학술논문
Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.
Document Type
Academic Journal
Author
Bellone S; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Jeong K; Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.; Halle MK; Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen 5009, Norway.; Krakstad C; Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.; Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen 5009, Norway.; McNamara B; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Greenman M; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Mutlu L; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Demirkiran C; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Hartwich TMP; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Yang-Hartwich Y; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Zipponi M; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Buza N; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.; Hui P; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.; Raspagliesi F; First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.; Lopez S; First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.; Paolini B; First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.; Milione M; First Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.; Perrone E; 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.; Scambia G; 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.; Altwerger G; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Ravaggi A; '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.; Bignotti E; '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.; Huang GS; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Andikyan V; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Clark M; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Ratner E; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Azodi M; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Schwartz PE; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.; Quick CM; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.; Angioli R; Department of Obstetrics and Gynecology, Università Campus Bio-Medico di Roma, Rome 00128, Italy.; Terranova C; Department of Obstetrics and Gynecology, Università Campus Bio-Medico di Roma, Rome 00128, Italy.; Zaidi S; Department of Genitourinary Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10069.; Nandi S; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093.; Alexandrov LB; Department of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093.; Siegel ER; Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205.; Choi J; Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.; Schlessinger J; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.; Santin AD; Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Source
Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
Subject
Language
English
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.
Competing Interests: 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.
Competing Interests: 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.