Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix
Authors
Stefania Bellone, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Kyungjo Jeong, Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.
Mari Kyllesø Halle, Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
Camilla Krakstad, Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.
Blair McNamara, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Michelle Greenman, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Levent Mutlu, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Cem Demirkiran, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Tobias Max Hartwich, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Yang Yang-Hartwich, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Margherita Zipponi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Natalia Buza, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Pei Hui, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Francesco Raspagliesi, First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.
Salvatore Lopez, First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.
Biagio Paolini, First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.
Massimo Milione, First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.
Emanuele Perrone, Unit of Gynecologic Oncology, Department Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome 00168, Italy.
Giovanni Scambia, Unit of Gynecologic Oncology, Department Woman and Child Health Sciences and Public Health, Fondazione Policlinico Universitario A. Gemelli Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome 00168, Italy.
Gary Altwerger, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Antonella Ravaggi, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili and University of Brescia, Brescia 25123, Italy.
Eliana Bignotti, "Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics and Gynecology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili and University of Brescia, Brescia 25123, Italy.
Gloria S. Huang, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Vaagn Andikyan, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Mitchell Clark, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena Ratner, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Masoud Azodi, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Peter E. Schwartz, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Charles M. Quick, Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.
Roberto Angioli, Department of Obstetrics and Gynecology, Università Campus Bio-Medico di Roma, Rome 00128, Italy.
Corrado Terranova, Department of Obstetrics and Gynecology, Università Campus Bio-Medico di Roma, Rome 00128, Italy.
Samir Zaidi, Department of Genitourinary Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10069.
Publication Title
Proceedings of the National Academy of Sciences of the United States of America
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.
DOI
10.1073/pnas.2321898121
Publication Date
4-23-2024
Recommended Citation
Bellone, Stefania; Jeong, Kyungjo; Halle, Mari Kyllesø; Krakstad, Camilla; McNamara, Blair; Greenman, Michelle; Mutlu, Levent; Demirkiran, Cem; Hartwich, Tobias Max; 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; and Zaidi, Samir, "Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix" (2024). Obstetrics and Gynecology. 139.
https://scholar.bridgeporthospital.org/obgyn/139
Identifier
38625939 (pubmed); PMC11046577 (pmc); 10.1073/pnas.2321898121 (doi)
