Mutational Signature and Integrative Genomic Analysis of Human Papillomavirus-Associated Penile Squamous Cell Carcinomas from Latin American Patients

Abstract

High-throughput DNA sequencing has allowed for the identification of genomic alterations and their impact on tumor development, progression, and therapeutic responses. In PSCC, for which the incidence has progressively increased worldwide, there are still limited data on the molecular mechanisms involved in the disease pathogenesis. In this study, we characterized the mutational signature of 30 human papillomavirus (HPV)-associated PSCC cases from Latin Americans, using whole-exome sequencing. Copy number variations (CNVs) were also identified and compared to previous array-generated data. Enrichment analyses were performed to reveal disrupted pathways and to identify alterations mapped to HPV integration sites (HPVis) and miRNA–mRNA hybridization regions. Among the most frequently mutated genes were NOTCH1, TERT, TTN, FAT1, TP53, CDKN2A, RYR2, CASP8, FBXW7, HMCN2, and ITGA8. Of note, 92% of these altered genes were localized at HPVis. We also found mutations in ten novel genes (KMT2C, SMARCA4, PTPRB, AJUBA, CR1, KMT2D, NBEA, FAM135B, GTF2I, and CIC), thus increasing our understanding of the potential HPV-disrupted pathways. Therefore, our study reveals innovative targets with potential therapeutic benefits for HPV-associated PSCCs. The CNV analysis by sequencing (CNV-seq) revealed five cancer-associated genes as the most frequent with gains (NOTCH1, MYC, NUMA1, PLAG1, and RAD21), while 30% of the tumors showed SMARCA4 with loss. Additionally, four cancer-associated genes (CARD11, CSMD3, KDR, and TLX3) carried untranslated regions (UTRs) variants, which may impact gene regulation by affecting the miRNAs hybridization regions. Altogether, these data contribute to the characterization of the mutational spectrum and its impact on cellular signaling pathways in PSCC, thus reinforcing the pivotal role of HPV infection in the molecular pathogenesis of these tumors.

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

“…However, these SNPs were not related to ASM in penile SCC, as the genotype frequency was not different between HPV+ and HPV-, and it was not related to the methylated or unmethylated stretch. Canto et al (2022) showed HPV-related mutations in penile cancer, and these alterations were localized to HPV integration sites (HPVis) and miRNA regions [ 57 ]. A recent study showed that a high somatic tumour mutation burden (TMB) is associated with HPV-positive penile SCC, and these data show that the molecular scenario for this disease may depend on viral infection [ 58 ].…”

Microbiome reveals inflammatory‐related bacteria and putative functional pathways involved in human papillomavirus‐associated penile squamous cell carcinoma

“…Adjacent tissues were collected 2 cm away from the primary tumor, within the surgical safety margin, and classified through histopathological and immunohistochemical analysis 20 . In addition, gene expression, miRNA expression, copy number alteration, and exome sequencing data support that penile tumor‐adjacent tissues are a suitable normal control in relation to the tumors 21–23 . The cancer staging was determined using the 2016 World Health Organization tumor–node–metastasis (TNM) classification 24,25 …”

“…20 In addition, gene expression, miRNA expression, copy number alteration, and exome sequencing data support that penile tumor-adjacent tissues are a suitable normal control in relation to the tumors. [21][22][23] The cancer staging was determined using the 2016 World Health Organization tumor-node-metastasis (TNM) classification. 24,25 The mean age of patients at the time of diagnosis was 62.6 ± 16.5 years, with a range of 32-85 years.…”