The next generation sequencing of cancer-related genes in small cell neuroendocrine carcinoma of the cervix

Objective. Small cell neuroendocrine carcinoma of the cervix (SCNEC) is a lethal malignancy and little treat-ment 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. Methods. 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 per-formed for the detection of seven high-risk HPV types. Results. 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 fam-ily(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. Conclusions. 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 carci-noma. We identified several targetable mutated genes, including KRAS, PIK3CA, IRS2, SOX2, and HRR genes, indi-cating the potential efficacy of target therapies in these patients. MSI-H/dMMR individuals may benefit from checkpoint blockade therapies. (c) 2021 Published by Elsevier Inc.

Automated summary

Small cell neuroendocrine carcinoma of the cervix (SCNEC) is specifically associated with HPV 18 infection and characterized by a high genetic mutation rate, with mutations in genes related to the p53 pathway potentially affecting prognosis. Some patients harbor mutations in homogeneous recombination repair (HRR) genes, providing therapeutic targets. The study suggests that targeted therapies against certain mutated genes may have potential efficacy in SCNEC patients.