Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix

Stefania Bellone, Kyungjo Jeong, Mari Kyllesø Halle, Camilla Krakstad, Blair McNamara, Michelle Greenman, Levent Mutlu, Cem Demirkiran, Tobias Max Philipp Hartwich, Yang Yang-Hartwich, Margherita Zipponi, Natalia Buza, Pei Hui, Francesco Raspagliesi, Salvatore Lopez, Biagio Paolini, Massimo Milione, Emanuele Perrone, Giovanni Scambia, Gary AltwergerAntonella Ravaggi, Eliana Bignotti, Gloria S. Huang, Vaagn Andikyan, Mitchell Clark, Elena Ratner, Masoud Azodi, Peter E. Schwartz, Charles M. Quick, Roberto Angioli, Corrado Terranova, Samir Zaidi, Shuvro Nandi, Ludmil B. Alexandrov, Eric R. Siegel, Jungmin Choi, Joseph Schlessinger, Alessandro D. Santin

Research output: Contribution to journalArticlepeer-review

Abstract

High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D/MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p 22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4, a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib (P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies.

Original languageEnglish
Article numbere2321898121
JournalProceedings of the National Academy of Sciences of the United States of America
Volume121
Issue number17
DOIs
Publication statusPublished - 2024 Apr 23

Bibliographical note

Publisher Copyright:
Copyright © 2024 the Author(s).

Keywords

  • cancer
  • genetic analysis
  • mutations
  • neuroendocrine
  • oncogene

ASJC Scopus subject areas

  • General

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