Objective: The aim of this study was to evaluate the DNA methylation of the CDKN2B/CDKN2B-AS1 enhancer with Huntington’s disease and lung cancer.

Background: Phenomenon of an inverse comorbidity or dystropy have shown reductions in risk of cancer in patients with neurodegenerative disorders. The 9p21.3 locus, where the long non-coding RNAs are located is associated with vascular dementia, Alzheimer’s disease and oncological diseases. We proposed that such epigenetic modification as DNA methylation of this region may explain the inverse association between cancer and neurodegenerative diseases.

Method: We assessed DNA methylation within enhancer of the CDKN2B/CDKN2B-AS1 (31 CpG-sites in chr9:22005065-22005876, GRCh37/hg19) in blood leukocytes. High-throughput bisulfite DNA sequencing was performed on a MiSeq instrument (Illumina).The groups of patients with lung cancer consisted of 9 people (aged 59,9±6,3 years) and with Huntington’s disease consisted of 17 people (aged 61,0±8,5 years). The control group included 14 individuals (aged 65,6±8,1 years).

Results: The most significant differences of the methylation levels between the studied groups are observed in CpG sites chr9:22005100 and chr9:22005401. The mean methylation levels at the chr9:22005100 were in patients with Huntington’s disease [24,5 ± 11,0]%, in patients with lung cancer [13,1 ± 8,5]%, in the control group [16,9 ± 6,5]%. The mean methylation levels of CpG site chr9:22005401 were in patients with Huntington’s disease [27,2±5,4]%, in patients with lung cancer [12,2±7,6]%, in the control group [21,9±1,3]%. In total significant differences in mean CpG sites methylation levels were observed between groups of patients with neurodegenerative diseases and cancer, p=0,025 (chr9:22005100) and p=0,005 (chr9:22005401).

Conclusion: We identified multi-directional epigenetic changes in the methylation level of the CpG sites chr9: 22005100 and chr9: 22005401 in blood leukocytes of lung cancer patients and Huntington’s disease patients relative to the individuals of control group. In this way the CDKN2B/CDKN2B-AS1 locus may be implicated in the mechanism of inverse comorbidity of cancer and neurodegenerative diseases. Further studies in the independent cohorts are needed before claiming the involvement of a gene with inverse comorbidity.
This study was supported by the RFBR (№ 19-015-00391).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dna-methylation-of-cdkn2b-cdkn2b-as1-enhancer-in-huntingtons-disease-and-lung-cancer/