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. 2024 Apr 23;121(17):e2321898121.
doi: 10.1073/pnas.2321898121. Epub 2024 Apr 16.

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

Stefania Bellone #  1 , Kyungjo Jeong #  2 , Mari Kyllesø Halle  3   4 , Camilla Krakstad  3   4 , Blair McNamara  1 , Michelle Greenman  1 , Levent Mutlu  1 , Cem Demirkiran  1 , Tobias Max Philipp Hartwich  1 , Yang Yang-Hartwich  1 , Margherita Zipponi  1 , Natalia Buza  5 , Pei Hui  5 , Francesco Raspagliesi  6 , Salvatore Lopez  6 , Biagio Paolini  6 , Massimo Milione  6 , Emanuele Perrone  7 , Giovanni Scambia  7 , Gary Altwerger  1 , Antonella Ravaggi  8 , Eliana Bignotti  8 , Gloria S Huang  1 , Vaagn Andikyan  1 , Mitchell Clark  1 , Elena Ratner  1 , Masoud Azodi  1 , Peter E Schwartz  1 , Charles M Quick  9 , Roberto Angioli  10 , Corrado Terranova  10 , Samir Zaidi  11 , Shuvro Nandi  12 , Ludmil B Alexandrov  12 , Eric R Siegel  13 , Jungmin Choi  2 , Joseph Schlessinger  14 , Alessandro D Santin  1
Affiliations

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

Stefania Bellone et al. Proc Natl Acad Sci U S A. .

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 (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). 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.

Keywords: cancer; genetic analysis; mutations; neuroendocrine; oncogene.

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Conflict of interest statement

Competing interests statement:A.D.S. is listed as author in a paper (i.e., N. Engl. J. Med. 2022; 386:437–448, DOI: 10.1056/NEJMoa2108330) where G.E.K. is listed as group author. A.D.S. had no interactions with G.E.K. (or any other of the 309-KEYNOTE-775 multicenter clinical trial Investigators) over the course of the research and writing of this paper.

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