{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T00:10:23Z","timestamp":1792887023843,"version":"4.5.0"},"reference-count":44,"publisher":"Wiley","issue":"24","license":[{"start":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T00:00:00Z","timestamp":1691712000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acsjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2023,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune\u2010checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Evaluation was done retrospectively of the landscape of somatic alterations and ICI\u2010related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV\u2010dependent oncogenesis. The pSCC tumors were analyzed by using next\u2010generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD\u2010L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; \u22651%), and NGS. Tumor mutational burden (TMB)\u2013high was defined as \u226510 mutations\/Mb. HPV16\/18 status was determined by using whole\u2010exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (\n                      <jats:italic>q<\/jats:italic>\n                      value &lt; .05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NGS of the overall cohort (\n                      <jats:italic>N<\/jats:italic>\n                      \u00a0=\u00a0108) revealed\n                      <jats:italic>TP53<\/jats:italic>\n                      (46%),\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      (26%), and\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      (25%) to be the most common mutations. Overall, 51% of tumors were PD\u2010L1+, 10.7% had high TMB, and 1.1% had mismatch repair\u2013deficient (dMMR)\/MSI\u2010high status. Twenty\u2010nine patients had their HPV status made available by WES (HPV16\/18+,\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a013; HPV16\/18\u2212,\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a016).\n                      <jats:italic>KMT2C<\/jats:italic>\n                      mutations (33% vs. 0%) and\n                      <jats:italic>FGF3<\/jats:italic>\n                      amplifications (30.8% vs. 0%) were specific to HPV16\/18+ tumors, whereas\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      mutations (0% vs. 37.5%) were exclusive to HPV16\/18\u2212 tumors. TMB\u2010high was exclusively found in the HPV16\/18+ group (30.8%). The two groups had comparable PD\u2010L1 and dMMR\/MSI\u2010H status.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In a large and comprehensive NGS\u2010based evaluation of somatic alterations in pSCC, HPV16\/18+ versus HPV16\/18\u2212 pSCCs were molecularly distinct tumors. Our finding that TMB\u2010high is exclusive to HPV16\/18+ tumors requires confirmation in larger data sets.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Plain Language Summary<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune\u2010checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Using next\u2010generation sequencing, we explored the genetic landscape and ICI\u2010related biomarkers of pSCC and HPV\u2010driven oncogenic molecular signatures.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our results indicate that HPV\u2010positive and HPV\u2010negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV\u2010positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI\u2010based therapies.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI\u2010based clinical trials.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cncr.34982","type":"journal-article","created":{"date-parts":[[2023,8,11]],"date-time":"2023-08-11T10:08:54Z","timestamp":1691748534000},"page":"3884-3893","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Comprehensive genomic profiling of penile squamous cell carcinoma and the impact of human papillomavirus status on immune\u2010checkpoint inhibitor\u2010related biomarkers"],"prefix":"10.1002","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6385-1329","authenticated-orcid":false,"given":"Bassel","family":"Nazha","sequence":"first","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Medical Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Department of Medicine Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Wu","sequence":"additional","affiliation":[{"name":"Caris Life Sciences  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline T.","family":"Brown","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Medical Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Magee","sequence":"additional","affiliation":[{"name":"Caris Life Sciences  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley C.","family":"Carthon","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Medical Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Kucuk","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Medical Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chadi","family":"Nabhan","sequence":"additional","affiliation":[{"name":"Caris Life Sciences  Phoenix Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro C.","family":"Barata","sequence":"additional","affiliation":[{"name":"University Hospitals Seidman Cancer Center  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth I.","family":"Heath","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute  Detroit Michigan USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles J.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Division of Hematology Oncology and Transplantation University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana R.","family":"McKay","sequence":"additional","affiliation":[{"name":"Department of Hematology and Medical Oncology University of California San Diego  La Jolla California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viraj A.","family":"Master","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Urology Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3775-9737","authenticated-orcid":false,"given":"Mehmet Asim","family":"Bilen","sequence":"additional","affiliation":[{"name":"Winship Cancer Institute, Emory University  Atlanta Georgia USA"},{"name":"Department of Hematology and Medical Oncology Emory University School of Medicine  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,8,11]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"Key Statistics for Penile Cancer.American Cancer Society.2022. 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