%0 Journal Article %J Genome Biol %D 2019 %T Global impact of somatic structural variation on the DNA methylome of human cancers. %A Zhang, Yiqun %A Yang, Lixing %A Kucherlapati, Melanie %A Hadjipanayis, Angela %A Pantazi, Angeliki %A Bristow, Christopher A %A Lee, Eunjung Alice %A Mahadeshwar, Harshad S %A Tang, Jiabin %A Zhang, Jianhua %A Seth, Sahil %A Lee, Semin %A Ren, Xiaojia %A Song, Xingzhi %A Sun, Huandong %A Seidman, Jonathan %A Luquette, Lovelace J %A Xi, Ruibin %A Chin, Lynda %A Protopopov, Alexei %A Park, Peter J %A Kucherlapati, Raju %A Creighton, Chad J %K CpG Islands %K Epigenome %K Genomic Structural Variation %K Humans %K Neoplasms %X

BACKGROUND: Genomic rearrangements exert a heavy influence on the molecular landscape of cancer. New analytical approaches integrating somatic structural variants (SSVs) with altered gene features represent a framework by which we can assign global significance to a core set of genes, analogous to established methods that identify genes non-randomly targeted by somatic mutation or copy number alteration. While recent studies have defined broad patterns of association involving gene transcription and nearby SSV breakpoints, global alterations in DNA methylation in the context of SSVs remain largely unexplored.

RESULTS: By data integration of whole genome sequencing, RNA sequencing, and DNA methylation arrays from more than 1400 human cancers, we identify hundreds of genes and associated CpG islands (CGIs) for which the nearby presence of a somatic structural variant (SSV) breakpoint is recurrently associated with altered expression or DNA methylation, respectively, independently of copy number alterations. CGIs with SSV-associated increased methylation are predominantly promoter-associated, while CGIs with SSV-associated decreased methylation are enriched for gene body CGIs. Rearrangement of genomic regions normally having higher or lower methylation is often involved in SSV-associated CGI methylation alterations. Across cancers, the overall structural variation burden is associated with a global decrease in methylation, increased expression in methyltransferase genes and DNA damage response genes, and decreased immune cell infiltration.

CONCLUSION: Genomic rearrangement appears to have a major role in shaping the cancer DNA methylome, to be considered alongside commonly accepted mechanisms including histone modifications and disruption of DNA methyltransferases.

%B Genome Biol %V 20 %P 209 %8 2019 Oct 15 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/31610796?dopt=Abstract %R 10.1186/s13059-019-1818-9 %0 Journal Article %J Cell Rep %D 2018 %T A Pan-Cancer Compendium of Genes Deregulated by Somatic Genomic Rearrangement across More Than 1,400 Cases. %A Zhang, Yiqun %A Yang, Lixing %A Kucherlapati, Melanie %A Chen, Fengju %A Hadjipanayis, Angela %A Pantazi, Angeliki %A Bristow, Christopher A %A Lee, Eunjung A %A Mahadeshwar, Harshad S %A Tang, Jiabin %A Zhang, Jianhua %A Seth, Sahil %A Lee, Semin %A Ren, Xiaojia %A Song, Xingzhi %A Sun, Huandong %A Seidman, Jonathan %A Luquette, Lovelace J %A Xi, Ruibin %A Chin, Lynda %A Protopopov, Alexei %A Li, Wei %A Park, Peter J %A Kucherlapati, Raju %A Creighton, Chad J %K Base Sequence %K Carcinogenesis %K DNA Copy Number Variations %K Enhancer Elements, Genetic %K Gene Expression Regulation, Neoplastic %K Gene Rearrangement %K Genes, Neoplasm %K Genome, Human %K Humans %K Neoplasms %X

A systematic cataloging of genes affected by genomic rearrangement, using multiple patient cohorts and cancer types, can provide insight into cancer-relevant alterations outside of exomes. By integrative analysis of whole-genome sequencing (predominantly low pass) and gene expression data from 1,448 cancers involving 18 histopathological types in The Cancer Genome Atlas, we identified hundreds of genes for which the nearby presence (within 100 kb) of a somatic structural variant (SV) breakpoint is associated with altered expression. While genomic rearrangements are associated with widespread copy-number alteration (CNA) patterns, approximately 1,100 genes-including overexpressed cancer driver genes (e.g., TERT, ERBB2, CDK12, CDK4) and underexpressed tumor suppressors (e.g., TP53, RB1, PTEN, STK11)-show SV-associated deregulation independent of CNA. SVs associated with the disruption of topologically associated domains, enhancer hijacking, or fusion transcripts are implicated in gene upregulation. For cancer-relevant pathways, SVs considerably expand our understanding of how genes are affected beyond point mutation or CNA.

%B Cell Rep %V 24 %P 515-527 %8 2018 Jul 10 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/29996110?dopt=Abstract %R 10.1016/j.celrep.2018.06.025 %0 Journal Article %J Cancer Cell %D 2017 %T A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations. %A Zhang, Yiqun %A Kwok-Shing Ng, Patrick %A Kucherlapati, Melanie %A Chen, Fengju %A Liu, Yuexin %A Tsang, Yiu Huen %A De Velasco, Guillermo %A Jeong, Kang Jin %A Akbani, Rehan %A Hadjipanayis, Angela %A Pantazi, Angeliki %A Bristow, Christopher A %A Lee, Eunjung %A Mahadeshwar, Harshad S %A Tang, Jiabin %A Zhang, Jianhua %A Yang, Lixing %A Seth, Sahil %A Lee, Semin %A Ren, Xiaojia %A Song, Xingzhi %A Sun, Huandong %A Seidman, Jonathan %A Luquette, Lovelace J %A Xi, Ruibin %A Chin, Lynda %A Protopopov, Alexei %A Westbrook, Thomas F %A Shelley, Carl Simon %A Choueiri, Toni K %A Ittmann, Michael %A Van Waes, Carter %A Weinstein, John N %A Liang, Han %A Henske, Elizabeth P %A Godwin, Andrew K %A Park, Peter J %A Kucherlapati, Raju %A Scott, Kenneth L %A Mills, Gordon B %A Kwiatkowski, David J %A Creighton, Chad J %K Databases, Genetic %K Gene Expression Profiling %K Humans %K Mutation %K Neoplasms %K Phosphatidylinositol 3-Kinases %K Proteogenomics %K Proto-Oncogene Proteins c-akt %K Signal Transduction %K Survival Analysis %K TOR Serine-Threonine Kinases %X

Molecular alterations involving the PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11,219 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.

%B Cancer Cell %V 31 %P 820-832.e3 %8 2017 Jun 12 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28528867?dopt=Abstract %R 10.1016/j.ccell.2017.04.013 %0 Journal Article %J Proc Natl Acad Sci U S A %D 2014 %T Characterization of HPV and host genome interactions in primary head and neck cancers. %A Parfenov, Michael %A Pedamallu, Chandra Sekhar %A Gehlenborg, Nils %A Freeman, Samuel S %A Danilova, Ludmila %A Bristow, Christopher A %A Lee, Semin %A Hadjipanayis, Angela G %A Ivanova, Elena V %A Wilkerson, Matthew D %A Protopopov, Alexei %A Yang, Lixing %A Seth, Sahil %A Song, Xingzhi %A Tang, Jiabin %A Ren, Xiaojia %A Zhang, Jianhua %A Pantazi, Angeliki %A Santoso, Netty %A Xu, Andrew W %A Mahadeshwar, Harshad %A Wheeler, David A %A Haddad, Robert I %A Jung, Joonil %A Ojesina, Akinyemi I %A Issaeva, Natalia %A Yarbrough, Wendell G %A Hayes, D Neil %A Grandis, Jennifer R %A El-Naggar, Adel K %A Meyerson, Matthew %A Park, Peter J %A Chin, Lynda %A Seidman, J G %A Hammerman, Peter S %A Kucherlapati, Raju %K Base Sequence %K DNA Methylation %K Gene Expression Regulation, Neoplastic %K Genes, Neoplasm %K Genome, Human %K Head and Neck Neoplasms %K Host-Pathogen Interactions %K Humans %K Molecular Sequence Data %K Papillomaviridae %K Virus Integration %X

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. Twenty-five 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.

%B Proc Natl Acad Sci U S A %V 111 %P 15544-9 %8 2014 Oct 28 %G eng %N 43 %1 https://www.ncbi.nlm.nih.gov/pubmed/25313082?dopt=Abstract %R 10.1073/pnas.1416074111