title: No evidence of oncogenic KRAS mutations in squamous cell carcinomas of the anogenital tract and head and neck region independent of human papillomavirus and p16(INK4a) status.
abstract: Carcinogenesis of squamous cell carcinomas (SCCs) in the anogenital tract and head and neck region is heterogeneous. A substantial proportion of SCC in the vulva, anus, and head and neck follows a human papillomavirus (HPV)-induced carcinogenic pathway. However, the molecular pathways of carcinogenesis in the HPV-independent lesions are not completely understood. We hypothesized that oncogenic Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations might represent a carcinogenic mechanism in a proportion of those HPV-negative cancers. Considering the repeated observation of KRAS-associated p16(INK4a) overexpression in human tumors, it was assumed that KRAS mutations might be particularly present in the group of HPV-negative, p16(INK4a)-positive cancers. To test this hypothesis, we analyzed 66 anal, vulvar, and head and neck SCC with known immunohistochemical p16(INK4a) and HPV DNA status for KRAS mutations in exon 2 (codons 12, 13, and 15). We enriched the tumor collection with HPV DNA-negative, p16(INK4a)-positive cancers. A subset of 37 cancers was also analyzed for mutations in the B-Raf proto-oncogene, serine/threonine kinase (BRAF) gene. None of the 66 tumors harbored mutations in KRAS exon 2, thus excluding KRAS mutations as a common event in SCC of the anogenital and head and neck region and as a cause of p16(INK4a) expression in these tumors. In addition, no BRAF mutations were detected in the 37 analyzed tumors. Further studies are required to determine the molecular events underlying HPV-negative anal, vulvar, and head and neck carcinogenesis. Considering HPV-independent p16(INK4a) overexpression in some of these tumors, particular focus should be placed on alternative upstream activators and potential downstream disruption of the p16(INK4a) pathway.
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Elena-Sophie
authors.initials: ES
authors.lastname: Prigge
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Urban
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Stiegler
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Meike
authors.initials: M
authors.lastname: Müller
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Mai
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Martine
authors.initials: M
authors.lastname: Ottstadt
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lohr
authors.affiliation: Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, 35392 Giessen, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, 35392 Giessen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Wittekindt
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Giessen, 35392 Giessen, Germany.
authors.forename: Jens Peter
authors.initials: JP
authors.lastname: Klussmann
authors.affiliation: Department of Gynecology, University of Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Hampl
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Magnus
authors.initials: M
authors.lastname: von Knebel Doeberitz
authors.affiliation: Department of Applied Tumor Biology, Institute of Pathology, University of Heidelberg, and Clinical Cooperation Unit Applied Tumor Biology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: miriam.reuschenbach@med.uni-heidelberg.de.
authors.forename: Miriam
authors.initials: M
authors.lastname: Reuschenbach
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001005:Anus Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology / Q000821:virology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D030361:Papillomavirus Infections / Q000235:genetics* / Q000473:pathology / Q000821:virology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D014846:Vulvar Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D018631:ras Proteins / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: Anogenital; BRAF; HPV; Head and neck; KRAS; p16(INK4a)