1. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.
- Author
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Bellone, Stefania, Jeong, Kyungjo, Halle, Mari, Krakstad, Camilla, McNamara, Blair, Greenman, Michelle, Mutlu, Levent, Demirkiran, Cem, Hartwich, Tobias, 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, Andikyan, Vaagn, Clark, Mitchell, Ratner, Elena, Azodi, Masoud, Schwartz, Peter, Quick, Charles, Angioli, Roberto, Terranova, Corrado, Zaidi, Samir, Nandi, Shuvro, Alexandrov, Ludmil, Siegel, Eric, Choi, Jungmin, Schlessinger, Joseph, and Santin, Alessandro
- Subjects
cancer ,genetic analysis ,mutations ,neuroendocrine ,oncogene ,Humans ,Female ,Uterine Cervical Neoplasms ,Afatinib ,Phylogeny ,Phosphatidylinositol 3-Kinases ,Neuroendocrine Tumors ,Mutation ,Class I Phosphatidylinositol 3-Kinases ,Adenocarcinoma ,Carcinoma ,Neuroendocrine ,DNA Mutational Analysis - 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.
- Published
- 2024