Methylation of FBN1, SPG20, ITF2, RUNX3, SNCA, MLH1, and SEPT9 genes in circulating cell-free DNA as biomarkers of colorectal cancer

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Abstract

BACKGROUND: Investigating aberrant tumor-specific methylation in plasma cell-free DNA provides a promising and noninvasive biomarker for cancer detection. OBJECTIVE: We aimed to investigate methylation status of some promoter regions in the plasma and tumor tissues to find biomarkers for early detection of colorectal cancer. METHODS: This case-control study on seventy colorectal cancer patients and fifty matched healthy controls used Methylation-Specific High-Resolution Melting Curve analysis to evaluate the methylation of the selected promoter regions in converted genomic tissue DNA and plasma cfDNA. RESULTS: The methylation levels in selected regions of SPG20 (+24375 to +24680, +24209 to +24399, and +23625 to +23883), SNCA (+807 to +1013, +7 to +162, and -180 to +7), FBN1 (+223 to +429, +1 to +245, and -18 to -175), ITF2 (+296 to +436 and -180 to +55), SEPT9 (-914412 to -91590 and -99083 to -92264), and MLH1 (-13 to +22) were significantly higher in tumor tissues compared with normal adjacent tissues. The methylation levels of FBN1, ITF2, SNCA, and SPG20 promoters were significantly higher in the patient’s plasma compared to patient’s normal tissue and plasma of healthy control subjects. FBN1, SPG20, and SEPT9 promoter methylation had a good diagnostic performance for discriminating CRC tissues from normal adjacent tissues (AUC > 0.8). A panel of SPG20, FBN1, and SEPT9 methylation had a higher diagnostic value than that of any single biomarker and other panels in tissue-based assay (AUC > 0.9). The methylation of FBN1(a) and SPG20(a) regions, as the closest region to the first coding sequence (CDS), had a good diagnostic performance in plasma cfDNA (AUC > 0.8) while a panel consisted of FBN1(a) and SPG20(a) regions showed excellent diagnostic performance for CRC detection in plasma cfDNA (AUC > 0.9). CONCLUSION: Methylation of FBN1(a) and SPG20(a) promoter regions in the plasma cfDNA can be an excellent simple, non-invasive blood-based test for early detection of CRC.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors

Prashanth Rawla, Tagore Sunkara, Adam Barsouk (2019)

According to GLOBOCAN 2018 data, colorectal cancer (CRC) is the third most deadly and fourth most commonly diagnosed cancer in the world. Nearly 2 million new cases and about 1 million deaths are expected in 2018. CRC incidence has been steadily rising worldwide, especially in developing countries that are adopting the “western” way of life. Obesity, sedentary lifestyle, red meat consumption, alcohol, and tobacco are considered the driving factors behind the growth of CRC. However, recent advances in early detection screenings and treatment options have reduced CRC mortality in developed nations, even in the face of growing incidence. Genetic testing and better family history documentation can enable those with a hereditary predisposition for the neoplasm to take preventive measures. Meanwhile, the general population can reduce their risk by lowering their red meat, alcohol, and tobacco consumption and raising their consumption of fibre, wholesome foods, and certain vitamins and minerals.

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Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

Rafael A. Irizarry, Christine Ladd-Acosta, Bo Wen … (2009)

Alterations in DNA methylation (DNAm) in cancer have been known for 25 years, including hypomethylation of oncogenes and hypermethylation of tumor suppressor genes1. However, most studies of cancer methylation have assumed that functionally important DNAm will occur in promoters, and that most DNAm changes in cancer occur in CpG islands2,3. Here we show that most methylation alterations in colon cancer occur not in promoters, and also not in CpG islands but in sequences up to 2 kb distant which we term “CpG island shores.” CpG island shore methylation was strongly related to gene expression, and it was highly conserved in mouse, discriminating tissue types regardless of species of origin. There was a surprising overlap (45-65%) of the location of colon cancer-related methylation changes with those that distinguished normal tissues, with hypermethylation enriched closer to the associated CpG islands, and hypomethylation enriched further from the associated CpG island and resembling non-colon normal tissues. Thus, methylation changes in cancer are at sites that vary normally in tissue differentiation, and they are consistent with the epigenetic progenitor model of cancer4, that epigenetic alterations affecting tissue-specific differentiation are the predominant mechanism by which epigenetic changes cause cancer.

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Author and article information

Journal

Title: Cancer Biomarkers

Abbreviated Title: CBM

Publisher: IOS Press

ISSN (Electronic): 18758592

ISSN (Print): 15740153

Publication date Created: May 19 2022

Publication date (Print): May 19 2022

Volume: 34

Issue: 2

Pages: 221-250

Affiliations

[1 ]Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran

[2 ]Department of Surgery, Division of Colorectal Surgery, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran

[3 ]Cancer Institute of Iran, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran

Article

DOI: 10.3233/CBM-210315

PubMed ID: 34957998

SO-VID: 29295bf9-4756-4f4d-8640-404cc426c7e6

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