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Proc. Natl. Acad. Sci. USA, Apr 23 2024, 121 (17) | https://doi.org/10.1073/pnas.2321898121 Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix

Stefania Bellone^a,1, Kyungjo Jeong^b,1, Mari Kyllesø Halle^c,d, Camilla Krakstad^c,d, Blair McNamara^a, Michelle Greenman^a, Levent Mutlu^a, Cem Demirkiran^a, Tobias Max Philipp Hartwich^a, Yang Yang-Hartwich^a, Margherita Zipponi^a, Natalia Buza^e, Pei Hui^e, Francesco Raspagliesi^f, Salvatore Lopez^f,2, Biagio Paolini^f, Massimo Milione^f, Emanuele Perrone^g, Giovanni Scambiag, Gary Altwerger^a, Antonella Ravaggi^h, Eliana Bignotti^h, Gloria S. Huang^a, Vaagn Andikyan^a, Mitchell Clark^a, Elena Ratner^a, Masoud Azodi^a, Peter E. Schwartz^a, Charles M. Quickⁱ, Roberto Angioli^j, Corrado Terranova^j, Samir Zaidi^k, Shuvro Nandi^l, Ludmil B. Alexandrov^l, Eric R. Siegel^m, Jungmin Choi^b,3, Joseph Schlessinger^n,3, and Alessandro D. Santin^a,3

^aDepartment of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.

^bDepartment of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea.

^cCentre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway.

^dDepartment of Obstetrics and Gynecology, Haukeland University Hospital, Bergen 5009, Norway.

eDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06510.

fFirst Pathology Division, Fondazione Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori di Milano, Milano 20133, Italy.

gUnit 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.

h"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.

iDepartment of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205.

jDepartment of Obstetrics and Gynecology, Università Campus Bio-Medico di Roma, Rome 00128, Italy.

kDepartment of Genitourinary Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10069.

lDepartment of Cellular and Molecular Medicine, University of California San Diego, San Diego, CA 92093.

mDepartment of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR 72205.

nDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.

¹S.B. and K.J. contributed equally to this work.

²Present address: Gynecologic Oncology Unit, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Giovanni Paolo II, 70124 Bari, Italy.

³To whom correspondence may be addressed. : Jungmin Choi, Joseph Schlessinger, and Alessandro D. Santin

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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-17)
연구진국내(교신)+국외 연구진
분야 의약학 > 유전 및 유전체의학

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