Mutational signatures and chromosome alteration profiles of squamous cell carcinomas of the vulva

Mi-Ryung Han,Sang Yong Song,Sung Hak Lee,Min Sung Kim,Sun Shin,Yeun-Jun Chung,Sug Hyung Lee,Seung Hyun Jung,Hyeon-Chun Park

doi:10.1038/emm.2017.265

Abstract

Vulvar squamous cell carcinoma (SCC) consists of two different etiologic categories: human papilloma virus (HPV)-associated (HPV (+)) and HPV-non-associated (HPV (−)). There have been no genome-wide studies on the genetic alterations of vulvar SCCs or on the differences between HPV (+) and HPV (−) vulvar SCCs. In this study, we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (−) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (−) SCCs. In HPV (+), we found novel mutations in PIK3CA, BRCA2 and FBXW7 that had not been reported in vulvar SCCs. HPV (−) SCCs exhibited more mutational loads (numbers of nonsilent mutations and driver mutations) than HPV (+) SCCs, but the CNA loads and mutation signatures between HPV (+) and HPV (−) SCCs did not differ. Of note, 40% and 40% of the 15 vulvar SCCs harbored PIK3CA and FAT1 alterations, respectively. In addition, we found that the SCCs harbored kataegis (a localized hypermutation) in 2 HPV (+) SCCs and copy-neutral losses of heterozygosity in 4 (one HPV (+) and 3 HPV (−)) SCCs. Our data indicate that HPV (+) and HPV (−) vulvar SCCs may have different mutation and CNA profiles but that there are genomic features common to SCCs. Our data provide useful information for both HPV (+) and HPV (−) vulvar SCCs and may aid in the development of clinical treatment strategies.

Highlights

Vulvar cancer is a malignant invasive lesion occurring in the vaginal opening, the labia majora, the labia minora and the clitoris
The catalog of somatic mutations A total of 15 vulvar squamous cell carcinoma (SCC) genomes (6 human papillomavirus (HPV) (+) and 9 HPV ( − )) and paired normal tissue genomes were analyzed in this study (Table 1)
We identified a total of 56 cancer-related genes that contained known vulvar SCC mutations (TP53, CDKN2A, PIK3CA and HRAS) and previously unknown vulvar SCC mutations, including APC, FBXW7, BRCA2, RB1 and FAT1 (Figure 2a)

Summary

Introduction

Vulvar cancer is a malignant invasive lesion occurring in the vaginal opening, the labia majora (the most common site), the labia minora and the clitoris. Vulvar cancer accounts for 0.6% of all cancer diagnoses and 5% of gynecologic cancers.[1,2]. Vulvar cancer is typically a squamous cell carcinoma (SCC). That is common in other gynecologic organs, including the cervix and vagina.[1,2] Whereas almost all cervical SCCs occur with the background of human papillomavirus (HPV) infection,[3,4] vulvar SCCs consist of those associated with HPV as well as others independent of HPV infection.[1,2] Both HPV (+) and HPV ( − ) vulvar SCCs are preceded by vulvar intraepithelial neoplasia (VIN).[5,6] These two types of vulvar

Objectives

Methods

Results

Conclusion