%0 Journal Article %J Cell Rep %D 2019 %T Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. %A Donehower, Lawrence A %A Soussi, Thierry %A Korkut, Anil %A Liu, Yuexin %A Schultz, Andre %A Cardenas, Maria %A Li, Xubin %A Babur, Ozgun %A Hsu, Teng-Kuei %A Lichtarge, Olivier %A Weinstein, John N %A Akbani, Rehan %A David A Wheeler %K Databases, Nucleic Acid %K Gene Expression Regulation, Neoplastic %K Humans %K Loss of Heterozygosity %K MicroRNAs %K Neoplasms %K RNA, Neoplasm %K Tumor Suppressor Protein p53 %X

The TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes. Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins. A mutant TP53 RNA expression signature shows significant correlation with reduced survival in 11 cancer types. Thus, TP53 mutation has profound effects on tumor cell genomic structure, expression, and clinical outlook.

%B Cell Rep %V 28 %P 1370-1384.e5 %8 2019 Jul 30 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/31365877?dopt=Abstract %R 10.1016/j.celrep.2019.07.001 %0 Journal Article %J Cell Rep %D 2019 %T Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis. %A Majewski, Tadeusz %A Yao, Hui %A Bondaruk, Jolanta %A Chung, Woonbok %A Lee, Sangkyou %A Lee, June Goo %A Zhang, Shizhen %A Cogdell, David %A Yang, Guoliang %A Choi, Woonyoung %A Dinney, Colin %A Grossman, H Barton %A Logothetis, Christopher %A Steven E Scherer %A Guo, Charles C %A Zhang, Li %A Wei, Peng %A Weinstein, John N %A Issa, Jean-Pierre %A Baggerly, Keith %A McConkey, David J %A Czerniak, Bogdan %K Carcinogenesis %K Carcinoma %K Clonal Evolution %K DNA Methylation %K Genome, Human %K Humans %K Male %K Middle Aged %K Mucous Membrane %K Mutation %K Nuclear Proteins %K Urinary Bladder Neoplasms %K Urothelium %X

We used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.

%B Cell Rep %V 26 %P 2241-2256.e4 %8 2019 Feb 19 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/30784602?dopt=Abstract %R 10.1016/j.celrep.2019.01.095 %0 Journal Article %J Cancer Cell %D 2018 %T A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. %A Berger, Ashton C %A Korkut, Anil %A Kanchi, Rupa S %A Hegde, Apurva M %A Lenoir, Walter %A Liu, Wenbin %A Liu, Yuexin %A Fan, Huihui %A Shen, Hui %A Ravikumar, Visweswaran %A Rao, Arvind %A Schultz, Andre %A Li, Xubin %A Sumazin, Pavel %A Williams, Cecilia %A Mestdagh, Pieter %A Gunaratne, Preethi H %A Yau, Christina %A Bowlby, Reanne %A Robertson, A Gordon %A Tiezzi, Daniel G %A Wang, Chen %A Cherniack, Andrew D %A Godwin, Andrew K %A Kuderer, Nicole M %A Rader, Janet S %A Zuna, Rosemary E %A Sood, Anil K %A Lazar, Alexander J %A Ojesina, Akinyemi I %A Adebamowo, Clement %A Adebamowo, Sally N %A Baggerly, Keith A %A Chen, Ting-Wen %A Chiu, Hua-Sheng %A Lefever, Steve %A Liu, Liang %A MacKenzie, Karen %A Orsulic, Sandra %A Roszik, Jason %A Shelley, Carl Simon %A Song, Qianqian %A Vellano, Christopher P %A Wentzensen, Nicolas %A Weinstein, John N %A Mills, Gordon B %A Levine, Douglas A %A Akbani, Rehan %K Breast Neoplasms %K Databases, Genetic %K DNA Copy Number Variations %K Female %K Gene Expression Profiling %K Gene Expression Regulation, Neoplastic %K Gene Regulatory Networks %K Genetic Predisposition to Disease %K Genital Neoplasms, Female %K Humans %K Mutation %K Organ Specificity %K Prognosis %K Receptors, Estrogen %K RNA, Long Noncoding %X

We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories.

%B Cancer Cell %V 33 %P 690-705.e9 %8 2018 Apr 09 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/29622464?dopt=Abstract %R 10.1016/j.ccell.2018.03.014 %0 Journal Article %J Cell Rep %D 2018 %T Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. %A Knijnenburg, Theo A %A Wang, Linghua %A Zimmermann, Michael T %A Chambwe, Nyasha %A Gao, Galen F %A Cherniack, Andrew D %A Fan, Huihui %A Shen, Hui %A Way, Gregory P %A Greene, Casey S %A Liu, Yuexin %A Akbani, Rehan %A Feng, Bin %A Donehower, Lawrence A %A Miller, Chase %A Shen, Yang %A Karimi, Mostafa %A Chen, Haoran %A Kim, Pora %A Jia, Peilin %A Shinbrot, Eve %A Zhang, Shaojun %A Liu, Jianfang %A Hu, Hai %A Bailey, Matthew H %A Yau, Christina %A Wolf, Denise %A Zhao, Zhongming %A Weinstein, John N %A Li, Lei %A Ding, Li %A Mills, Gordon B %A Laird, Peter W %A Wheeler, David A %A Shmulevich, Ilya %A Monnat, Raymond J %A Xiao, Yonghong %A Wang, Chen %K Cell Line, Tumor %K DNA Damage %K Gene Silencing %K Genome, Human %K Humans %K Loss of Heterozygosity %K Machine Learning %K Mutation %K Neoplasms %K Recombinational DNA Repair %K Tumor Suppressor Proteins %X

DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy.

%B Cell Rep %V 23 %P 239-254.e6 %8 2018 Apr 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29617664?dopt=Abstract %R 10.1016/j.celrep.2018.03.076 %0 Journal Article %J Cell Rep %D 2018 %T Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. %A Campbell, Joshua D %A Yau, Christina %A Bowlby, Reanne %A Liu, Yuexin %A Brennan, Kevin %A Fan, Huihui %A Taylor, Alison M %A Wang, Chen %A Walter, Vonn %A Akbani, Rehan %A Byers, Lauren Averett %A Creighton, Chad J %A Coarfa, Cristian %A Shih, Juliann %A Cherniack, Andrew D %A Gevaert, Olivier %A Prunello, Marcos %A Shen, Hui %A Anur, Pavana %A Chen, Jianhong %A Cheng, Hui %A Hayes, D Neil %A Bullman, Susan %A Pedamallu, Chandra Sekhar %A Ojesina, Akinyemi I %A Sadeghi, Sara %A Mungall, Karen L %A Robertson, A Gordon %A Benz, Christopher %A Schultz, Andre %A Kanchi, Rupa S %A Gay, Carl M %A Hegde, Apurva %A Diao, Lixia %A Wang, Jing %A Ma, Wencai %A Sumazin, Pavel %A Chiu, Hua-Sheng %A Chen, Ting-Wen %A Gunaratne, Preethi %A Donehower, Larry %A Rader, Janet S %A Zuna, Rosemary %A Al-Ahmadie, Hikmat %A Lazar, Alexander J %A Flores, Elsa R %A Tsai, Kenneth Y %A Zhou, Jane H %A Rustgi, Anil K %A Drill, Esther %A Shen, Ronglei %A Wong, Christopher K %A Stuart, Joshua M %A Laird, Peter W %A Hoadley, Katherine A %A Weinstein, John N %A Peto, Myron %A Pickering, Curtis R %A Chen, Zhong %A Van Waes, Carter %K Carcinoma, Squamous Cell %K Cell Line, Tumor %K DNA Methylation %K Epithelial-Mesenchymal Transition %K Gene Expression Regulation, Neoplastic %K Genomics %K Humans %K Metabolic Networks and Pathways %K Polymorphism, Genetic %X

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

%B Cell Rep %V 23 %P 194-212.e6 %8 2018 Apr 03 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29617660?dopt=Abstract %R 10.1016/j.celrep.2018.03.063 %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 Clin Cancer Res %D 2014 %T Squamous cell carcinoma of the oral tongue in young non-smokers is genomically similar to tumors in older smokers. %A Pickering, Curtis R %A Zhang, Jiexin %A Neskey, David M %A Zhao, Mei %A Jasser, Samar A %A Wang, Jiping %A Ward, Alexandra %A Tsai, C Jillian %A Ortega Alves, Marcus V %A Zhou, Jane H %A Drummond, Jennifer %A El-Naggar, Adel K %A Gibbs, Richard %A Weinstein, John N %A Wheeler, David A %A Wang, Jing %A Frederick, Mitchell J %A Myers, Jeffrey N %K Adult %K Age Factors %K Carcinoma, Squamous Cell %K DNA Copy Number Variations %K DNA Mutational Analysis %K Female %K Humans %K Male %K Middle Aged %K Mutation %K Prognosis %K Smoking %K Tongue Neoplasms %X

PURPOSE: Epidemiologic studies have identified an increasing incidence of squamous cell carcinoma of the oral tongue (SCCOT) in younger patients.

EXPERIMENTAL DESIGN: DNA isolated from tongue tumors of young (<45 years, non-smokers) and old (>45 years) patients at was subjected to whole-exome sequencing and copy-number analysis. These data were compared with data from similar patients in the TCGA (The Cancer Genome Atlas) project.

RESULTS: In this study, we found that gene-specific mutation and copy-number alteration frequencies were similar between young and old patients with SCCOT in two independent cohorts. Likewise, the types of base changes observed in the young cohort were similar to those in the old cohort even though they differed in smoking history. TCGA data also demonstrate that the genomic effects of smoking are tumor site-specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.

CONCLUSIONS: Overall, tumors from young patients with SCCOT appear genomically similar to those of older patients with SCCOT, and the cause for the increasing incidence of young SCCOT remains unknown. These data indicate that the functional impact of smoking on carcinogenesis in SCCOT is still poorly understood.

%B Clin Cancer Res %V 20 %P 3842-8 %8 2014 Jul 15 %G eng %N 14 %1 https://www.ncbi.nlm.nih.gov/pubmed/24874835?dopt=Abstract %R 10.1158/1078-0432.CCR-14-0565 %0 Journal Article %J Nat Genet %D 2013 %T The Cancer Genome Atlas Pan-Cancer analysis project. %A Weinstein, John N %A Collisson, Eric A %A Mills, Gordon B %A Shaw, Kenna R Mills %A Ozenberger, Brad A %A Ellrott, Kyle %A Shmulevich, Ilya %A Sander, Chris %A Stuart, Joshua M %K Gene Expression Profiling %K Genome %K Humans %K Neoplasms %X

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

%B Nat Genet %V 45 %P 1113-20 %8 2013 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/24071849?dopt=Abstract %R 10.1038/ng.2764 %0 Journal Article %J Cancer Discov %D 2013 %T Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. %A Pickering, Curtis R %A Zhang, Jiexin %A Yoo, Suk Young %A Bengtsson, Linnea %A Moorthy, Shhyam %A Neskey, David M %A Zhao, Mei %A Ortega Alves, Marcus V %A Chang, Kyle %A Drummond, Jennifer %A Cortez, Elsa %A Xie, Tong-Xin %A Zhang, Di %A Chung, Woonbok %A Issa, Jean-Pierre J %A Zweidler-McKay, Patrick A %A Wu, Xifeng %A El-Naggar, Adel K %A Weinstein, John N %A Wang, Jing %A Muzny, Donna M %A Gibbs, Richard A %A Wheeler, David A %A Myers, Jeffrey N %A Frederick, Mitchell J %K Carcinoma, Squamous Cell %K Caspase 8 %K Cell Line, Tumor %K DNA Copy Number Variations %K DNA Methylation %K Gene Expression Regulation, Neoplastic %K Genomics %K Humans %K Mouth Neoplasms %K Point Mutation %K Receptors, Notch %X

The survival of patients with oral squamous cell carcinoma (OSCC) has not changed significantly in several decades, leading clinicians and investigators to search for promising molecular targets. To this end, we conducted comprehensive genomic analysis of gene expression, copy number, methylation, and point mutations in OSCC. Integrated analysis revealed more somatic events than previously reported, identifying four major driver pathways (mitogenic signaling, Notch, cell cycle, and TP53) and two additional key genes (FAT1, CASP8). The Notch pathway was defective in 66% of patients, and in follow-up studies of mechanism, functional NOTCH1 signaling inhibited proliferation of OSCC cell lines. Frequent mutation of caspase-8 (CASP8) defines a new molecular subtype of OSCC with few copy number changes. Although genomic alterations are dominated by loss of tumor suppressor genes, 80% of patients harbored at least one genomic alteration in a targetable gene, suggesting that novel approaches to treatment may be possible for this debilitating subset of head and neck cancers.

%B Cancer Discov %V 3 %P 770-81 %8 2013 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/23619168?dopt=Abstract %R 10.1158/2159-8290.CD-12-0537 %0 Journal Article %J Science %D 2011 %T Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. %A Agrawal, Nishant %A Frederick, Mitchell J %A Pickering, Curtis R %A Bettegowda, Chetan %A Chang, Kyle %A Li, Ryan J %A Fakhry, Carole %A Xie, Tong-Xin %A Zhang, Jiexin %A Wang, Jing %A Zhang, Nianxiang %A El-Naggar, Adel K %A Jasser, Samar A %A Weinstein, John N %A Treviño, Lisa %A Drummond, Jennifer A %A Muzny, Donna M %A Wu, Yuanqing %A Wood, Laura D %A Hruban, Ralph H %A Westra, William H %A Koch, Wayne M %A Califano, Joseph A %A Gibbs, Richard A %A Sidransky, David %A Vogelstein, Bert %A Velculescu, Victor E %A Papadopoulos, Nickolas %A Wheeler, David A %A Kinzler, Kenneth W %A Myers, Jeffrey N %K Carcinoma %K Carcinoma, Squamous Cell %K Cell Cycle Proteins %K Codon, Nonsense %K Exons %K F-Box Proteins %K F-Box-WD Repeat-Containing Protein 7 %K Gene Dosage %K Genes, p53 %K Genes, Tumor Suppressor %K Head and Neck Neoplasms %K Humans %K INDEL Mutation %K Mutation %K Mutation, Missense %K Neoplasms, Squamous Cell %K Nicotiana %K Oligonucleotide Array Sequence Analysis %K Oncogenes %K Papillomaviridae %K Papillomavirus Infections %K Receptor, Notch1 %K Sequence Analysis, DNA %K Smoking %K Squamous Cell Carcinoma of Head and Neck %K Ubiquitin-Protein Ligases %X

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomavirus (HPV) had more mutations than did HPV-positive tumors. Six of the genes that were mutated in multiple tumors were assessed in up to 88 additional HNSCCs. In addition to previously described mutations in TP53, CDKN2A, PIK3CA, and HRAS, we identified mutations in FBXW7 and NOTCH1. Nearly 40% of the 28 mutations identified in NOTCH1 were predicted to truncate the gene product, suggesting that NOTCH1 may function as a tumor suppressor gene rather than an oncogene in this tumor type.

%B Science %V 333 %P 1154-7 %8 2011 Aug 26 %G eng %N 6046 %1 https://www.ncbi.nlm.nih.gov/pubmed/21798897?dopt=Abstract %R 10.1126/science.1206923