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The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer.

Lin X, Stenvang J, Rasmussen MH, Zhu S, Jensen NF, Tarpgaard LS, Yang G, Belling K, Andersen CL, Li J, Bolund L, BrĂ¼nner N - BMC Genomics (2015)

Bottom Line: Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment.For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models.Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. xue.lin@biomed.au.dk.

ABSTRACT

Background: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown.

Results: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples.

Conclusion: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.

No MeSH data available.


Related in: MedlinePlus

The DNA methylation states (A) and the diversity of DNA methylation (entropy) (B) of the SOX1 gene for the 14 clinical samples.
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Fig6: The DNA methylation states (A) and the diversity of DNA methylation (entropy) (B) of the SOX1 gene for the 14 clinical samples.

Mentions: We extracted the DNA methylation information of the 14 clinical samples on the basis of the cytosine loci in set E. Furthermore, we estimated the diversity of DNA methylation states across the 14 clinical samples by measuring the DNA methylation entropy using QDMR [31]. Interestingly, many cytosine loci located in the SOX1 gene region showed high diversity of DNA methylation states across all the 14 clinical samples (Figure 6A and B). The cytosine loci harboured in the TSPYL2 gene and their DNA methylation level and entropy are shown in Additional file 7: Figure S2A and B.


The potential role of Alu Y in the development of resistance to SN38 (Irinotecan) or oxaliplatin in colorectal cancer.

Lin X, Stenvang J, Rasmussen MH, Zhu S, Jensen NF, Tarpgaard LS, Yang G, Belling K, Andersen CL, Li J, Bolund L, BrĂ¼nner N - BMC Genomics (2015)

The DNA methylation states (A) and the diversity of DNA methylation (entropy) (B) of the SOX1 gene for the 14 clinical samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4440512&req=5

Fig6: The DNA methylation states (A) and the diversity of DNA methylation (entropy) (B) of the SOX1 gene for the 14 clinical samples.
Mentions: We extracted the DNA methylation information of the 14 clinical samples on the basis of the cytosine loci in set E. Furthermore, we estimated the diversity of DNA methylation states across the 14 clinical samples by measuring the DNA methylation entropy using QDMR [31]. Interestingly, many cytosine loci located in the SOX1 gene region showed high diversity of DNA methylation states across all the 14 clinical samples (Figure 6A and B). The cytosine loci harboured in the TSPYL2 gene and their DNA methylation level and entropy are shown in Additional file 7: Figure S2A and B.

Bottom Line: Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment.For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models.Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedicine, University of Aarhus, the Bartholin Building, DK-8000, Aarhus C, Denmark. xue.lin@biomed.au.dk.

ABSTRACT

Background: Irinotecan (SN38) and oxaliplatin are chemotherapeutic agents used in the treatment of colorectal cancer. However, the frequent development of resistance to these drugs represents a considerable challenge in the clinic. Alus as retrotransposons comprise 11% of the human genome. Genomic toxicity induced by carcinogens or drugs can reactivate Alus by altering DNA methylation. Whether or not reactivation of Alus occurs in SN38 and oxaliplatin resistance remains unknown.

Results: We applied reduced representation bisulfite sequencing (RRBS) to investigate the DNA methylome in SN38 or oxaliplatin resistant colorectal cancer cell line models. Moreover, we extended the RRBS analysis to tumor tissue from 14 patients with colorectal cancer who either did or did not benefit from capecitabine + oxaliplatin treatment. For the clinical samples, we applied a concept of 'DNA methylation entropy' to estimate the diversity of DNA methylation states of the identified resistance phenotype-associated methylation loci observed in the cell line models. We identified different loci being characteristic for the different resistant cell lines. Interestingly, 53% of the identified loci were Alu sequences- especially the Alu Y subfamily. Furthermore, we identified an enrichment of Alu Y sequences that likely results from increased integration of new copies of Alu Y sequence in the drug-resistant cell lines. In the clinical samples, SOX1 and other SOX gene family members were shown to display variable DNA methylation states in their gene regions. The Alu Y sequences showed remarkable variation in DNA methylation states across the clinical samples.

Conclusion: Our findings imply a crucial role of Alu Y in colorectal cancer drug resistance. Our study underscores the complexity of colorectal cancer aggravated by mobility of Alu elements and stresses the importance of personalized strategies, using a systematic and dynamic view, for effective cancer therapy.

No MeSH data available.


Related in: MedlinePlus