{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:09:40Z","timestamp":1792271380743,"version":"4.4.0"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"26","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,6,26]]},"abstract":"<jats:p>Infection by carcinogenic human papillomaviruses (HPV) results in precancers [cervical intraepithelial neoplasia (CIN)] and cancers near the ectoendocervical squamocolumnar (SC) junction of the cervix. However, the specific cells targeted by HPV have not been identified and the cellular origin of cervical cancer remains elusive. In this study, we uncovered a discrete population of SC junctional cells with unique morphology and gene-expression profile. We also demonstrated that the selected junctional biomarkers were expressed by a high percentage of high-grade CIN and cervical cancers associated with carcinogenic HPVs but rarely in ectocervical\/transformation zone CINs or those associated with noncarcinogenic HPVs. That the original SC junction immunophenotype was not regenerated at new SC junctions following excision, not induced by expression of viral oncoproteins in foreskin keratinocytes, and not seen in HPV-related precursors of the vagina, vulva, and penis further support the notion that junctional cells are the source of cervical cancer. Taken together, our findings suggest that carcinogenic HPV-related CINs and cervical cancers are linked to a small, discrete cell population that localizes to the SC junction of the cervix, expresses a unique gene expression signature, and is not regenerated after excision. The findings in this study uncover a potential target for cervical cancer prevention, provide insight into the risk assessment of cervical lesions, and establish a model for elucidating the pathway to cervical cancer following carcinogenic HPV infection.<\/jats:p>","DOI":"10.1073\/pnas.1202684109","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T01:53:56Z","timestamp":1339466036000},"page":"10516-10521","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":401,"title":["A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer"],"prefix":"10.1073","volume":"109","author":[{"given":"Michael","family":"Herfs","sequence":"first","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA 02115;"},{"name":"Department of Pathology, Groupe Interdisciplinaire de G\u00e9noprot\u00e9omique Appliqu\u00e9e (GIGA)-Cancer, University of Liege, Liege, Belgium;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A-STAR), Singapore 138672;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laury","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, University of California, Los Angeles, CA 90095;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa R.","family":"Nucci","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret E.","family":"McLaughlin-Drubin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Channing Laboratory, Brigham and Women\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"M\u00fcnger","sequence":"additional","affiliation":[{"name":"Department of Medicine, Channing Laboratory, Brigham and Women\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Feldman","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology and Reproductive Biology, Brigham and Women\u2019s Hospital, Boston, MA 02115; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank D.","family":"McKeon","sequence":"additional","affiliation":[{"name":"Genome Institute of Singapore, Agency for Science, Technology and Research (A-STAR), Singapore 138672;"},{"name":"Department of Cell Biology, Harvard Medical School, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wa","family":"Xian","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA 02115;"},{"name":"Institute of Medical Biology, A-STAR, Singapore 138648"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Crum","sequence":"additional","affiliation":[{"name":"Division of Women\u2019s and Perinatal Pathology, Department of Pathology, Brigham and Women\u2019s Hospital, Boston, MA 02115;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,6,11]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.12.3812"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1984.tb01944.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198404053101403"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.58.1.225-229.1986"},{"key":"e_1_3_3_5_2","first-page":"301","article-title":"Cervical intraepithelial neoplasia","volume":"8","author":"Richart RM","year":"1973","unstructured":"RM Richart, Cervical intraepithelial neoplasia. Pathol Annu 8, 301\u2013328 (1973).","journal-title":"Pathol Annu"},{"key":"e_1_3_3_6_2","first-page":"444","article-title":"Original site of cervical carcinoma; topographical relationship of carcinoma of the cervix to the external os and to the squamocolumnar junction","volume":"7","author":"Marsh M","year":"1956","unstructured":"M Marsh, Original site of cervical carcinoma; topographical relationship of carcinoma of the cervix to the external os and to the squamocolumnar junction. Obstet Gynecol 7, 444\u2013452 (1956).","journal-title":"Obstet Gynecol"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70230-8"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djq562"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa020586"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908502106"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.7.2930"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.19.7169"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.05.026"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1097\/PGP.0b013e31819932f8"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)65689-1"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.1174"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1097\/00000478-200107000-00006"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2007.07.047"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0b013e3181e8b2c4"},{"key":"e_1_3_3_20_2","first-page":"428","article-title":"Cervical intraepithelial neoplasia III: Long-term outcome after cold-knife conization with clear margins","volume":"97","author":"Reich O","year":"2001","unstructured":"O Reich, H Pickel, M Lahousen, K Tamussino, R Winter, Cervical intraepithelial neoplasia III: Long-term outcome after cold-knife conization with clear margins. Obstet Gynecol 97, 428\u2013430 (2001).","journal-title":"Obstet Gynecol"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(80)90892-3"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200104123441503"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa065497"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1010971"},{"key":"e_1_3_3_25_2","first-page":"269","volume-title":"Diagnostic Gynecologic and Obstetric Pathology","author":"Crum CP","year":"2011","unstructured":"CP Crum, ES Cibas, PG Rose, WA Peters, Cervical squamous neoplasia. Diagnostic Gynecologic and Obstetric Pathology, eds CP Crum, MR Nucci, KR Lee (Elsevier, Philadelphia), pp. 269\u2013298 (2011)."},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1006\/mcpr.1996.0047"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.045"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1202684109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:12:08Z","timestamp":1649797928000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1202684109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,6,11]]},"references-count":27,"journal-issue":{"issue":"26","published-print":{"date-parts":[[2012,6,26]]}},"alternative-id":["10.1073\/pnas.1202684109"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1202684109","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.717952403.793457855","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,6,11]]},"assertion":[{"value":"2012-06-11","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}