Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia
Abstract Background In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made...
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | Clinical Epigenetics |
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| Online Access: | http://link.springer.com/article/10.1186/s13148-017-0356-0 |
| _version_ | 1818019349164720128 |
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| author | Lata Rani Nitin Mathur Ritu Gupta Ajay Gogia Gurvinder Kaur Jaspreet Kaur Dhanjal Durai Sundar Lalit Kumar Atul Sharma |
| author_facet | Lata Rani Nitin Mathur Ritu Gupta Ajay Gogia Gurvinder Kaur Jaspreet Kaur Dhanjal Durai Sundar Lalit Kumar Atul Sharma |
| author_sort | Lata Rani |
| collection | DOAJ |
| description | Abstract Background In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients. Results The integration of DNA methylation profile (n = 14) with the gene expression profile (n = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients (n = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup (p < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p = 0.005) or PAX9 (RR = 1.87, p = 0.001). High expression of CRY1 (HR: 3.53, p < 0.001) or PAX9 (HR: 3.14, p < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172–9.272, p = 0.016) was also predictive of shorter overall survival in CLL. Conclusions The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients. |
| first_indexed | 2024-04-14T07:51:07Z |
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| id | doaj.art-bd08f818ba194ac18064a19184d91d17 |
| institution | Directory Open Access Journal |
| issn | 1868-7075 1868-7083 |
| language | English |
| last_indexed | 2024-04-14T07:51:07Z |
| publishDate | 2017-05-01 |
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| series | Clinical Epigenetics |
| spelling | doaj.art-bd08f818ba194ac18064a19184d91d172022-12-22T02:05:11ZengBMCClinical Epigenetics1868-70751868-70832017-05-019111410.1186/s13148-017-0356-0Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemiaLata Rani0Nitin Mathur1Ritu Gupta2Ajay Gogia3Gurvinder Kaur4Jaspreet Kaur Dhanjal5Durai Sundar6Lalit Kumar7Atul Sharma8Laboratory Oncology Unit, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Laboratory Oncology Unit, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Laboratory Oncology Unit, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Department of Medical Oncology, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Laboratory Oncology Unit, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Department of Biochemical Engineering and Biotechnology, DBT-AIST International Laboratory of Advanced Biomedicine (DAILAB), Indian Institute of Technology (IIT) DelhiDepartment of Biochemical Engineering and Biotechnology, DBT-AIST International Laboratory of Advanced Biomedicine (DAILAB), Indian Institute of Technology (IIT) DelhiDepartment of Medical Oncology, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Department of Medical Oncology, Dr. B.R.A.IRCH, All India Institute of Medical Sciences (AIIMS)Abstract Background In chronic lymphocytic leukemia (CLL), epigenomic and genomic studies have expanded the existing knowledge about the disease biology and led to the identification of potential biomarkers relevant for implementation of personalized medicine. In this study, an attempt has been made to examine and integrate the global DNA methylation changes with gene expression profile and their impact on clinical outcome in early stage CLL patients. Results The integration of DNA methylation profile (n = 14) with the gene expression profile (n = 21) revealed 142 genes as hypermethylated-downregulated and; 62 genes as hypomethylated-upregulated in early stage CLL patients compared to CD19+ B-cells from healthy individuals. The mRNA expression levels of 17 genes identified to be differentially methylated and/or differentially expressed was further examined in early stage CLL patients (n = 93) by quantitative real time PCR (RQ-PCR). Significant differences were observed in the mRNA expression of MEIS1, PMEPA1, SOX7, SPRY1, CDK6, TBX2, and SPRY2 genes in CLL cells as compared to B-cells from healthy individuals. The analysis in the IGHV mutation based categories (Unmutated = 39, Mutated = 54) revealed significantly higher mRNA expression of CRY1 and PAX9 genes in the IGHV unmutated subgroup (p < 0.001). The relative risk of treatment initiation was significantly higher among patients with high expression of CRY1 (RR = 1.91, p = 0.005) or PAX9 (RR = 1.87, p = 0.001). High expression of CRY1 (HR: 3.53, p < 0.001) or PAX9 (HR: 3.14, p < 0.001) gene was significantly associated with shorter time to first treatment. The high expression of PAX9 gene (HR: 3.29, 95% CI 1.172–9.272, p = 0.016) was also predictive of shorter overall survival in CLL. Conclusions The DNA methylation changes associated with mRNA expression of CRY1 and PAX9 genes allow risk stratification of early stage CLL patients. This comprehensive analysis supports the concept that the epigenetic changes along with the altered expression of genes have the potential to predict clinical outcome in early stage CLL patients.http://link.springer.com/article/10.1186/s13148-017-0356-0Promoter methylationPAX9Circadian rhythmTranscription factors |
| spellingShingle | Lata Rani Nitin Mathur Ritu Gupta Ajay Gogia Gurvinder Kaur Jaspreet Kaur Dhanjal Durai Sundar Lalit Kumar Atul Sharma Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia Clinical Epigenetics Promoter methylation PAX9 Circadian rhythm Transcription factors |
| title | Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia |
| title_full | Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia |
| title_fullStr | Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia |
| title_full_unstemmed | Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia |
| title_short | Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia |
| title_sort | genome wide dna methylation profiling integrated with gene expression profiling identifies pax9 as a novel prognostic marker in chronic lymphocytic leukemia |
| topic | Promoter methylation PAX9 Circadian rhythm Transcription factors |
| url | http://link.springer.com/article/10.1186/s13148-017-0356-0 |
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