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An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression

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Abstract

Pancreatic cancer (PC) is assumed to be an intimidating and deadly malignancy due to being the leading cause of cancer-led mortality, predominantly affecting males of older age. The overall (5 years) survival rate of PC is less than 9% and is anticipated to be aggravated in the future due to the lack of molecular acquaintance and diagnostic tools for its early detection. Multiple factors are involved in the course of PC development, including genetics, cigarette smoking, alcohol, family history, and aberrant epigenetic signatures of the epigenome. In this review, we will mainly focus on the genetic mutations and epigenetic signature of PC. Multiple tumor suppressor and oncogene mutations are involved in PC initiation, including K-RAS, p53, CDKN2A, and SMAD4. The mutational frequency of these genes ranges from 50 to 98% in PC. The nature of mutation diagnosis is mostly homozygous deletion, point mutation, and aberrant methylation. In addition to genetic modification, epigenetic alterations particularly aberrant hypermethylation and hypomethylation also predispose patients to PC. Hypermethylation is mostly involved in the downregulation of tumor suppressor genes and leads to PC, while multiple genes also represent a hypomethylation status in PC. Several renewable drugs and detection tools have been developed to cope with this aggressive malady, but all are futile, and surgical resection remains the only choice for prolonged survival if diagnosed before metastasis. However, the available therapeutic development is insufficient to cure PC. Therefore, novel approaches are a prerequisite to elucidating the genetic and epigenetic mechanisms underlying PC progression for healthier lifelong survival.

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Abbreviations

PC:

Pancreatic cancer

PADC:

Pancreatic ductal adenocarcinoma

PanNET:

Pancreatic neuroendocrine tumor

IPMN:

Intraductal papillary mucinous neoplasms or tumors

K-RAS:

Kirsten rat sarcoma

TP53/ p53:

Tumor protein 53

CDKN2A:

Cyclin-dependent kinase inhibitor 2 A

DPC4/ SMAD4:

Deleted in pancreatic carcinoma 4/ Mother against decapentaplegic, homologs 4

BRCA1:

Breast cancer 2, early onset

BRCA2:

Breast cancer 2, early onset

PALB2:

Partner and localizer of BRCA2

SBE:

SMAD4 binding protein

DNMTs:

DNA methyltransferases

ATM:

Ataxia telangiectasia mutated

APC:

Adenomatous polyposis coli

STK11:

Serine/threonine kinase 11

MLH1:

MutL homolog

PRSS1:

Serine Protease 1

PMS2:

Postmeiotic Segregation Increased, S. Cerevisiae, 2

MSH2:

MutS protein homolog 2

MSH6:

MutS homolog 6

GTP:

Guanosine triphosphate

GDP:

Guanosine diphosphate

RTK:

Receptor tyrosine kinases

ERK:

Extracellular signal–regulated kinases

PI3K:

Phosphoinositide 3-kinase

PTEN:

Phosphatase and tensin homolog

AKT/ PKB:

Protein kinase B

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cell

MAPK:

Mitogen-activated Protein Kinase

IL-1 α:

Interleukin 1 Alpha

PRIMA-1:

Proline-rich membrane anchor 1

MDM2:

Mouse double minute 2 homolog

Yap:

Yes-associated protein

BCL2:

B-cell lymphoma 2

Rb:

Retinoblastoma

SNPs:

Single nucleotide polymorphism

qPCR:

Quantitative polymerase chain reaction

IGF1R/IR:

Insulin-like growth factor 1 receptor

TGFβ:

Transforming growth factor-β

TET:

Ten-eleven translocase

MBD4:

Methyl-CpG-binding domain protein 4

CCND2:

Cyclin D2

PENK:

Preproenkephalin

JAK-STAT:

Janus kinase signal transducers and activators of transcription

PCDH10:

Protocadherin 10

SOCS-1:

Suppressor of cytokine signaling – 1

MAD:

Mitosis Arrest DeFicient

MAP4K4:

Mitogen-activated protein 4 kinase 4

SERPINB5:

Serpin Family B Member 5

SULT1E1:

Sulfotransferase Family 1E Member 1

MUC4:

Mucin-4

5-mC:

5- methylcytosine

5-hmC:

5- hydroxy methylcytosine

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Funding

The study was supported by Natural Science Foundation China (Grant # 81702802) and Beijing Municipal Education Commission (Grant# KM201810005032 and Grant# KM201810005005).

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  1. Aamir Ali Khan and Xinhui Liu contributed equally to this work.

Authors and Affiliations

  1. College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China

    Aamir Ali Khan, Xinhui Liu, Xinlong Yan, Muhammad Tahir & Hua Huang

  2. College of Life Science, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian District, Beijing, 100081, China

    Sakhawat Ali

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Aamir Ali Khan and Xinhui Liu conceive the idea and write manuscripts of this study. Muhammad Tahir and Xinlong Yan write the abstract and make tables, respectively. Aamir Ali Khan and Sakhawat Ali make the figures. Hua Huang and Xinlong Yan critically revise the manuscript and provide supervision.

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Khan, A.A., Liu, X., Yan, X. et al. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev 40, 245–272 (2021). https://doi.org/10.1007/s10555-020-09952-0

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