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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, Brünner 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 distribution of differentially methylated cytosines (DMCs) in different genomic components. A shows the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CpG in different components of the human genome. B and C show the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CHH and CHG in different components of the human genome, respectively. The height of the left vertical axis indicates the number of total cytosines in the context of CpG (A), CHG (B) and CHH (C), respectively. The height of the right vertical axis indicates the number of the DMCs in the context of CpG (A), CHG (B) and CHH (C) for the given genomic components, respectively.
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Fig1: The distribution of differentially methylated cytosines (DMCs) in different genomic components. A shows the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CpG in different components of the human genome. B and C show the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CHH and CHG in different components of the human genome, respectively. The height of the left vertical axis indicates the number of total cytosines in the context of CpG (A), CHG (B) and CHH (C), respectively. The height of the right vertical axis indicates the number of the DMCs in the context of CpG (A), CHG (B) and CHH (C) for the given genomic components, respectively.

Mentions: Furthermore, we investigated the distribution of the DMCs in different genomic components. The DMCs (composed of CpG, CHH and CHG) were mainly located in intergenic and intronic regions. Notably, even though the majority of CpG loci harboured more frequently in introns and promoters than in intergenic regions, the largest number of DMCs in CpG context were found in intergenic regions (Figure 1A). Compared with the DMCs in a CpG context, DMCs in non-CpG contexts were less frequent, residing mainly in introns, intergenic regions and promoters (Figure 1B and Figure 1C). This result suggests that CpG DMCs contribute predominantly to the DNA methylation difference in intergenic regions.Figure 1


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, Brünner N - BMC Genomics (2015)

The distribution of differentially methylated cytosines (DMCs) in different genomic components. A shows the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CpG in different components of the human genome. B and C show the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CHH and CHG in different components of the human genome, respectively. The height of the left vertical axis indicates the number of total cytosines in the context of CpG (A), CHG (B) and CHH (C), respectively. The height of the right vertical axis indicates the number of the DMCs in the context of CpG (A), CHG (B) and CHH (C) for the given genomic components, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig1: The distribution of differentially methylated cytosines (DMCs) in different genomic components. A shows the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CpG in different components of the human genome. B and C show the distribution of total cytosines (blue bars) and DMCs (red bars) in the context of CHH and CHG in different components of the human genome, respectively. The height of the left vertical axis indicates the number of total cytosines in the context of CpG (A), CHG (B) and CHH (C), respectively. The height of the right vertical axis indicates the number of the DMCs in the context of CpG (A), CHG (B) and CHH (C) for the given genomic components, respectively.
Mentions: Furthermore, we investigated the distribution of the DMCs in different genomic components. The DMCs (composed of CpG, CHH and CHG) were mainly located in intergenic and intronic regions. Notably, even though the majority of CpG loci harboured more frequently in introns and promoters than in intergenic regions, the largest number of DMCs in CpG context were found in intergenic regions (Figure 1A). Compared with the DMCs in a CpG context, DMCs in non-CpG contexts were less frequent, residing mainly in introns, intergenic regions and promoters (Figure 1B and Figure 1C). This result suggests that CpG DMCs contribute predominantly to the DNA methylation difference in intergenic regions.Figure 1

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