ArticleProceedings of the National Academy of Sciences of the United States of America2019
Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.
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Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers, 2 of them syntheses that pooled it.
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44citing papers in PubMed, 2 pooled it
11.2field-weighted citation impact, top 1% of its field
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Who cites it
44 citing papers in PubMed, 2 syntheses or guidelines pooled it, 93 citations in OpenAlex.
- [Pregnancy-preserving and maternal-fetal management in a patient with rare large cell neuroendocrine carcinoma of the uterine cervix].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2021Pooled it
- Prevalence of HER2 overexpression and amplification in cervical cancer: A systematic review and meta-analysis.PloS one · 2021Pooled it
- Targeting HER2-mutant metastatic cervical cancer with neratinib: Final results from the phase 2 SUMMIT basket trial.Gynecologic oncology · 2024Trial
- Neratinib in patients with HER2-mutant, metastatic cervical cancer: Findings from the phase 2 SUMMIT basket trial.Gynecologic oncology · 2020Trial
- Preclinical in vitro and in vivo activity of trastuzumab deruxtecan againstGynecologic oncology reports · 2026Article
- Association of Increased MIEN1 Copy Number With Worse Outcomes in Lung Adenocarcinoma and Cervical Cancer.Cureus · 2026Article
- Comprehensive Genomic Characterization of 102 Cervical Adenocarcinoma Tumors.Medicina (Kaunas, Lithuania) · 2026Article
- Invasive stratified mucin-producing carcinoma of the cervix: a report of 34 cases of immunohistochemical and clinicopathological findings.Frontiers in oncology · 2026Article
- Comprehensive Insights into APOBEC Mutations in Thyroid Cancer: Prognostic and Therapeutic Discoveries.Biological procedures online · 2025Article
- Endocervical adenocarcinoma with a micropapillary component: a clinicopathologic analysis in the setting of current WHO classification.Virchows Archiv : an international journal of pathology · 2025Article
- Genomics of cervical, vulvar and vaginal cancers and the potential of precision medicine.Therapeutic advances in medical oncology · 2025Review
- Circulating Tumor DNA in Cervical Cancer: Clinical Utility and Medico-Legal Perspectives.Oncology research · 2025Review
- Pharmacotherapy for cervical cancer: current standard of care and new perspectives.Expert opinion on pharmacotherapy · 2024Review
- Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- CINNAMON-GUI: Revolutionizing Pap Smear Analysis with CNN-Based Digital Pathology Image Classification.F1000Research · 2024Article
- Mixed mucinous adenocarcinoma/large cell neuroendocrine carcinoma of the uterine cervix: case report and molecular characterization of a rare entity.Virchows Archiv : an international journal of pathology · 2024Article
- Article
- Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers.Nature communications · 2023Article
- Single-cell dissection of cellular and molecular features underlying human cervical squamous cell carcinoma initiation and progression.Science advances · 2023Article
- Application value of whole exome sequencing in screening and identifying novel mutations of hypopharyngeal cancer.Scientific reports · 2023Article
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Authors and funding
45 authors at 11 institutions in 3 countries.
Luca ZammataroDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Salvatore LopezDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Stefania BelloneDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Francesca PettinellaDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena BonazzoliDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Emanuele PerroneDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Siming ZhaoDepartment of Human Genetics, The University of Chicago, Chicago, IL 60637.
Gulden MenderesDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Gary AltwergerDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Chanhee HanDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Burak ZeybekDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Anna BianchiDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Aranzazu ManzanoDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Paola ManaraDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Emiliano CoccoHuman Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065.
Natalia BuzaDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Pei HuiDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Serena WongDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06520.
Antonella Ravaggi"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.ORCID 0000-0003-4661-9979
Eliana Bignotti"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.ORCID 0000-0001-6380-6181
Chiara Romani"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Paola Todeschini"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Laura Zanotti"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Franco Odicino"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Sergio Pecorelli"Angelo Nocivelli" Institute of Molecular Medicine, Department of Obstetrics, & Gynecology, University of Brescia, 25100 Brescia, Italy.
Carla DonzelliDepartment of Pathology, University of Brescia, 25100 Brescia, Italy.
Laura ArdighieriDepartment of Pathology, University of Brescia, 25100 Brescia, Italy.
Roberto AngioliDepartment of Gynecology and Obstetrics, Università Campus Bio-Medico di Roma, 00128 Rome, Italy.
Francesco RaspagliesiDepartment of Gynecology Oncology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori di Milano, 20133 Milan, Italy.
Giovanni ScambiaInstitute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
Jungmin ChoiDepartment of Genetics, The Rockefeller University, New York, NY 10065.
Weilai DongDepartment of Genetics, The Rockefeller University, New York, NY 10065.
Kaya BilguvarDepartment of Genetics, Yale University School of Medicine, New Haven, CT 06510.
Ludmil B AlexandrovDepartment of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093.ORCID 0000-0003-3596-4515
Dan-Arin SilasiDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Gloria S HuangDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Elena RatnerDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Masoud AzodiDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Peter E SchwartzDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Valentina PirazzoliYale Cancer Center, Yale University School of Medicine, New Haven, CT 06510.
Amy L StieglerDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
Titus J BoggonDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520.
Richard P LiftonDepartment of Genetics, The Rockefeller University, New York, NY 10065.
Joseph SchlessingerDepartment of Pharmacology, Yale University School of Medicine, New Haven, CT 06520 Joseph.Schlessinger@Yale.edu.
Alessandro D SantinDepartment of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510.
Yale University · USUniversity of Brescia · ITRockefeller University · USUniversità Cattolica del Sacro Cuore · ITFondazione IRCCS Istituto Nazionale dei Tumori · ITKorea University · KRMemorial Sloan Kettering Cancer Center · USUniversità Campus Bio-Medico · ITUniversity of California San Diego · USUniversity of Chicago · USYale Cancer Center · US
Funding
X-RAY CRYSTALLOGRAPHYP30CA008748 · NCI · SLOAN-KETTERING INSTITUTE FOR CANCER RES · PI Hongbiao Carl Lekaye · 1985 to 2026
$347.4MYale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MYale Pathology Tissue Services Shared ResourceP30CA016359 · NCI · YALE UNIVERSITY · PI MEGAN C KING · 1985 to 2026
$85.0MTranslational Research in Oncology Training ProgramT32CA160001 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI SAWYERS, CHARLES L. · 2011 to 2020
$2.0MIntegrated genomic analysis of racial disparities in endometrial cancerU01CA176067 · NCI · YALE UNIVERSITY · PI SANTIN, ALESSANDRO D · 2014 to 2018
$1.7MCPE Peptide-Based Nanoparticles for the Diagnosis and Therapy of Chemotherapy ResR01CA154460 · NCI · YALE UNIVERSITY · PI SANTIN, ALESSANDRO D · 2011 to 2015
$1.7MNCATS NIH HHS UL1 TR001863NCI NIH HHS P30 CA008748NCI NIH HHS P30 CA016359NCI NIH HHS R01 CA154460NCI NIH HHS T32 CA160001NCI NIH HHS U01 CA176067
Abstract
The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring
Indexed as
Exome SequencingMutationAnimalsCell Line, TumorClass I Phosphatidylinositol 3-KinasesCombined Modality TherapyDNA Copy Number VariationsErb-b2 Receptor Tyrosine KinasesFemaleHeterograftsHumansPolymorphism, Single NucleotideUterine Cervical NeoplasmsClass I Phosphatidylinositol 3-KinasesERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesPIK3CA protein, humancervical cancercopanlisibHER2/neuneratinibPIK3CA
Identifiers
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