gastrointestinal trasct”[MeSH Terms] , “Cancer of esophagus”[MeSH Terms], “Gastric cancer”[MeSH Terms], “Colonic Cancer”[MeSH Terms], “Colorectal cancer” [MeSH Terms], “ Cancer of pancreas”[MeSH Terms] , “Cholangiocarcinoma”[MeSH Terms]

Search Strategy

Epigenetics[MeSH Terms] OR Epigenetic process [MeSH Terms] OR Gene expression signature[ MeSH Terms] OR Field Defect OR Field Cancerization AND Carcinogenesis OR Tumorigenesis [MeSH Terms] OR Locoregional neoplasm recurrence [MeSH Terms] AND Cancer of gastrointestinal tract [MeSH Terms] OR Cancer of esophagus [MeSH Terms] OR Gastric Cancer [MeSH Terms] OR Colonic Cancer [MeSH Terms] OR Colorectal Cancer [MeSH Terms] OR Cancer of Pancreas [MeSH Terms] OR Cholangiocarcinoma [MeSH Terms]

The sample of PubMed Search Strategy is annexed for Figures 1 and 2

Study selection

Three reviewers (VK, EM, and AA) will do the primary screening of all text articles collected from all electronic databases by search strategy independently; the screening process will be blinded. The three reviewers will also evaluate and record the selected articles for full text screening based on the stipulated eligibility criteria and all conflict dissolution will be mitigated upon the mutual consensus or adjudication from the fourth party author (TS). The Rayyan or Covidence and RevMan software will be employed for screening and data synthesis .The screened results will be presented in PRISMA flow diagram shown in the annex figure 3 and the reason for exclusion of full text articles will be justified within the exclusion box of the diagram.

Data extraction

After the full text screening the three reviewers (VK, EM and AA) will use the piloted Microsoft, excel checklist to extract the data items for data synthesis all counterfeits encountered will be resolved by consensus or adjudication from the fourth party reviewer (TS)

Data Items

The data entities such as inclusion and exclusion criteria , study design, number and location of study area , sample size , epidemiological characteristics of study participants , study period , year of study publication , histological type of cancer , grade and stage.

Exposure gestures such as epigenetic signatures, signature pathways, epigenetics , field cancerization status and the outcome indices including carcinogenesis or tumorigenesis , metachronous status and locoregional recurrence of cancers.

Risk of bias (ROB) in individual studies

The ROB will be evaluated using the Modified Newcastle Ottawa Scale (NOS) for observational studies (15,16) and Cochran ROB tool Version 2 for RCT studies (17).The reviewers ( VK , EM and AA ) will assess the risk of bias and include only articles with NOS score above 4 and Low ROB based on D1-D5 for RCTs for Meta-analysis.

Measurement of effect

For RCTs, the Hazard Ratio (HR) for evaluation of the effect of intervention to the outcome will be employed and for dichotomous outcome in non-RCTs, the Relative Risk (RR) for evaluation of the effect of exposure to the outcome of interest will be analyzed. For continuous outcome, the Mean Difference (MD) and Standard Mean Difference (SMD) will be analyzed to evaluate the effect size across the groups of participants.

Data Synthesis

If optimal data extraction will be attained the Meta-analysis will be conducted based on Per Protocol (PP) analysis. The data reporting on epigenetic signatures and pathways, epigenetic phenotypes and field cancerization will be synthesized differently and the Random Effect Model (REM) across the study participants will be reported. For Dichotomous, outcomes the pooled RR at 95% CI will be determined and the MD or SMD at 95% CI will be reported for continuous variables.

The data consistency will be determined from the articles by evaluating the clinical heterogeneity, methodological heterogeneity, statistical heterogeneity and bias of publication. Heterogeneity will be analyzed and reported using the funnel plot, Chi-test and I² - test, if minimal consistency will be identified the meta-analysis will be aborted and instead the qualitative analysis with a scoping report will be implored.

For the optimal data suitable for Meta-analysis, the analysis will be employed using RevMan Software if the data extracted is limited for Meta-analysis synthesis, the scoping review will be conducted using the synthesis without meta-analysis (SWiM) protocol and the results will be presented in summary tables.

Risk of bias across studies

The publication bias will be analyzed and reported using a funnel plot for more than 10 articles combined for meta-analysis.

Subgroup Analysis

If a significance inconsistency is encountered, advanced analysis will be performed for specific subgroup determinants and outcomes

Epigenetic signature pathways, Epigenetic variations, Field Cancerization, Location and Histological types of gastrointestinal cancers

Sensitivity Analysis

The sensitivity analysis will be implored for evaluating the robustness of the synthesized data, the crude sensitivity of data results will be adjusted by eliminating the articles with high ROB, and missing data and any contradicting definition of determinants and outcome indices.

Strength of body of evidence

Three reviewers (VK , EM and AA) will critically appraise and estimated the certainty applicability of the reported evidence in this review using the Grading of Recommendation , Assessment , Development and Evaluation (GRADE) scheme , the strength of evidence will be rated according to for quality levels classified as high , moderate , low and very low LOE (18,19).

Ethical consideration and Dissemination

Contribution of Authors

Three reviewers VK, EM and AA developed the protocol. All authors reviewed and approved the final draft of this protocol. All matters pertinent to dissolutions of screening and data synthesis will be resolved by

Disclosure of Interest

All authors declares to have no competing interests

Funding

No funding source

Crew KD, Neugut AI. Epidemiology of upper gastrointestinal malignancies. Semin Oncol. 2004;31(4):450–64.
Hormati A, Hajrezaei Z, Jazi K, Aslani Kolur Z, Rezvan S, Ahmadpour S. Gastrointestinal and Pancratohepatobiliary Cancers: A Comprehensive Review on Epidemiology and Risk Factors Worldwide. Middle East J Dig Dis. 2022;14(1):5–23.
Curtius K, Wright NA, Graham TA. An evolutionary perspective on field cancerization. Nat Rev Cancer [Internet]. 2017;18(1):19–32. Available from: http://dx.doi.org/10.1038/nrc.2017.102
Vachaud G, Dane JH. Field. Methods Soil Anal Part 4 Phys Methods. 2018;260:937–62.
Selaru FM, David S, Meltzer SJ, Hamilton JP. Epigenetic events in gastrointestinal cancer. Am J Gastroenterol. 2009;104(8):1910–2.
Wallace SE, Mirzaa GM, Bean LJH. Resources for Genetics Professionals — Epigenetic Signature Analysis I . Introduction to Epigenetic Modifications II . Epigenetic Modifications to Specific Regions of the Genome Epigenetic modifications that occur early in embryogenesis to specific regions of the genome result in Genetic Alterations That Affect Epigenetic Modifications to Specific Regions of the Genome. 2023;1–10.
Li J, Jin H, Wang X. Epigenetic Biomarkers: Potential Applications in Gastrointestinal Cancers. ISRN Gastroenterol. 2014;2014:1–10.
Abdelfatah E, Kerner Z, Nanda N, Ahuja N. Epigenetic therapy in gastrointestinal cancer: The right combination. Therap Adv Gastroenterol. 2016;9(4):560–79.
Pereira A, Moreira F, Vinasco-Sandoval T, Cunha A, Vidal A, Ribeiro-Dos-Santos AM, et al. MiRNome reveals new insights into the molecular biology of field cancerization in gastric cancer. Front Genet. 2019;10(JUN).
Sundar R, Huang KK, Kumar V, Ramnarayanan K, Demircioglu D, Her Z, et al. Epigenetic promoter alterations in GI tumour immune-editing and resistance to immune checkpoint inhibition. Gut. 2022;71(7):1277–88.
Haller F, Zhang JD, Moskalev EA, Braun A, Otto C, Geddert H, et al. Combined DNA methylation and gene expression profiling in gastrointestinal stromal tumors reveals hypomethylation of SPP1 as an independent prognostic factor. Int J Cancer. 2015;136(5):1013–23.
Khan AA, Liu X, Yan X, Tahir M, Ali S, Huang H. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev. 2021;40(1):245–72.
Dakubo GD, Jakupciak JP, Birch-Machin MA, Parr RL. Clinical implications and utility of field cancerization. Cancer Cell Int. 2007;7:1–12.
Grzenda A, Ordog T, Urrutia R. Polycomb and the emerging epigenetics of pancreatic cancer. J Gastrointest Cancer. 2011;42(2):100–11.
Luchini C, Stubbs B, Solmi M, Veronese N. Assessing the quality of studies in meta-analyses: Advantages and limitations of the Newcastle Ottawa Scale. World J Meta-Analysis. 2017;5(4):80.
A Modified Newcastle-Ottawa Scale for the Assessment of Study Quality in Genetic Urological Research Joseph M. Norris. :1–5.
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:1–8.
Aguayo-Albasini JL, Flores-Pastor B, Soria-Aledo V. GRADE System: Classification of Quality of Evidence and Strength of Recommendation. Cirugía Española (English Ed. 2014;92(2):82–8.
Andrews JC, Schünemann HJ, Oxman AD, Pottie K, Meerpohl JJ, Coello PA, et al. GRADE guidelines: 15. Going from evidence to recommendation - Determinants of a recommendation’s direction and strength. J Clin Epidemiol. 2013;66(7):726–35.

Download PDF

Version 1

posted

You are reading this latest preprint version

Epigenetics and Field Cancerization the Caveats of Carcinogenesis and Recurrence of Gastrointestinal Malignancies – A Systematic Review and Meta-analysis Protocol

Status:

Version 1

Abstract

Figures

Introduction

Methods And Materials

Declarations

References

Status:

Version 1