Key Laboratory of Systems Biomedicine (Ministry of Education) and Collaborative Innovation Center of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
Shanghai-MOST Key Laboratory for Disease and Health Genomics, Chinese National Human Genome at Shanghai, Shanghai, China.
J Med Genet. 2019 Mar;56(3):186-194. doi: 10.1136/jmedgenet-2018-105745. Epub 2018 Dec 19.
To better understand the pathogenesis of cervical cancer (CC), we systematically analysed the genomic variation and human papillomavirus (HPV) integration profiles of cervical intraepithelial neoplasia (CIN) and CC.
We performed whole-genome sequencing or whole-exome sequencing of 102 tumour-normal pairs and human papillomavirus probe capture sequencing of 45 CCs, 44 CIN samples and 25 normal cervical samples, and constructed strict integrated workflow of genomic analysis.
Mutational analysis identified eight significantly mutated genes in CC including four genes (, , and ), which have not previously been reported in CC. Targetable alterations were identified in 55.9% of patients. In addition, HPV integration breakpoints occurred in 97.8% of the CC samples, 70.5% of the CIN samples and 42.8% of the normal cervical samples with HPV infection. Integrations of high-risk HPV strains in CCs, including HPV16, 18, 33 and 58, also occurred in the CIN samples. Moreover, gene mutations were detected in 52% of the CIN specimens, and 54.8% of these mutations occurred in genes that also mutated in CCs.
Our results lay the foundation for a deep understanding of the molecular mechanisms and finding new diagnostic and therapeutic targets of CC.
为了更好地了解宫颈癌（CC）的发病机制，我们系统地分析了宫颈上皮内瘤变（CIN）和 CC 的基因组变异和人乳头瘤病毒（HPV）整合谱。
我们对 102 对肿瘤-正常组织进行了全基因组测序或全外显子组测序，对 45 例 CC、44 例 CIN 样本和 25 例正常宫颈样本进行了人乳头瘤病毒探针捕获测序，并构建了严格的基因组分析综合工作流程。
突变分析在 CC 中鉴定出 8 个明显突变的基因，包括 4 个以前在 CC 中未报道过的基因（、、和）。在 55.9%的患者中发现了可靶向的改变。此外，在 97.8%的 CC 样本、70.5%的 CIN 样本和 42.8%的 HPV 感染的正常宫颈样本中发生了 HPV 整合断点。CC 中的高危 HPV 株（包括 HPV16、18、33 和 58）的整合也发生在 CIN 样本中。此外，在 52%的 CIN 标本中检测到基因突变，其中 54.8%的突变发生在 CC 中也发生突变的基因中。
我们的研究结果为深入了解 CC 的分子机制和寻找新的诊断和治疗靶点奠定了基础。
