Mabizela Nosipho, Soko Nyarai, Wu Hue-Tsi, Naidoo Richard, Dandara Collet
Pharmacogenomics and Drug Metabolism Group, Division of Human Genetics, Department of Pathology and Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Platform for Pharmacogenomics Research and Translation (PREMED) Unit, South Africa Medical Research Council, Cape Town, South Africa.
Infect Agent Cancer. 2025 Mar 17;20(1):18. doi: 10.1186/s13027-025-00647-1.
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.
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™ 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.
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).
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.
尽管抗逆转录病毒疗法在治疗HIV方面取得了成功，但宫颈癌仍是HIV感染女性中的主要恶性肿瘤。此外，HIV与HPV的合并感染会进一步加速宫颈癌的发展。关于宿主体细胞变异在感染HIV和未感染HIV的宫颈癌女性中的作用，相关研究较少。因此，本研究旨在调查和比较从患有宫颈上皮内瘤变3级的HIV感染女性和未感染HIV的女性的宫颈活检组织中获得的宿主体细胞基因变异，以了解基因组格局。同时还调查了HIV感染女性和未感染HIV的女性之间HPV类型的分布情况。
该项目采用年龄匹配的病例对照研究，利用2020年至2022年间在格罗特舒尔医院癌症诊所就诊的88名女性（44名HIV感染女性，44名未感染HIV女性）的存档宫颈活检组织。使用Anyplex™ II HPV28检测试剂盒确认HPV感染及类型。采用聚合酶链反应（PCR）和桑格测序对宫颈癌中四个常见突变基因（TP53、PIK3CA、PTEN和EGFR）的六个热点区域进行基因分型。使用SIFT、Polyphen-2和ClinVar工具评估变异的致病性。
HIV感染女性的中位年龄为37岁（四分位间距：34 - 41岁），未感染HIV女性的中位年龄为35岁（四分位间距：32 - 43岁）。与感染HIV的女性相比，未感染HIV的女性中报告吸烟（51% 对12%；p < 0.0001）、月经不规律（74% 对35%；p = 0.005）和使用避孕药具（77% 对59%；p = 0.019）的比例显著更高。鉴定出的常见HPV类型为HPV16（n = 43/88，49%）、HPV35（n = 12/88，14%）和HPV58（n = 10/88，11%）。共报告了232个基因变异。与未感染HIV的女性（15%）相比，感染HIV的女性中致病性变异的负担显著更高（p = 0.0406）（31%）。观察到的突变谱包括终止密码子获得、错义、同义及内含子变化。与未感染HIV的女性（n = 1/5）相比，TP53和PIK3CA中的大多数终止密码子获得突变见于感染HIV的女性（n = 4/5）。在两个队列中，有害变异在50岁以下女性中更为普遍。我们还报告了该队列中目前诊断HPV检测试剂盒未涵盖的罕见HPV亚型（HPV 82、42、43和53）。
HIV感染状态和年龄似乎是宫颈癌易感基因中致病性突变负担较高的危险因素。PIK3CA和TP53基因的突变谱可能是宫颈癌进展的生物标志物，但还需要更多研究。
