Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Zhongshan hospital, Fudan University, Shanghai 200032, China.
Gynecol Oncol. 2021 Jun;161(3):779-786. doi: 10.1016/j.ygyno.2021.04.019. Epub 2021 May 1.
Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treatment progress has been made for decades. We sought to map its genetic profiles, and identify whether SCNEC harbor mutations and potential targets for therapeutic interventions.
Primary tumor tissue and blood samples were obtained from 51 patients with SCNEC. The next-generation sequencing was carried out to detect mutations of 520 cancer-related genes, including the entire exon regions of 312 genes and the hotspot mutation regions of 208 genes. Quantitative multiplex PCR was performed for the detection of seven high-risk HPV types.
Of the 51 detected patients, 92.16% were positive for HPV 18. Ninety-eight percent of cases harbored genetic alterations. Two cases were observed with hypermutated phenotype and determined as MSI-H/dMMR. Genetic mutations were clustering in RTK/RAS(42.86%), PI3K-AKT(38.78%), p53 pathway(22.45%) and MYC family(20.41%). Mutations in genes involved in the p53 pathway indicate a poorer prognosis (3-year OS, 33.5% vs 59.9%, p = 0.031). A total of seven patients harboring mutations in homogeneous recombination repair (HRR) genes were reported. In addition, IRS2 and SOX2 were amplified in 14.9% and 6.12% of SCNEC patients, respectively.
SCNEC is specifically associated with HPV 18 infection. Its genetic alterations are characterized by a combined feature of high-risk HPV driven events and mutations observed in common neuroendocrine carcinoma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indicating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies.
宫颈小细胞神经内分泌癌（SCNEC）是一种致命的恶性肿瘤，几十年来治疗进展甚微。我们试图绘制其基因图谱，并确定 SCNEC 是否存在突变和潜在的治疗干预靶点。
从 51 例 SCNEC 患者中获取原发肿瘤组织和血液样本。进行下一代测序以检测 520 个与癌症相关的基因的突变，包括 312 个基因的整个外显子区域和 208 个基因的热点突变区域。进行定量多重 PCR 检测以检测七种高危 HPV 类型。
在检测的 51 例患者中，92.16%为 HPV 18 阳性。98%的病例存在遗传改变。有两例病例表现出高度突变表型，被确定为 MSI-H/dMMR。遗传突变聚类在 RTK/RAS（42.86%）、PI3K-AKT（38.78%）、p53 通路（22.45%）和 MYC 家族（20.41%）。参与 p53 通路的基因突变表明预后较差（3 年 OS，33.5%比 59.9%，p=0.031）。报道了总共 7 例具有同源重组修复（HRR）基因突变的患者。此外，IRS2 和 SOX2 在 14.9%和 6.12%的 SCNEC 患者中分别扩增。
SCNEC 与 HPV 18 感染密切相关。其遗传改变的特征是高危 HPV 驱动事件与常见神经内分泌癌中观察到的突变相结合。我们鉴定了几个可靶向的突变基因，包括 KRAS、PIK3CA、IRS2、SOX2 和 HRR 基因，表明这些患者可能受益于靶向治疗。MSI-H/dMMR 个体可能受益于检查点阻断治疗。
