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How do I find samples/patients in TCGA (the cancer genome atlas) that had radiation therapy?

How do I find samples/patients in TCGA (the cancer genome atlas) that had radiation therapy?


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I want to correlate the expression of a gene (for sample the KRAS gene) with survival and if the patient received radiation therapy using any suitable TCGA (the cancer genome atlas) dataset. However, I have so far been unable to figure out what patients have received radiation therapy.

Any suggestions?


The process is slightly painful but here is how you do it. Go to UCSC Xena, then launch the browser, hit the Visualize tab, pick your cohort of interest, then in the next menu pick phenotype, and then type radiotherapy in the box and pick the radiotherapy related columns you want. Then, once it has loaded the annotation bar, you can hit download and the downloaded spreadsheet will have this information along with the TCGA barcodes. As for clinical data, https://www.synapse.org/#!Synapse:syn7343873/wiki/412112 is a very good pancancer source.


Objective

Locally advanced oral squamous cell carcinoma (OSCC) shows lower locoregional control and disease specific survival rates than laryngeal and pharyngeal squamous cell carcinoma (L/P-SCC) after definitive chemoradiotherapy treatment. Despite clinical factors, this can point towards a different tumor biology that could impact chemoradiotherapy response rates. This prompted us to compare the mutational profiles of OSCC with L/P-SCC.

Methods

We performed target capture DNA sequencing on 111 HPV-negative HNSCC samples (NKI dataset), 55 oral and 56 laryngeal/pharyngeal, and identified somatic point mutations and copy number aberrations. We next expanded our analysis with 276 OSCC and 134 L/P-SCC sample data from The Cancer Genome Atlas (TCGA dataset). We focused our analyses on genes that are frequently mutated in HNSCC.

Results

The mutational profiles of OSCC and L/P-SCC showed many similarities. However, OSCC was significantly enriched for CASP8 (NKI: 15% vs 0% TCGA: 17% vs 2%) and HRAS (TCGA: 10% vs 1%) mutations. LAMA2 (TCGA: 5% vs 19%) and NSD1 (TCGA: 7% vs 25%) mutations were enriched in L/P-SCC. Overall, we find that OSCC had fewer somatic point mutations and copy number aberrations than L/P-SCC. Interestingly, L/P-SCC scored higher in mutational and genomic scar signatures associated with homologous recombination DNA repair defects.

Conclusion

Despite showing a similar mutational profile, our comparative genomic analysis revealed distinctive features in OSCC and L/P-SCC. Some of these genes and cellular processes are likely to affect the cellular response to radiation or cisplatin. Genomic characterizations may guide or enable personalized treatment in the future.


Background

Prostate cancer (PCa) is the second commonest malignancy and the fifth leading cause of cancer-related deaths in men [1]. Based on GLOBOCAN estimates, approximately 1.3 million new cases were clinically diagnosed with PCa in 2018, leading to approximately 359,000 PCa-related deaths worldwide [1]. Several therapeutic strategies, including radical prostatectomy and radiotherapy, have shown a better clinical outcome for patients with early-stage PCa [2, 3]. In contrast, patients with advanced stage PCa have distant metastases and consequently, worse prognosis because of the lack of the effective treatment options [4, 5]. Therefore, a novel molecular biomarker is required to improve the prognosis of patients with PCa.

Cancer stem cells (CSCs) are a small group of cells within tumors and are responsible for self-renewal, uncontrolled differentiation, and tumorigenicity [6, 7]. CSCs contribute to cancer development, progression, and metastasis [8,9,10]. Epithelial cell adhesion molecule (EpCAM), known as epithelial-specific antigen (ESA) or CD326, a membrane glycoprotein, plays an important role in Ca2+ independent hemophilic cell-to-cell adhesion, cell signaling, migration, proliferation, and differentiation [11, 12]. The presence of CSCs in PCa may partially play a role in cancer progression, metastasis, and chemoresistance [13, 14]. EpCAM is identified as a CSC marker and a potential therapeutic target for cancer [15]. EpCAM is expressed in many types of human cancer, such as breast cancer, gastric cancer, and colorectal cancer [16,17,18]. Recent studies also demonstrated that high EpCAM expression may predict poor clinical outcome in breast cancer [19], ovarian carcinoma [20], and hepatocellular carcinoma [21]. Some studies reported that EpCAM was frequently expressed and associated with worse prognosis of patients with PCa [22, 23].

The development of PCa develops involves the transition of normal epithelium to benign prostatic epithelium, and subsequent progression to malignant carcinoma through multiple sequences [24,25,26]. The role of EpCAM expression in PCa development and progression remains controversial. Ni 2013 et al. reported that the frequency of EpCAM expression was similar in PCa and benign prostatic tissue samples [22]. In contrast, Li et al. showed that EpCAM expression was notably higher in PCa than benign prostatic tissue samples [27]. Thus, the primary objective of this study was to identify the role of EpCAM in determining the risk of PCa development. The secondary objective was to perform a meta-analysis to assess the clinicopathological and prognostic value of EpCAM in PCa.


The Cancer Genome Atlas Identifies Distinct Subtypes of Deadly Brain Cancer That May Lead to New Treatment Strategies

The most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is not a single disease but appears to be four distinct molecular subtypes, according to a study by The Cancer Genome Atlas (TCGA) Research Network. The researchers of this study also found that response to aggressive chemotherapy and radiation differed by subtype. Patients with one subtype treated with this strategy appeared to succumb to their disease at a rate approximately 50 percent slower than patients treated with less aggressive therapy. This effect was seen to a lesser degree in two of the subtypes and not at all in the fourth subtype.

Although the findings do not affect current clinical practice, the researchers said the results may lead to more personalized approaches to treating groups of GBM patients based on their genomic alterations. The study, published Jan. 19, 2010 in Cancer Cell, provides a solid framework for investigation of targeted therapies that may improve the near uniformly fatal prognosis of this cancer. The research team for TCGA is a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.

"TCGA is mobilizing the entire cancer community to find new strategies in detecting and treating cancer faster," said NIH Director Francis Collins, M.D., Ph.D. "These findings are just a hint of what we expect to result from the comprehensive data generated by TCGA over the next few years."

GBM is a very fast-growing type of tumor. In recent years, 3 of every 100,000 Americans have been diagnosed with GBM, representing the highest incidence rate among malignant brain tumors. Most patients with GBM die of the disease within approximately 14 months of diagnosis.

"These new findings offer critical insights into stratifying patients based on the unique molecular characteristics of their disease," said John E. Niederhuber, M.D., NCI director. "As we learn more and more about the genetic underpinnings of cancer, we hope to achieve a similar level of molecular understanding for all cancers and eventually to generate recipes of highly targeted therapies uniquely suited to the individual patient."

The TCGA researchers expanded on previous studies, which had established gene expression profiling as a means to identify distinct subgroups of GBM.

"We discovered a bundle of events that unequivocally occur almost exclusively within a subtype," said lead author D. Neil Hayes, M.D., University of North Carolina at Chapel Hill. "These are critical events in the history of the tumor's development and spread, and evidence is increasing that they may relate to the initial formation of the tumors."

TCGA researchers reported that the nature of these events indicate that the underlying pathology of each subtype may begin from different types of cells. This may provide a better understanding of which cell types undergo changes that ultimately drive initial cancer formation. This finding has potential clinical significance since determining the types of cells that form GBM is critical for establishing effective treatment regimens. Because the response to aggressive chemotherapy and radiation differed by subtype, some classes of drugs would be expected to work for some tumor subtypes and not others.

"The ability to differentiate GBM tumors based on their altered genetic code lays the groundwork for more effective treatment strategies to combat this deadly cancer," said Eric D. Green, M.D., Ph.D., NHGRI director. "These findings demonstrate the power of using a cancer's genome to unravel the molecular changes that occur in the various cancer types targeted by TCGA. I’m optimistic that this type of knowledge will someday lead to improved personalized therapies and care for cancer patients."

The new findings build on TCGA's detailed view of GBM genomic changes reported in Nature in October 2008. TCGA, launched in 2006, is a comprehensive and coordinated effort to accelerate understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing.


The Cancer Genome Atlas Identifies Distinct Subtypes of Deadly Brain Cancer That May Lead to New Treatment Strategies

BETHESDA, Md., Tues., Jan. 19, 2010 — The most common form of malignant brain cancer in adults, glioblastoma multiforme (GBM), is not a single disease but appears to be four distinct molecular subtypes, according to a study by The Cancer Genome Atlas (TCGA) Research Network. The researchers of this study also found that response to aggressive chemotherapy and radiation differed by subtype. Patients with one subtype treated with this strategy appeared to succumb to their disease at a rate approximately 50 percent slower than patients treated with less aggressive therapy. This effect was seen to a lesser degree in two of the subtypes and not at all in the fourth subtype.

Although the findings do not affect current clinical practice, the researchers said the results may lead to more personalized approaches to treating groups of GBM patients based on their genomic alterations. The study, published Jan. 19, 2010 in Cancer Cell, provides a solid framework for investigation of targeted therapies that may improve the near uniformly fatal prognosis of this cancer. The research team for TCGA is a collaborative effort funded by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.

"TCGA is mobilizing the entire cancer community to find new strategies in detecting and treating cancer faster," said NIH Director Francis Collins, M.D., Ph.D. "These findings are just a hint of what we expect to result from the comprehensive data generated by TCGA over the next few years."

GBM is a very fast-growing type of tumor. In recent years, three of every 100,000 Americans have been diagnosed with GBM, representing the highest incidence rate among malignant brain tumors. Most patients with GBM die of the disease within approximately 14 months of diagnosis.

"These new findings offer critical insights into stratifying patients based on the unique molecular characteristics of their disease," said John E. Niederhuber, M.D., NCI director. "As we learn more and more about the genetic underpinnings of cancer, we hope to achieve a similar level of molecular understanding for all cancers and eventually to generate recipes of highly targeted therapies uniquely suited to the individual patient."

The TCGA researchers expanded on previous studies, which had established gene expression profiling as a means to identify distinct subgroups of GBM.

"We discovered a bundle of events that unequivocally occur almost exclusively within a subtype," said lead author D. Neil Hayes, M.D., University of North Carolina at Chapel Hill. "These are critical events in the history of the tumor's development and spread, and evidence is increasing that they may relate to the initial formation of the tumors."

TCGA researchers reported that the nature of these events indicate that the underlying pathology of each subtype may begin from different types of cells. This may provide a better understanding of which cell types undergo changes that ultimately drive initial cancer formation. This finding has potential clinical significance since determining the types of cells that form GBM is critical for establishing effective treatment regimens. Because the response to aggressive chemotherapy and radiation differed by subtype, some classes of drugs would be expected to work for some tumor subtypes and not others.

"The ability to differentiate GBM tumors based on their altered genetic code lays the groundwork for more effective treatment strategies to combat this deadly cancer," said Eric D. Green, M.D., Ph.D., NHGRI director. "These findings demonstrate the power of using a cancer's genome to unravel the molecular changes that occur in the various cancer types targeted by TCGA. I'm optimistic that this type of knowledge will someday lead to improved personalized therapies and care for cancer patients."

The new findings build on TCGA's detailed view of GBM genomic changes reported in Nature in October 2008. TCGA, launched in 2006, is a comprehensive and coordinated effort to accelerate understanding of the molecular basis of cancer through the application of genome analysis technologies, including large-scale genome sequencing.


4. Discussion

PACA is a deadly cancer type that is forecast to become the second leading cancer-associated cause of mortality in the future [11]. As such, novel diagnostic and prognostic biomarkers associated with this disease must be identified in an effort to improve patient treatment and survival outcomes. Prior research has shown that genes that are dysregulated in PACA may offer value as prognostic or diagnostic biomarkers for patients with this cancer type [12�]. Plasma biomarkers are particularly attractive targets for patient diagnosis, staging, and monitoring as they can be assessed via a relatively noninvasive liquid biopsy approach. After being released from cells, RNA molecules form complexes with lipids that protect these RNAs from nuclease-mediated degradation [17�]. In general, cancer patients exhibit higher levels of circulating RNA than do healthy individuals owing to the higher rates of tumor cell proliferation and apoptotic death in the former cohort [20]. As such, in the present study, we sought to identify candidate plasma mRNA biomarkers capable of predicting PACA patient survival outcomes.

We began by employing a bioinformatics approach to assess PACA-related mRNA expression profiles in the TCGA database as a means of detecting potential prognostic biomarkers in these cancer patients. However, mRNAs that are differentially expressed in tumor tissues may not necessarily be differentially expressed in patient plasma samples, given that normal tissues also contribute to plasma RNA profiles and have the potential to mask tumor-derived mRNA signals in circulation [21]. By comparing our TCGA findings to the results of a microarray analysis of PACA patient plasma samples, we identified just three prognosis-related DE mRNAs in these plasma samples: PTPN6, EVL, and SMAP2.

Through further validation experiments, we confirmed that EVL mRNA expression was decreased in PACA patient plasma samples relative to samples from healthy controls. Decreased EVL mRNA expression was associated with poor OS and with tumor pathological stage and was an independent predictor of PACA patient prognosis. EVL is an Ena/VASP (enabled/vasodilator-stimulated phosphoprotein) family member protein involved in actin cytoskeleton regulation [22, 23]. Alterations in cytoskeletal composition can influence cellular motility, ultimately driving or suppressing tumor cell invasion and migration. Mouneimne et al. suggested that EVL downregulation was capable of suppressing tumor cell migration and invasion in vitro and in vivo, and decreased EVL expression in human tumor cells has been shown to be associated with high invasive activity, increased protrusion, decreased contractility, and reduced adhesion [24]. Grady et al. found EVL to be commonly downregulated in human colorectal cancer through a mechanism associated with altered CpG methylation upstream of EVL [25]. Li et al. found EVL mRNA expression to be decreased in cervical cancer [26]. As such, we hypothesize that EVL downregulation in PACA patients promotes disease progression via driving tumor invasion and metastasis, ultimately leading to poor patient outcomes.


Materials and methods

TCGA data description

The publically available TCGA datasets were directly downloaded from the TCGA Data Portal at https://tcga-data.nci.nih.gov/tcga/. The detailed information of the TCGA data structures can be reviewed at https://tcga-data.nci.nih.gov/tcga/tcgaDataType.jsp. The detailed information of the microarray and RNA-Seq experiments, protocols, and software used can be found at the TCGA Data Portal at https://tcga-data.nci.nih.gov/tcga/. For gene expression data, we selected the level-3 microarray dataset, in which Agilent 244K (G4502A), a custom designed microarray platform, was used in the experiments. The microarray data was normalized by Lowess method and presented as calculated Log2 ratio. Additional information regarding the level of the data and methods used in the process can be found at TCGA website (https://tcga-data.nci.nih.gov/tcga/). For RNA-Seq data sets, we selected the level 3 RNA-Seq data which was produced on Illunima HiSeq 2000 sequencers. The RNA-Seq gene expression level 3 data contain Counts which are simply the number of reads overlapping a given gene. The total number of reads for a given transcript is proportional to the expression level of the transcript. Both microarray and RNA-Seq datasets were generated by the laboratories located at University of North Carolina at Chapel Hill. A total of 595 GBM and 10 normal brain microarray data files, 163 RNA-Seq data files, and corresponding clinical data files were downloaded from TCGA website on Sept 27, 2013. These microarray datasets for GBM samples have not changed significantly since they were uploaded at the database.

Data transformation and classification

The Agilent gene expression microarray data down-loaded from TCGA is presented as log2 ratio of GBM/HuRNA, or Normal brain/HuRNA. In the microarray experiments, Agilent HuRNA (Human universal reference RNA previously Stratagene HuRNA) was used as a common reference to calculate Log2 ratio. The HuRNA is composed of total RNA pooled from 10 human cancer cell lines. In order to eliminate the potential bias by using the HuRNA as the common reference, we first transformed the original Log2 ratio of GBM/HuRNA to Log2 ratio GBM/Normal brain by using the following formula:

Here, the Log2 ratio (normal brain/HuRNA) is the mean value of log2 ratios from the 10 normal brain data files. Then, we used the transformed gene expression data, which was the Log2 ratio of GBM compared to Normal brain, in the rest of our study [26].

In the TCGA datasets, each clinical dataset represented a unique patient case. Survival was defined as the time interval from the date of surgery to the date of death. In order to elucidate a possible correlation between IL-13Rα2 gene expression and the clinical outcome, we only selected patients with survival > 30 days, indicating that the patient survived from the initial surgery and radiation treatments. A total of 428 GBM gene expression data files having clinical data satisfied the condition for the further gene expression and survival analysis.

By utilizing the transformed datasets, we classified the TCGA GBM tumors into three groups based on the level of IL-13Rα2 gene expression. Of 428 GBM tumors studied, 128 cases (29.9%) were classified into group I, which did not express IL-13Rα2 120 cases (28%) were identified in the group II, which expressed IL-13Rα2 with Log2 ratio of > 0 and < 2 and 180 cases (42.1%) were in the group III, which was defined as the IL-13Rα2 highly expressed group with Log2 ratio of IL-13Rα2 ≥ 2 (Fig. 1a).

Classification of GBM tumors based on expression analysis of TCGA data base for IL-13Rα2 and α1 mRNA: Group I: no expression Group II: low to moderate expression and Group III: high expression. a IL-13Rα2 log2 ratio b IL-13Rα1 log2 ratio

Same classification was used for IL-13Rα1 gene expression. Among 428 GBM tumors studied, 33 cases (7.7%) were classified into group I, which did not express IL-13Rα1 328 cases (76.6%) were identified in group II, which expressed IL-13Rα1 with Log2 ratio of > 0 and < 2 and 67 cases (15.7%) were in group III, which was defined as the IL-13Rα1 highly expressed group with Log2 ratio of IL-13Rα1 ≥ 2 (Fig. 1b).

Statistics analyses

An independent t test was performed to calculate the difference between groups. Kaplan–Meier survival analysis was performed to compare the survival distribution between different groups by using GraphPad Prism software (Version 5, GraphPad software Inc., San Diego, CA). A plot of the Kaplan–Meier analysis with appropriate sample size provides the information on the length of survival, median survival time of the distinct sample populations, and significance of the difference between the survival curves.


New Research Directions

The researchers' findings provide important insights into the mechanisms underlying bladder cancer, which is estimated to cause more than 15,000 deaths in the United States in 2014. TCGA is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.

"TCGA Research Network scientists continue to unravel the genomic intricacies of many common and often intractable cancers, and these findings are defining new research directions and accelerating the development of new cancer therapies," said NIH Director Francis Collins, M.D., Ph.D.

In this study, published online Jan. 29, 2014 in Nature, investigators examined bladder cancer that invades the muscle of the bladder, the deadliest form of the disease. The current standard treatments for muscle-invasive bladder cancer include surgery and radiation combined with chemotherapy. There are no recognized second-line therapies - second choices for treatments when the initial therapy does not work - and no approved targeted agents for this type of bladder cancer. Approximately 72,000 new cases of bladder cancer will be diagnosed in the United States in 2014.

"This project has dramatically improved our understanding of the molecular basis of bladder cancers and their relationship to other cancer types," said lead author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston. "In the long run, the potential molecular targets identified may help us to personalize therapy based on the characteristics of each patient's tumor."

"The real excitement about this project is that we now have a menu of treatment and research directions to pursue," said Seth Lerner, M.D., professor and chair in urologic oncology at Baylor College of Medicine in Houston, and one of the senior authors of the paper. "The field is poised to use this information to make new advances toward therapies for a very difficult to treat form of bladder cancer."

The research team analyzed DNA, RNA and protein data generated from the study of 131 muscle-invasive bladder cancer from patients who had not yet been treated with chemotherapy, radiation or any type of therapy. The scientists found recurrent mutations in 32 genes, including nine that were not previously known to be significantly mutated. They discovered mutations in the TP53 gene in nearly half of the tumor samples, and mutations and other aberrations in the RTK/RAS pathway (which is commonly affected in cancers) in 44 percent of tumors. TP53 makes the p53 tumor suppressor protein, which helps regulate cell division. RTK/RAS is involved in regulating cell growth and development.

The investigators also showed that genes that regulate chromatin - a combination of DNA and protein within a cell's nucleus that determines how genes are expressed - were more frequently mutated in bladder cancer than in any other common cancer studied to date. These findings suggest the possibility of developing therapies to target alterations in chromatin remodeling.

Overall, the researchers identified potential drug targets in 69 percent of the tumors evaluated. They found frequent mutations in the ERBB2, or HER2, gene. The researchers also identified recurring mutations as well as fusions involving other genes such as FGFR3 and in the PI3-kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.

Because the HER2 gene and its encoded protein, HER2 - which affects cell growth and development - are implicated in a significant portion of breast cancers, scientists would like to find out if new agents under development against breast cancer can also be effective in treating subsets of bladder cancer patients.

"We've organized our medical care around the affected organ system," Dr. Lerner said. "We have thought of each of these cancers as having its own characteristics unique to the affected organ. Increasingly, we are finding that cancers cross those lines at the molecular level, where some individual cancers affecting different organs look very similar. As targeted drug agents go through preclinical and clinical development, we hope that rather than treating 10 percent of breast cancers or 5 percent of bladder cancers, it eventually will make sense to treat multiple cancer types where the target is expressed." The same theme runs through TCGA's Pan-Cancer project, which is aimed at identifying genomic similarities across cancer types, with the goal of gaining a more global understanding of cancer behavior and development.

"It is increasingly evident that there are genomic commonalities among cancers that we can take advantage of in the future," said NHGRI Director Eric D. Green, M.D., Ph.D. "TCGA is providing us with a repertoire of possibilities for developing new cancer therapeutics."

The scientists also uncovered a potential viral connection to bladder cancer. It is known that animal papilloma viruses can cause bladder cancer. In a small number of cases, DNA from viruses - notably, from HPV16, a form of the virus responsible for cervical cancer - was found in bladder tumors. This suggests that viral infection can contribute to bladder cancer development.

Tobacco is a major risk factor for bladder cancer more than 70 percent of the cases analyzed in this study occurred in former or current smokers. However, the analysis did not identify major molecular differences between the tumors that developed in patients with or without a history of smoking.

"The definitive molecular portrait of bladder cancer by the TCGA Network has uncovered a promising array of potential therapeutic targets that provides a blueprint for investigations into the activity of existing and novel therapeutic agents in this cancer," said Louis Staudt, M.D., Ph.D., director, NCI Center for Cancer Genomics.

TCGA data are freely available prepublication to the research community through the TCGA Data Portal

This work was supported by the following grants from NIH: U54HG003273, U54HG003067, U54HG003079, U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, and U24CA144025.

Reference: The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. Online January 29, 2014. DOI: 10.1038/nature12965.


TCGA bladder cancer study reveals potential drug targets, similarities to several cancers

Investigators with The Cancer Genome Atlas (TCGA) Research Network have identified new potential therapeutic targets for a major form of bladder cancer, including important genes and pathways that are disrupted in the disease. They also discovered that, at the molecular level, some subtypes of bladder cancer — also known as urothelial carcinoma — resemble subtypes of breast, head and neck and lung cancers, suggesting similar routes of development.

The researchers’ findings provide important insights into the mechanisms underlying bladder cancer, which is estimated to cause more than 15,000 deaths in the United States in 2014. TCGA is a collaboration jointly supported and managed by the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI), both parts of the National Institutes of Health.

“TCGA Research Network scientists continue to unravel the genomic intricacies of many common and often intractable cancers, and these findings are defining new research directions and accelerating the development of new cancer therapies,” said NIH Director Francis Collins, M.D., Ph.D.

In this study, published online Jan. 29, 2014 in Nature, investigators examined bladder cancer that invades the muscle of the bladder, the deadliest form of the disease. The current standard treatments for muscle-invasive bladder cancer include surgery and radiation combined with chemotherapy. There are no recognized second-line therapies — second choices for treatments when the initial therapy does not work — and no approved targeted agents for this type of bladder cancer. Approximately 72,000 new cases of bladder cancer will be diagnosed in the United States in 2014.

“This project has dramatically improved our understanding of the molecular basis of bladder cancers and their relationship to other cancer types,” said lead author John Weinstein, M.D., Ph.D., professor and chair of the Department of Bioinformatics and Computational Biology at The University of Texas M.D. Anderson Cancer Center in Houston. “In the long run, the potential molecular targets identified may help us to personalize therapy based on the characteristics of each patient’s tumor.”

“The real excitement about this project is that we now have a menu of treatment and research directions to pursue,” said Seth Lerner, M.D., professor and chair in urologic oncology at Baylor College of Medicine in Houston, and one of the senior authors of the paper. “The field is poised to use this information to make new advances toward therapies for a very-difficult-to-treat form of bladder cancer.”

The research team analyzed DNA, RNA and protein data generated from the study of 131 muscle-invasive bladder cancer from patients who had not yet been treated with chemotherapy. The scientists found recurrent mutations in 32 genes, including nine that were not previously known to be significantly mutated. They discovered mutations in the TP53 gene in nearly half of the tumor samples, and mutations and other aberrations in the RTK/RAS pathway (which is commonly affected in cancers) in 44 percent of tumors. TP53 makes the p53 tumor suppressor protein, which helps regulate cell division. RTK/RAS is involved in regulating cell growth and development.

The investigators also showed that genes that regulate chromatin — a combination of DNA and protein within a cell’s nucleus that determines how genes are expressed — were more frequently mutated in bladder cancer than in any other common cancer studied to date. These findings suggest the possibility of developing therapies to target alterations in chromatin remodeling.

Overall, the researchers identified potential drug targets in 69 percent of the tumors evaluated. They found frequent mutations in the ERBB2, or HER2, gene. The researchers also identified recurring mutations as well as fusions involving other genes such as FGFR3 and in the PI3-kinase/AKT/mTOR pathway, which help control cell division and growth and for which targeted drugs already exist.

Because the HER2 gene and its encoded protein, HER2 — which affects cell growth and development — are implicated in a significant portion of breast cancers, scientists would like to find out if new agents under development against breast cancer can also be effective in treating subsets of bladder cancer patients.

“We’ve organized our medical care around the affected organ system,” Dr. Lerner said. “We have thought of each of these cancers as having its own characteristics unique to the affected organ. Increasingly, we are finding that cancers cross those lines at the molecular level, where some individual cancers affecting different organs look very similar. As targeted drug agents go through preclinical and clinical development, we hope that rather than treating 10 percent of breast cancers or 5 percent of bladder cancers, it eventually will make sense to treat multiple cancer types where the target is expressed.” The same theme runs through TCGA’s Pan-Cancer project, which is aimed at identifying genomic similarities across cancer types, with the goal of gaining a more global understanding of cancer behavior and development.

“It is increasingly evident that there are genomic commonalities among cancers that we can take advantage of in the future,” said NHGRI Director Eric D. Green, M.D., Ph.D. “TCGA is providing us with a repertoire of possibilities for developing new cancer therapeutics.”

The scientists also uncovered a potential viral connection to bladder cancer. It is known that animal papilloma viruses can cause bladder cancer. In a small number of cases, DNA from viruses — notably, from HPV16, a form of the virus responsible for cervical cancer — was found in bladder tumors. This suggests that viral infection can contribute to bladder cancer development.

Tobacco is a major risk factor for bladder cancer more than 70 percent of the cases analyzed in this study occurred in former or current smokers. However, the analysis did not identify major molecular differences between the tumors that developed in patients with or without a history of smoking.

“The definitive molecular portrait of bladder cancer by the TCGA Network has uncovered a promising array of potential therapeutic targets that provides a blueprint for investigations into the activity of existing and novel therapeutic agents in this cancer,” said Louis Staudt, M.D., Ph.D., director, NCI Center for Cancer Genomics.

TCGA data are freely available prepublication to the research community through the TCGA Data Portal and .

To date, TCGA Research Network has published analyses on these cancers:

This work was supported by the following grants from NIH: U54HG003273, U54HG003067, U54HG003079, U24CA143799, U24CA143835, U24CA143840, U24CA143843, U24CA143845, U24CA143848, U24CA143858, U24CA143866, U24CA143867, U24CA143882, U24CA143883, and U24CA144025.

The TCGA Research Network consists of more than 150 researchers at dozens of institutions across the nation. A list of participants is available at http://cancergenome.nih.gov/abouttcga/overview. More details about The Cancer Genome Atlas, including Quick Facts, Q&A, graphics, glossary, a brief guide to genomics and a media library of available images can be found at http://cancergenome.nih.gov.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the prevalence of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI website at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

NHGRI is one of the 27 institutes and centers at the National Institutes of Health. The NHGRI Extramural Research Program supports grants for research and training and career development at sites nationwide. Additional information about NHGRI can be found at http://www.genome.gov.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

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Reference

The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. Online January 29, 2014. DOI: 10.1038/nature12965.


Conclusion

Recent advances in cancer screening and next-generation sequencing technology have set the stage for an unprecedented opportunity to characterize the genomic alterations associated with premalignant disease progression. While TCGA has provided us with a comprehensive catalog of driver genes for each tumor type, the sequence of these genomic events that characterize the progression of premalignant lesions to invasive cancer remains to be unraveled. In addition, we know little about how changes in the immune cells and premalignant microenvironment contribute to disease initiation and progression. Comprehensive profiling of genomic and microenvironment changes that occur longitudinally in premalignant lesions as they progress towards (or regress away from) invasive cancer, a “Pre-Cancer Genome Atlas (PCGA),” will provide novel targets for disease interception that can be used to both develop early detection biomarkers as well as enable personalized therapeutic approaches. Creation of this PCGA will require a multi-institutional and multidisciplinary collaborative big-data “pre-cancer moonshot” effort (consistent and aligned with the recent Obama/Biden initiative) to collect, annotate, and profile premalignant lesions across multiple tumor types. This initiative will also require development of novel high-throughput functional screens in the premalignant in vitro setting as well as in vivo models of premalignancy to test the functional role of candidate genes and immune cell types. Ultimately, the PCGA will help usher in a new era of precision medicine for cancer detection and prevention.