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

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.

Somatic mutation profiling of vulvar cancer: Exploring therapeutic targets

“…Similar rates of pathogenic mutations were detected in hrHPV(+) VSCC tumors and the hrHPV independent tumors (65% and 59%), which is inconsistent with previous reports by Trietch et al [11] and by Han et al [14] that described significantly lower mutation frequencies in HPV-positive vulvar cancers. On the other hand, Nooij et al and Weberpals et al observed slightly lower mutation rates in both HPVpositive (86% and 73% [15,16]) than in HPV-negative VSSC tumor samples (90% [15,16]).…”

“…The mutational patterns of VSCC cannot be reliably compared between the reported studies due to different methods used and different numbers of genes examined, i.e. Sanger sequencing has been applied for TP53 and MALDI-TOF mass spectrometry based genotyping for 13-gene analysis reported by Trietch et al [11], NGS for 17 genes by Nooij et al [15], whole-exome sequencing by Han et al [14] and the same NGS method as the one used in our study by Weberpals et al [16]. In addition, different cohorts and relatively small sample sets have been investigated.…”

Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

“…The overall frequency of mutated TrkC in cancer types. cSCC [50], DM [51], CM: TCGA Dataset, BCC: [52], LA: [53], EC: TCGA Dataset, VV-SCC: [54], NSCLC: [55], UTUC [56], CTCL: [57], AS:…”

“…TCGA Dataset, CRC: [58], GC: TCGA Dataset, CSCC: TCGA Dataset, EAC: [59], HNC: TCGA Dataset, RMS: [60], PAC: [61], DLBCL: TCGA Dataset, HCC: TCGA Dataset, AC: Ampullary carcinoma [62], UCS: TCGA Dataset, BUC: TCGA Dataset, RCC: TCGA Dataset, PA: [63], CC: [64], GC: [65], PDTC & ATC: [66,67], OSC: TCGA Dataset, BC: [68], CCRCC: TCGA Dataset, CLL: [69], DG: [70]. [50], DM [51], CM: TCGA Dataset, BCC: [52], LA: [53], EC: TCGA Dataset, VV-SCC: [54], NSCLC: [55], UTUC [56], CTCL: [57], AS: TCGA Dataset, CRC: [58], GC: TCGA Dataset, CSCC: TCGA Dataset, EAC: [59], HNC: TCGA Dataset, RMS: [60], PAC: [61], DLBCL: TCGA Dataset, HCC: TCGA Dataset, AC: Ampullary carcinoma [62], UCS: TCGA Dataset, BUC: TCGA Dataset, RCC: TCGA Dataset, PA: [63], CC: [64], GC: [65], PDTC & ATC: [66,67], OSC: TCGA Dataset, BC: [68], CCRCC: TCGA Dataset, CLL: [69], DG: [70].…”

Computational tools to detect signatures of mutational processes in DNA from tumours: a review and empirical comparison of performance

“…If similarity is observed with more than one reference signature, the one with the largest value of similarity is chosen, supplementary Figure 1. This assignment step crucially depends on the choice of the cut-off ℎ that has been so far inconsistent in the literature with some studies using a value of 0.75 [7] whereas others 0.80 [15,16]. Another difficulty is that different signatures might have very close cosine similarity, as it happens also between COSMIC signatures, supplementary Figure 2, so that a unique assignment is not always possible.…”