A comparative analysis of somatic mutational profiles according to HIV status among women with cervical intraepithelial neoplasia 3 (CIN3): a focus on hotspots in TP53, PIK3CA, PTEN, and EGFR

Background Despite the success of antiretroviral therapy in HIV treatment, cervical cancer remains a leading malignancy in HIV-infected women. Additionally, co-infection by HIV and HPV further accelerates cervical cancer development. There are limited studies on the role of host somatic variations in HIV infected and HIV-negative women with cervical cancer. Therefore, this study aimed to investigate and compare host somatic genetic variation in cervical biopsies obtained from HIV infected and HIV-negative women with cervical intraepithelial neoplasia 3 to understand the genomic landscape. The distribution of HPV types was also investigated between HIV infected and HIV-negative women. Methods The project used an age-matched case-control study utilizing archived cervical biopsies from 88 women (44 HIV infected, 44 HIV-negative) attending Groote Schuur Hospital Cancer Clinic between 2020 and 2022. HPV infection and type were confirmed using the Anyplex (TM) II HPV28 Detection kit. Six hotspot regions in the four commonly mutated genes (TP53, PIK3CA, PTEN, and EGFR) in cervical cancer were genotyped using PCR and Sanger Sequencing. Variant pathogenicity was assessed using SIFT, Polyphen-2, and ClinVar tools. Results The median age was 37 years (IQR: 34-41) for HIV infected women and 35 years (IQR:32- 43) for HIV-negative women. Significantly more HIV-negative women (51% vs. 12%) reported tobacco smoking (p < 0.0001), menstruation irregularities (74% vs. 35%; p = 0.005), and contraception usage (77% vs. 59%; p = 0.019), when compared to their HIV-infected counterparts. Common HPV types identified were HPV16 (n = 43/88, 49%), HPV35 (n = 12/88, 14%), and HPV58 (n = 10/88, 11%). A total of 232 genetic variants were reported. HIV infected women had a significantly higher (p = 0.0406) burden of pathogenic variants (31%) compared to the HIV-negative (15%). The spectrum of observed mutations included stop-gain, missense, synonymous, and intronic changes. Most of the stop gain mutations in TP53 and PIK3CA were reported among HIV infected women (n = 4/5), compared to HIV-negative women (n = 1/5). Damaging variants were more prevalent in women under 50 in both cohorts. We also report on rare HPV subtypes currently not included in the diagnostic HPV test kits in this cohort (HPV 82, 42, 43 and 53). Conclusion HIV-infection status and age appear to be risk factors for higher burden of pathogenic mutations in genes that predispose to cervical cancer. Mutation profiles in PIK3CA and TP53 genes could be biomarkers of cervical cancer progression but more studies are needed.