FC 03-03DNA COPY NUMBER ABERRATIONS ASSOCIATED WITH HPV-DEPENDENT AND -INDEPENDENT VULVAR CARCINOGENESIS

24. Vulvar diseases and neoplasia
D. Swarts 1, Q. Voorham 1, A. Van Splunter 1, S. Duin 1, D. Pronk 1, D. Sie 1, D. Heideman 1, P. Snijders 1, C. Meijer 1, G. Kenter 2, M. Van Beurden 3, R. Steenbergen 1, M. Bleeker 4.
1Department of Pathology, VU University Medical Center, Amsterdam (Netherlands), 2Departments of Obstetrics and Gynecology, VU University Medical Center, Amsterdam Medical Center, Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands), 3Department of Obstetrics and Gynecology, Antoni van Leeuwenhoek Hospital, Amsterdam (Netherlands), 4Departments of Pathology, VU University Medical Center, Amsterdam Medical Center, Amsterdam (Netherlands)

Background / Objectives

Vulvar squamous cell carcinoma (VSCC) can develop through HPV-dependent (25%) and HPV-independent pathways, indicating a heterogeneous disease. High-grade vulvar intraepithelial neoplasia (VIN) is the precancerous state of VSCC but only a minority of VINs progress to cancer. Current clinical and histological classifications are insufficient to predict the cancer risk. Consequently, affected women are treated similarly with mutilating interventions. Hence there is a clinical need for objective biomarkers reflecting the cancer risk. Here we analysed copy number alterations (CNA) to assess the significance of molecular heterogeneity of vulvar lesions in relation to HPV status and cancer risk.


Methods

25 VSCC and 42 VIN, including VIN of women with associated VSCC (VIN with VSCC) and VIN of women who did not develop VSCC during > 10 year follow-up (VIN without VSCC) were analysed for HPV-status by means of p16INK4a immunohistochemistry and HPV testing. CNA were determined by whole-genome next-generation shallow sequencing and CGHcall, CGHregion and CGHtest analysis.


Results

HPV-positive VSCC (n=11) and HPV-negative VSCC (n=14) showed a partially overlapping pattern of recurrent CNA, including frequent gains of 3q and 8q. HPV-negative VIN (n=11) had significantly less CNA (P = 0.010), mainly consisting of 8q gains and 8p losses. Amplification of 11q13/cyclinD1 was exclusively found in 46% of HPV-negative lesions. In HPV-positive lesions no difference in CNA frequency was found between VIN with VSCC (n=17) and VSCC (P = 0.48), though CNA were less frequent in VIN without VSCC (n=14; P = 0.058). Interestingly, almost all (88%) HPV-positive VIN with VSCC had chromosome 1 gain, whereas this alteration was infrequent (21%) in VIN without VSCC.


Conclusion

HPV-dependent and independent vulvar carcinogenesis is characterized by frequent alterations of chromosome 3 and 8, as well as distinct CNA such 11q13 amplification in HPV-independent lesions. The extent of CNA in HPV-positive VIN was found to reflect the cancer progression risk. In particular, gain of chromosome 1 was strongly associated with cancer progression.


References