Search

Human papillomavirus (HPV) causes 5% of all cancers and frequently integrates into host chromosomes. The HPV oncoproteins E6 and E7 are necessary but insufficient for cancer formation, indicating that additional secondary genetic events are required. Here, we investigate potential oncogenic impacts of virus integration. Analysis of 105 HPV-positive oropharyngeal cancers by whole-genome sequencing detects virus integration in 77%, revealing five statistically significant sites of recurrent integration near genes that regulate epithelial stem cell maintenance (i.e., SOX2, TP63, FGFR, MYC ) and immune evasion (i.e., CD274 ). Genomic copy number hyperamplification is enriched 16-fold near HPV integrants, and the extent of focal host genomic instability increases with their local density. The frequency of genes expressed at extreme outlier levels is increased 86-fold within ±150 kb of integrants. Across 95% of tumors with integration, host gene transcription is disrupted via intragenic integrants, chimeric transcription, outlier expression, gene breaking, and/or de novo expression of noncoding or imprinted genes. We conclude that virus integration can contribute to carcinogenesis in a large majority of HPV-positive oropharyngeal cancers by inducing extensive disruption of host genome structure and gene expression., (© 2022 Symer et al.; Published by Cold Spring Harbor Laboratory Press.)

Human papillomavirus (HPV) is a necessary but insufficient cause of a subset of oral squamous cell carcinomas (OSCCs) that is increasing markedly in frequency. To identify contributory, secondary genetic alterations in these cancers, we used comprehensive genomics methods to compare 149 HPV-positive and 335 HPV-negative OSCC tumor/normal pairs. Different behavioral risk factors underlying the two OSCC types were reflected in distinctive genomic mutational signatures. In HPV-positive OSCCs, the signatures of APOBEC cytosine deaminase editing, associated with anti-viral immunity, were strongly linked to overall mutational burden. In contrast, in HPV-negative OSCCs, T>C substitutions in the sequence context 5'-ATN-3' correlated with tobacco exposure. Universal expression of HPV E6*1 and E7 oncogenes was a sine qua non of HPV-positive OSCCs. Significant enrichment of somatic mutations was confirmed or newly identified in PIK3CA , KMT2D , FGFR3 , FBXW7 , DDX3X , PTEN , TRAF3 , RB1 , CYLD , RIPK4 , ZNF750 , EP300 , CASZ1 , TAF5 , RBL1 , IFNGR1 , and NFKBIA Of these, many affect host pathways already targeted by HPV oncoproteins, including the p53 and pRB pathways, or disrupt host defenses against viral infections, including interferon (IFN) and nuclear factor kappa B signaling. Frequent copy number changes were associated with concordant changes in gene expression. Chr 11q (including CCND1 ) and 14q (including DICER1 and AKT1 ) were recurrently lost in HPV-positive OSCCs, in contrast to their gains in HPV-negative OSCCs. High-ranking variant allele fractions implicated ZNF750 , PIK3CA , and EP300 mutations as candidate driver events in HPV-positive cancers. We conclude that virus-host interactions cooperatively shape the unique genetic features of these cancers, distinguishing them from their HPV-negative counterparts., (© 2019 Gillison et al.; Published by Cold Spring Harbor Laboratory Press.)

Second-generation sequencing technologies deliver DNA sequence data at unprecedented high throughput. Common to most biological applications is a mapping of the reads to an almost identical or highly similar reference genome. Due to the large amounts of data, efficient algorithms and implementations are crucial for this task. We present an efficient read mapping tool called RazerS. It allows the user to align sequencing reads of arbitrary length using either the Hamming distance or the edit distance. Our tool can work either lossless or with a user-defined loss rate at higher speeds. Given the loss rate, we present an approach that guarantees not to lose more reads than specified. This enables the user to adapt to the problem at hand and provides a seamless tradeoff between sensitivity and running time.