Altered cfDNA Fragmentation Profile in Hypomethylated Regions as Diagnostic Marker in Breast Cancer

Abstract Backgroud: Breast cancer, the most common malignancy in women, has been proved to have both altered plasma cell-free DNA (cfDNA) methylation and fragmentation profiles, nevertheless, simultaneously detecting both of them for breast cancer diagnosis has never been reported. Moreover, although fragmentation pattern of cfDNA is determined by nuclease digestion of chromatin, structure of which may be affected by DNA methylation, whether cfDNA methylation and fragmentation are biologically related or not still remains unclear.Methods: Improved cfMeDIP-seq were utilized to characterize both cfDNA methylation and fragmentation profiles in 25 plasma samples from both healthy individuals and patients with breast cancer. The feasibility of using cfDNA fragmentation profile in hypo- and hyper- methylated regions as diagnostic markers for breast cancer was evaluated. Results: Mean size of cfDNA fragments ranging from 100 to 220 base pairs (bp) was found to increase from 170.06 (Input libraries) to 173.04 (IP libraries) bp in healthy individuals, which was not observed in patients with breast cancer (170.51 to 170.71 bp). Furthermore, mean size of cfDNA fragments mapped to hypomethylated regions decreased more win patients with breast cancer (4.60 bp, 172.33 bp in hypermethylated regions to 167.73 bp in hypomethylated regions) than healthy individuals (2.87 bp, 174.54 bp in hypermethylated regions to 171.67 bp in hypomethylated regions). The feasibility of using abnormality of short cfDNA fragments ratio in hypomethylated genomic regions for diagnosis of breast cancer in validation cohort was evaluated. 7 out of 11 patients were detected as having breast cancer (63.6% sensitivity), whereas no healthy individuals were mis-detected (100% specificity). Conclusion: We identified enriched short cfDNA fragments after 5mC-immunoprecipitation (IP) in patients with breast cancer, and demonstrated the enriched short cfDNA fragments might originated from hypomethylated genomic regions. Furthermore, we proved the feasibility of using differentially methylated regions (DMRs)-dependent cfDNA fragmentation profile for breast cancer diagnosis.

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Differentially methylated regions (DMRs)-dependent cfDNA fragmentation profile for diagnosis of breast cancer

10.21203/rs.3.rs-403375/v1 ◽

2021 ◽

Author(s):

Jun Wang ◽

Ming Yang ◽

Mingyang Su ◽

Lirong Shu ◽

Hongxian Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Diagnosis ◽

Validation Cohort ◽

Breast Cancer Diagnosis ◽

Fragmentation Pattern ◽

Healthy Individuals ◽

Differentially Methylated Regions ◽

Nuclease Digestion ◽

Mean Size ◽

Genomic Regions

Abstract Background Breast cancer, the most common malignancy in women, has been proved to have both altered plasma cell-free DNA (cfDNA) methylation and fragmentation profile, nevertheless, simultaneously detecting both of them for breast cancer diagnosis has never been reported. Moreover, although it is known that fragmentation pattern of cfDNA is determined by nuclease digestion of chromatin, structure of which may be affected by DNA methylation, whether cfDNA methylation and fragmentation are biologically related or not still remains unclear.Methods A total of 25 plasm samples from both healthy individuals and patients with breast cancer were divided into discovery cohort and validation cohort. Improved cfMeDIP-seq were utilized to simultaneously profile both cfDNA methylation and fragments size, short fragments ratio were investigated in differentially methylated regions (DMRs). The feasibility of using cfDNA fragmentation profile in hypo- and hyper- methylated regions as a diagnostic marker for breast cancer was evaluated.Results Mean cfDNA fragments size ranging from 100 to 220 base pairs (bp) was found to increase from 170.06 (Input libraries) to 173.04 (IP libraries) bp in healthy individuals, which was not observed in patients with breast cancer (170.51 to 170.71 bp). Furthermore, mean size of cfDNA fragments mapped to hypomethylated regions decreased more in patients with breast cancer (4.60 bp, 172.33 bp in hypermethylated regions to 167.73 bp in hypomethylated regions) than healthy individuals (2.87 bp, 174.54 bp in hypermethylated regions to 171.67 bp in hypomethylated regions). An approach called ‘correlation assessment of DMRs-dependent cfDNA fragmentation profile’ was developed to evaluate the feasibility of using abnormality of short cfDNA fragments ratio in hypomethylated genomic windows for diagnosis of breast cancer in validation cohort. 7 out of 11 patients were detected as having breast cancer (63.6% sensitivity), whereas no healthy individuals were mis-detected (100% specificity).Conclusion We identified enriched short cfDNA fragments after 5mC-immunoprecipitation (IP) in patients with breast cancer, and demonstrated the enriched short cfDNA fragments might originated from hypomethylated genomic regions. Furthermore, we proved the feasibility of using differentially methylated regions (DMRs)-dependent cfDNA fragmentation profile for breast cancer diagnosis.

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Risk Factors of Breast Cancer in Indian Context

International Journal of Computational Models and Algorithms in Medicine ◽

10.4018/jcmam.2012070101 ◽

2012 ◽

Vol 3 (3) ◽

pp. 1-9

Author(s):

Biswa Bandita ◽

Dipti Mohanty ◽

S. K. Pradhan ◽

S. N. Rath ◽

Madhusmita Sahu ◽

...

Keyword(s):

Breast Cancer ◽

Risk Factors ◽

Cancer Diagnosis ◽

Delayed Diagnosis ◽

Breast Cancer Diagnosis ◽

Cancer Risks ◽

Upward Trend ◽

Screening Programs ◽

Indian Context ◽

Common Malignancy

The upward trend in breast cancer globally and in India has become a matter of great concern. Breast cancer is the most common malignancy among women globally. The objective of the authors’ study was to explore the various risk factors of breast cancer in among women in an Indian context. A search was performed using the search engine Pubmed during years 2005-2011 using key words risk factor and breast cancer and India. They searched criteria found 16 final analyzable articles. Results of the review showed high mortality due to late stage breast cancer diagnosis as women usually present at an advanced stage. The results showed that the predominant reason was because of lack of awareness about the risk factors of breast cancer and non-existence of breast cancer screening programs. Financial and social reasons were other factors that resulted in delay in seeking advice for this problem resulting in its delayed diagnosis. Educational awareness might be an effective tool for modifying lifestyles and thereby reducing breast cancer risks.

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