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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00951

Cervical Tumour Biopsy DNA Shows More Frequency Of Chromosomal Loss Of Heterozygosity (LOH) And Microsatellite Instability (MSI) At The HLA II Locus In HIV/HPV Co-Infected Women Than In HIV Seronegative Women in South Africa.

  • 1University of Cape Town, South Africa
  • 2Division of Medical Virology, Faculty of Health Sciences, University of Cape Town, South Africa
  • 3School of Medicine, University of Namibia, Namibia
  • 4Clinical Gynaecological Cancer Research Centre, University of Cape Town, South African Medical Research Council, South Africa
  • 5Groothe Schuur Hospital, Department of Obstetrics & Gynaecology, Faculty of Health Sciences, University of Cape Town, South Africa
  • 6Institute of Infectious Diseases and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, South Africa
  • 7Division of Immunology, Faculty of Health Sciences, University of Cape Town, South Africa
  • 8Department of Biomedicine and Genetics, Medical University of Lodz, Poland
  • 9Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, South Africa

Background
A subset of women who are co-infected with human immunodeficiency virus type 1 (HIV) and human papillomavirus (HPV) progress rapidly to cervical disease regardless of high CD4 counts. Chromosomal loss of heterozygosity (LOH) and microsatellite instability (MSI) are early frequent genetic alterations occurring in solid tumours. Loss of an allele or part of a chromosome can have multiple functional effects on immune response genes, oncogenes, DNA damage-repair genes and tumour suppressor genes. To characterise the genetic alterations that may influence rapid tumour progression in some HIV positive women, we have compared the extent of LOH and MSI at the HLA II locus on chromosome 6p in cervical tumour biopsy DNA samples with regard to HIV/HPV co-infection in South African women.
Methods
A total of 164 women with cervical disease were recruited for this study, of which 74 were HIV positive and 90 were HIV seronegative. DNA from cervical tumours and matched buccal swabs were used for analyses. Chromosomal single locus assay by capillary array electrophoresis DNA microsatellites analyses was used to study LOH and MSI with six fluorescently-labelled oligonucleotide primer pairs in a multiplex PCR amplification. Pearson chi-squared test for homogeneity of proportions using an exact p value, a two-proportion Z-score test, ROC curves and a logistic regression model were used for statistical analyses. All p-values were corrected for false discovery rate (FDR) by Benjamini-Hochberg test and the adjusted p-values (q-values) were reported. All tests were significant when both p and q<0.05.
Results
Tumour DNA from HIV/HPV co-infected women demonstrated a higher frequency of LOH/MSI at the HLA II locus than tumour DNA from HIV seronegative women at 6p21.21 (D6S2447, 74.2% versus 42.6%; p=0.001, q=0.003), 6p21.31 (D6S2881, 78.3% versus 42.9%; p=0.002, q=0.004), 6p21.32 (D6S2666, 79% versus 57.1%; p=0.035, q=0.052), and 6p21.33 (D6S2746, 64.3% versus 29.4%; p<0.001, q<0.001), respectively.
Conclusions
HPV infection alone can induce LOH/MSI at the HLA II locus in cervical tumour DNA, whereas HIV co-infection exacerbates it, this may accelerate cervical disease progression in a subset of HIV positive women.

Keywords: cervical cancer, Loss of Heterozygosity, Microsatellite Instability, HLA II locus on chromosome 6, HIV/HPV co-infection, genetic alterations

Received: 25 Jul 2019; Accepted: 09 Sep 2019.

Copyright: © 2019 Chambuso, Kaambo, Denny, Gray, Williamson, Migdalska-Sęk, Agenbag, Rebello and Ramesar. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Mx. Ramadhani S. Chambuso, University of Cape Town, Cape Town, South Africa, rchambuso@outlook.com