Host somatic variation between women living with HIV with cervical intraepitheial lesions (CIN3) and their HIV negative counterparts

Mabizela, Nosipho

Host somatic variation between women living with HIV with cervical intraepitheial lesions (CIN3) and their HIV negative counterparts

Thesis / Dissertation

2024

Publisher

University of Cape Town

Department

Department of Pathology

Faculty

Faculty of Health Sciences

Abstract

Despite the use of antiretroviral therapy, cervical cancer remains a leading malignancy in women with HIV, who face a six-fold increased risk. Infection with HIV and HPV has been linked to accelerated cervical cancer development. However, there are limited studies on the role of host somatic variations in HIV-positive and HIV-negative women on cervical cancer. Understanding these variations may help identify potential genetic factors that contribute to accelerated cervical cancer development and differential response to treatment. This knowledge is important in targeting interventions and improving outcomes for women with HIV and cervical cancer. Therefore, this study aims to investigate host somatic genetic variation between cervical biopsies obtained from HIV-positive or HIV-negative women with histologically confirmed CIN3 to determine potential differences in genomic landscapes and HPV infection between HIV-positive and HIV-negative women. The matched case-control study utilized archived cervical biopsies from 88 women (44 HIV positive, 44 HIV-negative) attending Groote Schuur Hospital Cancer Clinic between 2020 and 2022. The cases and controls were carefully age matched. HPV infection and type were confirmed using the Anyplex™ II HPV28 Detection kit. In cervical cancer, six hotspot regions in the four commonly mutated genes (TP53, PIK3CA, PTEN, and EGFR) were genotyped using Polymerase Chain Reaction and validated using Sanger Sequencing. Missense variant pathogenicity was assessed using SIFT, Polyphen-2, and ClinVar tools. The median age was [37 years (IQR:34-41)] for HIV-positive women and [35 years (IQR:32- 43)] for HIV-negative women. In the HIV-negative cohort the women reported tobacco smoking (p<0.0001), menstruation irregularities (p=0.005), and contraception usage (p=0.019). These parameters were statistically significant when compared to HIV-positive cohort. Common HPV types identified were HPV 16 (43/88, 49%), 35 (12/88, 14%), and 58 (10/88, 11%). A total of 232 genetic variants were identified, with HIV-positive women having a significantly higher burden of pathogenic variants (31%) compared to 15% among the HIV-negative (p=0.0406). Identified mutations included stop-gain, missense, synonymous, and intron variants. The genes TP53 and PIK3CA had more stop-gain variants among HIV-positive women (4/5) compared to HIV-negative women with 1/5 of the 5 mutations. These damaging variants were more prevalent in women under 50 in both cohorts. In conclusion, younger women (<50 years) showed predominantly damaging variants, indicating more aggressive cancer, and a possible reason for early onset in the younger cohort. HIV-positive women displayed a higher mutation burden in PIK3CA and pathogenic variants in TP53, emphasizing the need to further explore these genes in gene expression studies.