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Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study
Background Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomar...
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| Published in: | Cancer medicine (Malden, MA) MA), 2022-11, Vol.11 (21), p.4033-4042 |
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| container_end_page | 4042 |
| container_issue | 21 |
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| container_title | Cancer medicine (Malden, MA) |
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| creator | Fan, Zhiyuan Qin, Yu Zhou, Jing Chen, Ru Gu, Jianhua Li, Minjuan Zhou, Jiachen Li, Xinqing Lin, Dongmei Wang, Jinwu Deng, Dajun Wei, Wenqiang |
| description | Background
Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomarker for early detection of ESCdys and ESCC.
Methods
Paired esophageal biopsy and cytology specimens (exfoliated cells) were obtained from subjects at different stages of ESCC development. The methylation status of P16 gene in these two specimen types was determined using a 115‐bp MethyLight assay. Categorical data were compared by the Chi‐square test. Logistic regression was performed to assess adjusted odds ratios of P16 methylation associated with ESCC and ESCdys. Prediction models for identifying individuals at risk of ESCC and high‐grade ESCdys (high‐grade intraepithelial neoplasia, HGIN) were developed by multivariable logistic regression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Internal validation of the prediction models was performed using the 1000‐bootstrap resample.
Results
A total of 105 subjects with diagnoses ranging from normal mucosa through ESCC were included in this study. An increase in P16 methylation frequency was observed with increasing severity of esophageal lesions (p for trend |
| doi_str_mv | 10.1002/cam4.4718 |
| format | article |
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Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomarker for early detection of ESCdys and ESCC.
Methods
Paired esophageal biopsy and cytology specimens (exfoliated cells) were obtained from subjects at different stages of ESCC development. The methylation status of P16 gene in these two specimen types was determined using a 115‐bp MethyLight assay. Categorical data were compared by the Chi‐square test. Logistic regression was performed to assess adjusted odds ratios of P16 methylation associated with ESCC and ESCdys. Prediction models for identifying individuals at risk of ESCC and high‐grade ESCdys (high‐grade intraepithelial neoplasia, HGIN) were developed by multivariable logistic regression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Internal validation of the prediction models was performed using the 1000‐bootstrap resample.
Results
A total of 105 subjects with diagnoses ranging from normal mucosa through ESCC were included in this study. An increase in P16 methylation frequency was observed with increasing severity of esophageal lesions (p for trend <0.001). In the adjusted logistic regression models, P16 methylation in cytology specimens was positively associated with ESCC and ESCdys risk, whereas P16 methylation in biopsy specimens was only associated with a higher risk of developing ESCC. The predictive capacity of base model I (AUC, 0.816) for ESCC and HGIN was significantly increased by adding P16 methylation in cytology specimens (model III; AUC, 0.882; p = 0.043), but not P16 methylation in biopsy specimens (model II; AUC, 0.850; p = 0.225). Bootstrap validation showed optimism‐corrected AUC of 0.789 for model I, 0.822 for model II, and 0.854 for model III.
Conclusion
P16 methylation as a cytologic marker was associated with the ESCC development and has the potential for application in minimally invasive ESCC screening.
P16 methylation as a cytologic marker has the potential for application in minimally invasive screening for esophageal squamous cell carcinoma.</description><identifier>ISSN: 2045-7634</identifier><identifier>EISSN: 2045-7634</identifier><identifier>DOI: 10.1002/cam4.4718</identifier><identifier>PMID: 35352503</identifier><language>eng</language><publisher>United States: John Wiley & Sons, Inc</publisher><subject>Alcohol ; Biomarkers - metabolism ; Biopsy ; Carcinoma, Squamous Cell - diagnosis ; Carcinoma, Squamous Cell - genetics ; Carcinoma, Squamous Cell - metabolism ; Cellular biology ; Cytology ; DNA Methylation ; Dysplasia ; early detection ; Endoscopy ; Esophageal cancer ; Esophageal Neoplasms - diagnosis ; Esophageal Neoplasms - genetics ; Esophageal Neoplasms - metabolism ; esophageal squamous cell carcinoma ; Esophageal Squamous Cell Carcinoma - diagnosis ; Esophageal Squamous Cell Carcinoma - genetics ; Esophagus ; Family medical history ; Feasibility Studies ; Genes, p16 ; Humans ; Medical screening ; minimally invasiveness ; P16 methylation ; p16 Protein ; Pilot Projects ; Prediction models ; Regression analysis ; Smoking ; Squamous cell carcinoma</subject><ispartof>Cancer medicine (Malden, MA), 2022-11, Vol.11 (21), p.4033-4042</ispartof><rights>2022 The Authors. published by John Wiley & Sons Ltd.</rights><rights>2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.</rights><rights>2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5768-7ef81217954867a154bae7dd2796ff23940a6bb5bfab3fa9f6335abb745aa62a3</citedby><cites>FETCH-LOGICAL-c5768-7ef81217954867a154bae7dd2796ff23940a6bb5bfab3fa9f6335abb745aa62a3</cites><orcidid>0000-0003-3794-071X ; 0000-0002-1578-6814 ; 0000-0003-2554-0874 ; 0000-0003-2078-9056</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2731953587/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2731953587?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,11562,25753,27924,27925,37012,44590,46052,46476,53791,53793,74998</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35352503$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fan, Zhiyuan</creatorcontrib><creatorcontrib>Qin, Yu</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Chen, Ru</creatorcontrib><creatorcontrib>Gu, Jianhua</creatorcontrib><creatorcontrib>Li, Minjuan</creatorcontrib><creatorcontrib>Zhou, Jiachen</creatorcontrib><creatorcontrib>Li, Xinqing</creatorcontrib><creatorcontrib>Lin, Dongmei</creatorcontrib><creatorcontrib>Wang, Jinwu</creatorcontrib><creatorcontrib>Deng, Dajun</creatorcontrib><creatorcontrib>Wei, Wenqiang</creatorcontrib><title>Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study</title><title>Cancer medicine (Malden, MA)</title><addtitle>Cancer Med</addtitle><description>Background
Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomarker for early detection of ESCdys and ESCC.
Methods
Paired esophageal biopsy and cytology specimens (exfoliated cells) were obtained from subjects at different stages of ESCC development. The methylation status of P16 gene in these two specimen types was determined using a 115‐bp MethyLight assay. Categorical data were compared by the Chi‐square test. Logistic regression was performed to assess adjusted odds ratios of P16 methylation associated with ESCC and ESCdys. Prediction models for identifying individuals at risk of ESCC and high‐grade ESCdys (high‐grade intraepithelial neoplasia, HGIN) were developed by multivariable logistic regression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Internal validation of the prediction models was performed using the 1000‐bootstrap resample.
Results
A total of 105 subjects with diagnoses ranging from normal mucosa through ESCC were included in this study. An increase in P16 methylation frequency was observed with increasing severity of esophageal lesions (p for trend <0.001). In the adjusted logistic regression models, P16 methylation in cytology specimens was positively associated with ESCC and ESCdys risk, whereas P16 methylation in biopsy specimens was only associated with a higher risk of developing ESCC. The predictive capacity of base model I (AUC, 0.816) for ESCC and HGIN was significantly increased by adding P16 methylation in cytology specimens (model III; AUC, 0.882; p = 0.043), but not P16 methylation in biopsy specimens (model II; AUC, 0.850; p = 0.225). Bootstrap validation showed optimism‐corrected AUC of 0.789 for model I, 0.822 for model II, and 0.854 for model III.
Conclusion
P16 methylation as a cytologic marker was associated with the ESCC development and has the potential for application in minimally invasive ESCC screening.
P16 methylation as a cytologic marker has the potential for application in minimally invasive screening for esophageal squamous cell carcinoma.</description><subject>Alcohol</subject><subject>Biomarkers - metabolism</subject><subject>Biopsy</subject><subject>Carcinoma, Squamous Cell - diagnosis</subject><subject>Carcinoma, Squamous Cell - genetics</subject><subject>Carcinoma, Squamous Cell - metabolism</subject><subject>Cellular biology</subject><subject>Cytology</subject><subject>DNA Methylation</subject><subject>Dysplasia</subject><subject>early detection</subject><subject>Endoscopy</subject><subject>Esophageal cancer</subject><subject>Esophageal Neoplasms - diagnosis</subject><subject>Esophageal Neoplasms - genetics</subject><subject>Esophageal Neoplasms - metabolism</subject><subject>esophageal squamous cell carcinoma</subject><subject>Esophageal Squamous Cell Carcinoma - diagnosis</subject><subject>Esophageal Squamous Cell Carcinoma - genetics</subject><subject>Esophagus</subject><subject>Family medical history</subject><subject>Feasibility Studies</subject><subject>Genes, p16</subject><subject>Humans</subject><subject>Medical screening</subject><subject>minimally invasiveness</subject><subject>P16 methylation</subject><subject>p16 Protein</subject><subject>Pilot Projects</subject><subject>Prediction models</subject><subject>Regression analysis</subject><subject>Smoking</subject><subject>Squamous cell carcinoma</subject><issn>2045-7634</issn><issn>2045-7634</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp1kU1v1DAQhiMEolXpgT-ALHHisK2_nXBAWq0oVCqCA5ytiWNnvTjx1k5A4dfj7ZaqPeCLrfGjZ2b0VtVrgi8IxvTSwMAvuCL1s-qUYi5WSjL-_NH7pDrPeYfLUZhKRV5WJ0wwQQVmp9WfKwvZtz74aUHRoTn7sUffiESDnbZLgMnHEUFGgMwyxRB7b9AA6adNyMWEbI77LfQWAsq3MwxxzsjYEJCBZPwYB0DZJGvHon2P1mjvQ5xQnuZueVW9cBCyPb-_z6ofVx-_bz6vbr5-ut6sb1ZGKFmvlHU1oUQ1gtdSARG8Bau6jqpGOkdZwzHIthWtg5Y5aJxkTEDbKi4AJAV2Vl0fvV2End4nX8ZfdASv7wox9RrS5E2wWuK6s8Q0wnHKa2Fq1gpHSEMbwYyRuLg-HF37uR1sZ-w4JQhPpE9_Rr_VffylG8mkILQI3t4LUrydbZ70Ls5pLPtrqhgpfUStCvXuSJkUc07WPXQgWB9S14fU9SH1wr55PNID-S_jAlwegd8-2OX_Jr1Zf-F3yr95Cbef</recordid><startdate>202211</startdate><enddate>202211</enddate><creator>Fan, Zhiyuan</creator><creator>Qin, Yu</creator><creator>Zhou, Jing</creator><creator>Chen, Ru</creator><creator>Gu, Jianhua</creator><creator>Li, Minjuan</creator><creator>Zhou, Jiachen</creator><creator>Li, Xinqing</creator><creator>Lin, Dongmei</creator><creator>Wang, Jinwu</creator><creator>Deng, Dajun</creator><creator>Wei, Wenqiang</creator><general>John Wiley & Sons, Inc</general><general>John Wiley and Sons Inc</general><general>Wiley</general><scope>24P</scope><scope>WIN</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0003-3794-071X</orcidid><orcidid>https://orcid.org/0000-0002-1578-6814</orcidid><orcidid>https://orcid.org/0000-0003-2554-0874</orcidid><orcidid>https://orcid.org/0000-0003-2078-9056</orcidid></search><sort><creationdate>202211</creationdate><title>Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study</title><author>Fan, Zhiyuan ; Qin, Yu ; Zhou, Jing ; Chen, Ru ; Gu, Jianhua ; Li, Minjuan ; Zhou, Jiachen ; Li, Xinqing ; Lin, Dongmei ; Wang, Jinwu ; Deng, Dajun ; Wei, Wenqiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5768-7ef81217954867a154bae7dd2796ff23940a6bb5bfab3fa9f6335abb745aa62a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Alcohol</topic><topic>Biomarkers - metabolism</topic><topic>Biopsy</topic><topic>Carcinoma, Squamous Cell - diagnosis</topic><topic>Carcinoma, Squamous Cell - genetics</topic><topic>Carcinoma, Squamous Cell - metabolism</topic><topic>Cellular biology</topic><topic>Cytology</topic><topic>DNA Methylation</topic><topic>Dysplasia</topic><topic>early detection</topic><topic>Endoscopy</topic><topic>Esophageal cancer</topic><topic>Esophageal Neoplasms - diagnosis</topic><topic>Esophageal Neoplasms - genetics</topic><topic>Esophageal Neoplasms - metabolism</topic><topic>esophageal squamous cell carcinoma</topic><topic>Esophageal Squamous Cell Carcinoma - diagnosis</topic><topic>Esophageal Squamous Cell Carcinoma - genetics</topic><topic>Esophagus</topic><topic>Family medical history</topic><topic>Feasibility Studies</topic><topic>Genes, p16</topic><topic>Humans</topic><topic>Medical screening</topic><topic>minimally invasiveness</topic><topic>P16 methylation</topic><topic>p16 Protein</topic><topic>Pilot Projects</topic><topic>Prediction models</topic><topic>Regression analysis</topic><topic>Smoking</topic><topic>Squamous cell carcinoma</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fan, Zhiyuan</creatorcontrib><creatorcontrib>Qin, Yu</creatorcontrib><creatorcontrib>Zhou, Jing</creatorcontrib><creatorcontrib>Chen, Ru</creatorcontrib><creatorcontrib>Gu, Jianhua</creatorcontrib><creatorcontrib>Li, Minjuan</creatorcontrib><creatorcontrib>Zhou, Jiachen</creatorcontrib><creatorcontrib>Li, Xinqing</creatorcontrib><creatorcontrib>Lin, Dongmei</creatorcontrib><creatorcontrib>Wang, Jinwu</creatorcontrib><creatorcontrib>Deng, Dajun</creatorcontrib><creatorcontrib>Wei, Wenqiang</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Wiley Free Archive</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health Medical collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biological Sciences</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content (ProQuest)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Cancer medicine (Malden, MA)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fan, Zhiyuan</au><au>Qin, Yu</au><au>Zhou, Jing</au><au>Chen, Ru</au><au>Gu, Jianhua</au><au>Li, Minjuan</au><au>Zhou, Jiachen</au><au>Li, Xinqing</au><au>Lin, Dongmei</au><au>Wang, Jinwu</au><au>Deng, Dajun</au><au>Wei, Wenqiang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study</atitle><jtitle>Cancer medicine (Malden, MA)</jtitle><addtitle>Cancer Med</addtitle><date>2022-11</date><risdate>2022</risdate><volume>11</volume><issue>21</issue><spage>4033</spage><epage>4042</epage><pages>4033-4042</pages><issn>2045-7634</issn><eissn>2045-7634</eissn><abstract>Background
Early diagnosis and treatment of esophageal squamous cell dysplasia (ESCdys) and esophageal squamous cell carcinoma (ESCC) could significantly reduce the incidence and mortality of ESCC. This pilot study aimed to investigate whether P16/CDKN2A methylation could serve as a cytologic biomarker for early detection of ESCdys and ESCC.
Methods
Paired esophageal biopsy and cytology specimens (exfoliated cells) were obtained from subjects at different stages of ESCC development. The methylation status of P16 gene in these two specimen types was determined using a 115‐bp MethyLight assay. Categorical data were compared by the Chi‐square test. Logistic regression was performed to assess adjusted odds ratios of P16 methylation associated with ESCC and ESCdys. Prediction models for identifying individuals at risk of ESCC and high‐grade ESCdys (high‐grade intraepithelial neoplasia, HGIN) were developed by multivariable logistic regression. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. Internal validation of the prediction models was performed using the 1000‐bootstrap resample.
Results
A total of 105 subjects with diagnoses ranging from normal mucosa through ESCC were included in this study. An increase in P16 methylation frequency was observed with increasing severity of esophageal lesions (p for trend <0.001). In the adjusted logistic regression models, P16 methylation in cytology specimens was positively associated with ESCC and ESCdys risk, whereas P16 methylation in biopsy specimens was only associated with a higher risk of developing ESCC. The predictive capacity of base model I (AUC, 0.816) for ESCC and HGIN was significantly increased by adding P16 methylation in cytology specimens (model III; AUC, 0.882; p = 0.043), but not P16 methylation in biopsy specimens (model II; AUC, 0.850; p = 0.225). Bootstrap validation showed optimism‐corrected AUC of 0.789 for model I, 0.822 for model II, and 0.854 for model III.
Conclusion
P16 methylation as a cytologic marker was associated with the ESCC development and has the potential for application in minimally invasive ESCC screening.
P16 methylation as a cytologic marker has the potential for application in minimally invasive screening for esophageal squamous cell carcinoma.</abstract><cop>United States</cop><pub>John Wiley & Sons, Inc</pub><pmid>35352503</pmid><doi>10.1002/cam4.4718</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0003-3794-071X</orcidid><orcidid>https://orcid.org/0000-0002-1578-6814</orcidid><orcidid>https://orcid.org/0000-0003-2554-0874</orcidid><orcidid>https://orcid.org/0000-0003-2078-9056</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Alcohol Biomarkers - metabolism Biopsy Carcinoma, Squamous Cell - diagnosis Carcinoma, Squamous Cell - genetics Carcinoma, Squamous Cell - metabolism Cellular biology Cytology DNA Methylation Dysplasia early detection Endoscopy Esophageal cancer Esophageal Neoplasms - diagnosis Esophageal Neoplasms - genetics Esophageal Neoplasms - metabolism esophageal squamous cell carcinoma Esophageal Squamous Cell Carcinoma - diagnosis Esophageal Squamous Cell Carcinoma - genetics Esophagus Family medical history Feasibility Studies Genes, p16 Humans Medical screening minimally invasiveness P16 methylation p16 Protein Pilot Projects Prediction models Regression analysis Smoking Squamous cell carcinoma |
| title | Feasibility of using P16 methylation as a cytologic marker for esophageal squamous cell carcinoma screening: A pilot study |
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