Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, USA.
Cancer Genomics Research Laboratory, Leidos Biomedical Research, Inc., Frederick, MD, USA.
Nat Commun. 2024 Sep 12;15(1):7895. doi: 10.1038/s41467-024-51713-y.
Invasive cervical cancers (ICC), caused by HPV infections, have a heterogeneous molecular landscape. We investigate the detection, timing, and HPV type specificity of somatic mutations in 3929 HPV-positive exfoliated cervical cell samples from individuals undergoing cervical screening in the U.S. using deep targeted sequencing in ICC cases, precancers, and HPV-positive controls. We discover a subset of hotspot mutations rare in controls (2.6%) but significantly more prevalent in precancers, particularly glandular precancer lesions (10.2%), and cancers (25.7%), supporting their involvement in ICC carcinogenesis. Hotspot mutations differ by HPV type, and HPV18/45-positive ICC are more likely to have multiple hotspot mutations compared to HPV16-positive ICC. The proportion of cells containing hotspot mutations is higher (i.e., higher variant allele fraction) in ICC and mutations are detectable up to 6 years prior to cancer diagnosis. Our findings demonstrate the feasibility of using exfoliated cervical cells for detection of somatic mutations as potential diagnostic biomarkers.
HPV 感染引起的浸润性宫颈癌（ICC）具有异质性的分子特征。我们在美国进行的宫颈筛查中，对 3929 例 HPV 阳性的宫颈脱落细胞样本进行了深度靶向测序，以研究 ICC 病例、癌前病变和 HPV 阳性对照中体细胞突变的检测、发生时间和 HPV 型特异性。我们发现了一组在对照组中罕见（2.6%）但在癌前病变中更为常见的热点突变（尤其是腺性癌前病变，10.2%）和癌症（25.7%），支持它们参与 ICC 的发生发展。热点突变因 HPV 型而异，与 HPV16 阳性 ICC 相比，HPV18/45 阳性 ICC 更有可能存在多个热点突变。在 ICC 中，含有热点突变的细胞比例更高（即更高的变异等位基因分数），并且可以在癌症诊断前长达 6 年检测到这些突变。我们的研究结果表明，使用宫颈脱落细胞检测体细胞突变作为潜在的诊断生物标志物是可行的。
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