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

• 成果类型: Article
• 署名作者: Bellone, Stefania; Jeong, Kyungjo; Halle, Mari Kylleso; Krakstad, Camilla; Mcnamara, Blair; Greenman, Michelle; Mutlu, Levent; Demirkiran, Cem; Hartwich, Tobias Max Philipp; Yang-Hartwich, Yang; Zipponi, Margherita; Buza, Natalia; Hui, Pei; Raspagliesi, Francesco; Lopez, Salvatore; Paolini, Biagio; Milione, Massimo; Perrone, Emanuele; Scambia, Giovanni; Altwerger, Gary; Ravaggi, Antonella; Bignotti, Eliana; Huang, Gloria S.; Andikyan, Vaagn; Clark, Mitchell; Ratner, Elena; Azodi, Masoud; Schwartz, Peter E.; Quick, Charles M.; Angioli, Roberto; Terranova, Corrado; Zaidi, Samir; Nandi, Shuvro; Alexandrov, Ludmil B.; Siegel, Eric R.; Choi, Jungmin; Schlessinger, Joseph; Santin, Alessandro D.
• 署名单位: Yale University; Korea University; Korea University Medicine (KU Medicine); University of Bergen; University of Bergen; Haukeland University Hospital; Yale University; Fondazione IRCCS Istituto Nazionale Tumori Milan; Catholic University of the Sacred Heart; IRCCS Policlinico Gemelli; Hospital Spedali Civili Brescia; University of Brescia; University of Arkansas System; University of Arkansas Medical Sciences; University Campus Bio-Medico - Rome Italy; Memorial Sloan Kettering Cancer Center; University of California System; University of California San Diego; University of Arkansas System; University of Arkansas Medical Sciences; Yale University; IRCCS Istituto Tumori Bari Giovanni Paolo II
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14680
• DOI: 10.1073/pnas.2321898121
• 发表日期: 2024-04-23
• 关键词: cancer; genes; tumors

摘要

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 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 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.