期刊
FRONTIERS IN ONCOLOGY
卷 11, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.560296
关键词
Botswana; invasive cervical cancer; human immunodeficiency virus; DNA methylation; tumor supressor gene; human papillomavirus
类别
资金
- Sub-Saharan African Collaborative HIV and Cancer Consortia-U54 [1U54 CA190158-01]
- American Cancer Society International Fellowships for Beginning Investigators (ACSBI)
- Conquer Cancer Foundation Young Investigator Award
- Mentored Patient Oriented Career Research Development Award [1-K08CA230170-01A1]
- Penn Center for AIDS Research [5-P30-AI-045008-17]
- Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE), a DELTAS Africa Initiative [DEL-15-006]
- New Partnership for Africa's Development Planning and Coordinating Agency (NEPAD Agency)
- Wellcome Trust [107752/Z/15/Z]
The study revealed a high promoter methylation rate of multiple tumor suppressor genes in cervical cancer patients, which was associated with increased risk of cervical cancer. Methylation of the RARB gene showed the strongest association with cervical cancer, and both cervical cancer and promoter methylation of RARB and DAPK1 genes were associated with increasing age.
Background: Epidemics of human immunodeficiency virus (HIV) and cervical cancer are interconnected. DNA hypermethylation of host genes' promoter in cervical lesions has also been recognized as a contributor to cervical cancer progression. Methods: For this purpose we analyzed promoter methylation of four tumor suppressor genes (RARB, CADM1, DAPK1 and PAX1) and explored their possible association with cervical cancer in Botswana among women of known HIV status. Overall, 228 cervical specimens (128 cervical cancers and 100 non-cancer subjects) were used. Yates-corrected chi-square test and Fisher's exact test were used to explore the association of promoter methylation for each host gene and cancer status. Subsequently, a logistic regression analysis was performed to find which factors, HIV status, high risk-HPV genotypes, patient's age and promoter methylation, were associated with the following dependent variables: cancer status, cervical cancer stage and promoter methylation rate. Results: In patients with cervical cancer the rate of promoter methylation observed was greater than 64% in all the genes studied. Analysis also showed a higher risk of cervical cancer according to the increased number of methylated promoter genes (OR = 6.20; 95% CI: 3.66-10.51; P < 0.001). RARB methylation showed the strongest association with cervical cancer compared to other genes (OR = 15.25; 95% CI: 6.06-40.0; P < 0.001). Cervical cancer and promoter methylation of RARB and DAPK1 genes were associated with increasing age (OR = 1.12; 95% CI: 1.01-1.26; P = 0.037 and OR = 1.05; 95% CI: 1.00-1.10; P = 0.040). The presence of epigenetic changes at those genes appeared to be independent of HIV status among subjects with cervical cancer. Moreover, we found that cervical cancer stage was influenced by RARB (chi(2)= 7.32; P = 0.002) and CADM1 (chi(2)=12.68; P = 0.013) hypermethylation, and HIV status (chi(2)= 19.93; P = 0.001). Conclusion: This study confirms the association between invasive cervical cancer and promoter gene methylation of tumor suppressing genes at the site of cancer. HIV infection did not show any association to methylation changes in this group of cervical cancer patients from Botswana. Further studies are needed to better understand the role of HIV in methylation of host genes among cancer subjects leading to cervical cancer progression.
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