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. 2021 Mar 10;13(6):1215.
doi: 10.3390/cancers13061215.

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix

Daisuke Takayanagi  1 , Sou Hirose  2 , Ikumi Kuno  1   3 , Yuka Asami  1   4 , Naoya Murakami  5 , Maiko Matsuda  1 , Yoko Shimada  1 , Kuniko Sunami  1 , Masaaki Komatsu  6   7 , Ryuji Hamamoto  6   7 , Mayumi Kobayashi Kato  8 , Koji Matsumoto  4 , Takashi Kohno  1 , Tomoyasu Kato  8 , Kouya Shiraishi  1 , Hiroshi Yoshida  9
Affiliations

Comparative Analysis of Genetic Alterations, HPV-Status, and PD-L1 Expression in Neuroendocrine Carcinomas of the Cervix

Daisuke Takayanagi et al. Cancers (Basel). .

Abstract

Neuroendocrine carcinoma of the cervix (NECC) is a rare and highly aggressive tumor with no efficient treatment. We examined genetic features of NECC and identified potential therapeutic targets. A total of 272 patients with cervical cancer (25 NECC, 180 squamous cell carcinoma, 53 adenocarcinoma, and 14 adenosquamous carcinoma) were enrolled. Somatic hotspot mutations in 50 cancer-related genes were detected using the Ion AmpliSeq Cancer Hotspot Panel v2. Human papillomavirus (HPV)-positivity was examined by polymerase chain reaction (PCR)-based testing and in situ hybridization assays. Programmed cell death-ligand 1 (PD-L1) expression was examined using immunohistochemistry. Somatic mutation data for 320 cases of cervical cancer from the Project GENIE database were also analyzed. NECC showed similar (PIK3CA, 32%; TP53, 24%) and distinct (SMAD4, 20%; RET, 16%; EGFR, 12%; APC, 12%) alterations compared with other histological types. The GENIE cohort had similar profiles and RB1 mutations in 27.6% of NECC cases. Eleven (44%) cases had at least one actionable mutation linked to molecular targeted therapies and 14 (56%) cases showed more than one combined positive score for PD-L1 expression. HPV-positivity was observed in all NECC cases with a predominance of HPV-18. We report specific gene mutation profiles for NECC, which can provide a basis for the development of novel therapeutic strategies.

Keywords: HPV; PD-L1; cervical cancer; neuroendocrine carcinomas; next-generation sequencing; targeted therapy.

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Conflict of interest statement

The authors state that there are no conflict of interest to declare.

Figures

Figure 1
Figure 1
Somatic alterations in cervical cancer and associated clinicopathological features. Two hundred and seventy-two cases were categorized according to their (A) histological types and clinicopathological features, (B) major mutated genes of neuroendocrine carcinoma, and (C) copy number alterations. Mutated genes are color-coded according to their mutation type.
Figure 2
Figure 2
Association between genetic alterations and histological types in cervical cancer. Percentages of samples mutated in individual tumor types are shown. (A) the present study, (B) Project GENIE v8.0. The p-value was calculated using the Fisher’s exact test, * p < 0.05, ** p < 0.001. NEC: neuroendocrine carcinoma; SCC: squamous cell carcinoma; ADC: adenocarcinoma; ASC: adenosquamous carcinoma.
Figure 3
Figure 3
Frequency of actionable genetic mutations in cervical cancers. Percentages of samples mutated in individual tumor types are shown. NEC, neuroendocrine carcinoma; SCC, squamous cell carcinoma; ADC, adenocarcinoma; ASC, adenosquamous carcinoma.
Figure 4
Figure 4
Correlation between histological types and human papillomavirus (HPV) genotypes in 272 cervical cancer specimens. HPV genotypes were compared with neuroendocrine carcinoma (NEC) and other histological types of cervical cancer, including squamous cell carcinoma (SCC), adenocarcinoma (ADC), and adenosquamous carcinoma (ASC). The P-value was calculated using the Fisher’s exact test, * p < 0.05, ** p < 0.01.
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