{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:21:40Z","timestamp":1791199300319,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T00:00:00Z","timestamp":1713225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100023790","name":"HHS | NIH | NCI | Advancing Science and Practice in the Retail Environment","doi-asserted-by":"publisher","award":["U01 CA176067-01A1"],"award-info":[{"award-number":["U01 CA176067-01A1"]}],"id":[{"id":"10.13039\/100023790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023790","name":"HHS | NIH | NCI | Advancing Science and Practice in the Retail Environment","doi-asserted-by":"publisher","award":["CA-16359"],"award-info":[{"award-number":["CA-16359"]}],"id":[{"id":"10.13039\/100023790","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF2022R1A4A2000827"],"award-info":[{"award-number":["NRF2022R1A4A2000827"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,23]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic>PIK3CA, KMT2D\/MLL2, K-RAS, ARID1A, NOTCH2,<\/jats:italic>\n                    and\n                    <jats:italic>RPL10.<\/jats:italic>\n                    The top mutated genes included\n                    <jats:italic>RB1, ARID1A, PTEN, KMT2D<\/jats:italic>\n                    \/\n                    <jats:italic>MLL2,<\/jats:italic>\n                    and\n                    <jats:italic>WDFY3,<\/jats:italic>\n                    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\n                    <jats:italic>ACLY-CRHR1<\/jats:italic>\n                    and\n                    <jats:italic>PVT1-MYC<\/jats:italic>\n                    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 &gt; T at CpG consistent with deficiencies in\n                    <jats:italic>MBD4<\/jats:italic>\n                    , 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 (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2321898121","type":"journal-article","created":{"date-parts":[[2024,4,16]],"date-time":"2024-04-16T13:51:48Z","timestamp":1713275508000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":26,"title":["Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix"],"prefix":"10.1073","volume":"121","author":[{"given":"Stefania","family":"Bellone","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06510"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyungjo","family":"Jeong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2660-8271","authenticated-orcid":false,"given":"Mari Kylles\u00f8","family":"Halle","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway"},{"name":"Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen 5009, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camilla","family":"Krakstad","sequence":"additional","affiliation":[{"name":"Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen 5021, Norway"},{"name":"Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen 5009, 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