Prigge Elena-Sophie, Urban Katharina, Stiegler Sandrine, Müller Meike, Kloor Matthias, Mai Sabine, Ottstadt Martine, Lohr Frank, Wenz Frederik, Wagner Steffen, Wittekindt Claus, Klussmann Jens Peter, Hampl Monika, von Knebel Doeberitz Magnus, Reuschenbach Miriam
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.
Department of Radiation Oncology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Hum Pathol. 2014 Nov;45(11):2347-54. doi: 10.1016/j.humpath.2014.08.001. Epub 2014 Aug 23.
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.
肛管、生殖器及头颈部区域的鳞状细胞癌（SCC）的致癌过程具有异质性。外阴、肛门及头颈部的大部分SCC遵循人乳头瘤病毒（HPV）诱导的致癌途径。然而，HPV非依赖性病变的致癌分子途径尚未完全明确。我们推测致癌性Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）突变可能是部分HPV阴性癌症的致癌机制。鉴于在人类肿瘤中反复观察到KRAS相关的p16（INK4a）过表达，推测KRAS突变可能特别存在于HPV阴性、p16（INK4a）阳性的癌症组中。为验证这一假设，我们分析了66例已知免疫组化p16（INK4a）和HPV DNA状态的肛管、外阴及头颈部SCC，检测其KRAS基因第2外显子（密码子12、13和15）的突变情况。我们纳入了HPV DNA阴性、p16（INK4a）阳性的癌症以丰富肿瘤样本。还对37例癌症的子集分析了B-Raf原癌基因丝氨酸/苏氨酸激酶（BRAF）基因的突变情况。66例肿瘤中均未检测到KRAS第2外显子突变，因此排除了KRAS突变是肛管、生殖器及头颈部区域SCC的常见事件以及这些肿瘤中p16（INK4a）表达原因的可能性。此外，在37例分析的肿瘤中未检测到BRAF突变。需要进一步研究以确定HPV阴性的肛管、外阴及头颈部致癌的分子事件。鉴于其中一些肿瘤存在HPV非依赖性p16（INK4a）过表达，应特别关注p16（INK4a）途径的替代上游激活因子和潜在下游破坏因素。
