Recent genomic analyses of pathologically-defined tumor types identify “within-a-tissue” disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head & neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multi-platform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All datasets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twentyfive cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter-and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...

Summary Molecular alterations involving PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11219 human cancers representing 32 major types. Within specific mutated genes, frequency, mutation hotspot residues, in silico predictions, and functional assays were all informative in distinguishing the subset of genetic variants more likely to have functional relevance. Multiple oncogenic pathways including PI3K/AKT/mTOR converged on similar sets of downstream transcriptional targets. In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance. A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.

Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4+T cells. Some of these CD4+T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4+ T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1–infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4+T cells can be a reservoir of infectious HIV-1.