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

Hum Pathol. 2014 Nov;45(11):2347-54. doi: 10.1016/j.humpath.2014.08.001. Epub 2014 Aug 23.

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.

Keywords: Anogenital; BRAF; HPV; Head and neck; KRAS; p16(INK4a).

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Anus Neoplasms / genetics*
  • Anus Neoplasms / pathology
  • Anus Neoplasms / virology
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / virology
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Female
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / virology
  • Humans
  • Male
  • Middle Aged
  • Mutation
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / pathology
  • Papillomavirus Infections / virology
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins p21(ras)
  • Vulvar Neoplasms / genetics*
  • Vulvar Neoplasms / pathology
  • Vulvar Neoplasms / virology
  • ras Proteins / genetics*

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins