Aleksandra Klemba^1,2, Wojciech Kukwa³, Andrzej Semczuk⁴, Anna M. Czarnecka^1,2

1Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 5a Pawinskiego Street, 02-106, Warsaw, Poland, ²Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine, ul. Szaserow 128, 04-141 Warsaw, Poland, ³Department of Otolaryngology, Czerniakowski Hospital, Medical University of Warsaw, 19/25 Stępinska Street, 00-739 Warsaw, Poland, ⁴II^ND Department of Gynecology, Lublin Medical University, Lublin, Poland

TABLE OF CONTENTS

1. Abstract

2. Introduction

2.1. Epidemiology

2.2. Cancer types

2.3. Precancerous stages

2.3.1. Vulvar intraepithelial neoplasia (VIN)

2.3.2. Lichen sclerosus (LS)

3. Molecular biology of human vulvar cancer

3.1. Two pathways of vulvar carcinogenesis

3.2. HPV infection as main vulvar transformation factor

3.3. Cell-cycle alterations in vulvar carcinogenesis

3.4. TP53 as vulvar cancer guardian

3.5. p21WAF/CIP as metastasis vulvar cancer marker

3.6. 14-3-3sigma - a negative vulvar cancer regulator

3.7. INK4a/ARF locus products as vulvar cancer markers

3.8. Cyclins as vulvar cancer regulators

3.9. pRb alterations in vulvar carcinogenesis

3.10. Matrix Metalloproteinases as tumor invasiveness

3.11. Genomic abnormalities in vulvar cancer

3.12. Aberrant genome methylation in vulvar cancer

3.13. Immune system deficiency in vulvar cancer

3.14. Other potential molecular markers

4. Summary and perspectives

5. Acknowledgements

6. References

1. ABSTRACT

Vulvar carcinoma is a rare female genital neoplasm. Although numerous molecular defects in vulvar carcinomas have been reported until now, no molecular markers that could be applied in daily clinical work have been identified so far. However, there is emerging evidence that specific mutations and gene expression patterns may be used as diagnostic tools in oncology. In this article we systematically review genetic alterations that may contribute to the development and progression of vulvar carcinoma. We conclude by suggesting molecular markers of potential clinical value in the diagnostics of this type of cancer.