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Unveiling the genetic and epigenetic landscape of colorectal cancer: new insights into pathogenic pathways

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Abstract

Colorectal cancer (CRC) is a complex disease characterized by genetic and epigenetic alterations, playing a crucial role in its development and progression. This review aims to provide insights into the emerging landscape of these alterations in CRC pathogenesis to develop effective diagnostic tools and targeted therapies. Genetic alterations in signaling pathways such as Wnt/β-catenin, and PI3K/Akt/mTOR are pivotal in CRC development. Genetic profiling has identified distinct molecular subtypes, enabling personalized treatment strategies. Epigenetic modifications, including DNA methylation and histone modifications, also contribute to CRC pathogenesis by influencing critical cellular processes through gene silencing or activation. Non-coding RNAs have emerged as essential players in epigenetic regulation and CRC progression. Recent research highlights the interplay between genetic and epigenetic alterations in CRC. Genetic mutations can affect epigenetic modifications, leading to dysregulated gene expression and signaling cascades. Conversely, epigenetic changes can modulate genetic expression, amplifying or dampening the effects of genetic alterations. Advancements in understanding pathogenic pathways have potential clinical applications. Identifying genetic and epigenetic markers as diagnostic and prognostic biomarkers promises more accurate risk assessment and early detection. Challenges remain, including validating biomarkers and developing robust therapeutic strategies through extensive research and clinical trials. The dynamic nature of genetic and epigenetic alterations necessitates a comprehensive understanding of their temporal and spatial patterns during CRC progression. In conclusion, the genetic and epigenetic landscape of CRC is increasingly being unraveled, providing valuable insights into its pathogenesis. Integrating genetic and epigenetic knowledge holds great potential for improving diagnostics, prognostics, and personalized therapies in CRC. Continued research efforts are vital to translate these findings into clinical practice, ultimately improving patient outcomes.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

4E-BP1:

4E-binding protein 1

Akt:

Ak transforming strain

APC:

Adenomatous polyposis coli

aCGH:

Array comparative genomic hybridization

BRAF:

V-Raf murine sarcoma viral oncogene homolog B

CAF:

Cancer-associated fibroblasts

CIMP:

CpG island methylator phenotype

circRNA:

Circular RNA

CpG:

Cytosine and guanine separated by phosphate

CRC:

Colorectal cancer

CTLA:

Cytotoxic T-lymphocyte-associated protein 4

DNA:

Deoxyribonucleic acid

DNMT:

DNA methyltransferases

DUSP6:

Dual-specificity phosphatase 6

ECM:

Extra cellular matrix

EGFR:

Epithelial growth factor receptor

EMT:

Epithelial-to-mesenchymal transition

ERK:

Extracellular signal-regulated kinase

FAP:

Familial adenomatous polyposis

GSK 3β:

Glycogen synthase kinase 3 beta

HAT:

Histone acetyltransferase

HIF 1α:

Hypoxia-inducible factor 1-alpha

HMT:

Histone methyltransferases

IFN-γ:

Interferon-gamma

KRAS:

Kirsten rat sarcoma

lncRNA:

Long non-coding RNA

MAPK:

Mitogen-activated protein kinase

mRNA:

Messenger RNA

miRNA:

Micro RNA

MIG6:

Mitogen-inducible gene 6

MMP:

Matrix metalloproteinases

MMR:

Mismatch repair

MSI:

Microsatellite instability

MSP:

Methylation-specific PCR

mTOR:

Mammalian target of Rapamycin

ncRNA:

Non-coding RNA

NGS:

Next generation sequencing

PD1/PDL1:

Programmed cell death receptor/ligand-1

PI3K:

Phosphoinositide 3-kinase

PI3KCA:

Phosphatidyl inositide–4,5–bisphosphonate–3-kinase catalytic subunit–α

PIP:

Phosphatidylinositol 4,5-bisphosphate

RNA:

Ribonucleic acid

RTK:

Receptor tyrosine kinase

SNP:

Single nucleotide polymorphisms

SPRY2:

Sprouty proteins

TET:

Ten-eleven translocation

TGF:

Transforming growth factor-beta

TME:

Tumour microenvironment

TP53:

Tumour protein 53

TSC:

Tuberous sclerosis complex

VEGF:

Vascular endothelial growth factors

Wnt:

Wingless-related integration site

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Acknowledgements

The authors are grateful to Prof. Gaurang B. Shah, Department of Pharmacology, L. M. College of Pharmacy, Ahmedabad, Gujarat, India for kind support and guidance in manuscript preparation. The authors also extend their appreciation to L. M. College of Pharmacy, Ahmedabad, India for providing continuous library resources support throughout literature survey and data collection. The authors are also thankful to Sharaman Sci-Med Writing Association, India for writing assistance in revision 1 and providing continuous support for improvising figures dpi.

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  1. Humzah Postwala and Yesha Shah have been contributed equally to this work.

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  1. Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India

    Humzah Postwala, Yesha Shah & Mehul R. Chorawala

  2. AV Pharma LLC, 1545 University Blvd N Ste A, Jacksonville, Florida, 32211, USA

    Priyajeet S. Parekh

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HP, YS: Manuscript original first draft preparation and subsequent editing, Literature and data survey, Figures and diagram designing; PP: Manuscript draft review and editing, Referencing; MRC: Review topic conception, Design of content and skeleton, Manuscript draft review and editing; Figures and Tables conception.

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Correspondence to Mehul R. Chorawala.

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Postwala, H., Shah, Y., Parekh, P.S. et al. Unveiling the genetic and epigenetic landscape of colorectal cancer: new insights into pathogenic pathways. Med Oncol 40, 334 (2023). https://doi.org/10.1007/s12032-023-02201-8

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