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1. Whole genomes redefine the mutational landscape of pancreatic cancer

Author

Biankin, Andrew V, Johns, Amber L, Mawson, Amanda, Chang, David K, Scarlett, Christopher J, Brancato, Mary-Anne L, Rowe, Sarah J, Simpson, Skye H, Martyn-Smith, Mona, Thomas, Michelle T, Chantrill, Lorraine A, Chin, Venessa T, Chou, Angela, Cowley, Mark J, Humphris, Jeremy L, Jones, Marc D, Scott Mead, R, Nagrial, Adnan M, Pajic, Marina, Pettit, Jessica, Pinese, Mark, Rooman, Ilse, Wu, Jianmin, Tao, Jiang, DiPietro, Renee, Watson, Clare, Steinmann, Angela, Ching Lee, Hong, Wong, Rachel, Pinho, Andreia V, Giry-Laterriere, Marc, Daly, Roger J, Musgrove, Elizabeth A, Sutherland, Robert L, Grimmond, Sean M, Waddell, Nicola, Kassahn, Karin S, Miller, David K, Wilson, Peter J, Patch, Ann-Marie, Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Christina, Nones, Katia, Lynn Fink, J, Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Newell, Felicity, Pearson, John V, Bailey, Peter, Quinn, Michael, Nagaraj, Shivashankar, Kazakoff, Stephen, Waddell, Nick, Krisnan, Keerthana, Quek, Kelly, Wood, David, Fadlullah, Muhammad ZH, Samra, Jaswinder S, Gill, Anthony J, Pavlakis, Nick, Guminski, Alex, Toon, Christopher, Asghari, Ray, Merrett, Neil D, Pavey, Darren, Das, Amitabha, Cosman, Peter H, Ismail, Kasim, O’Connnor, Chelsie, Lam Duncan McLeod, Vincent W, Pleass, Henry C, Richardson, Arthur, James, Virginia, Kench, James G, Cooper, Caroline L, Joseph, David, Sandroussi, Charbel, Crawford, Michael, Gallagher, James, Texler, Michael, Forest, Cindy, Laycock, Andrew, Epari, Krishna P, Ballal, Mo, Fletcher, David R, Mukhedkar, Sanjay, and Spry, Nigel A

Subjects
Cancer, Human Genome, Pancreatic Cancer, Digestive Diseases, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, DNA Mutational Analysis, DNA Repair, Female, Genes, BRCA1, Genes, BRCA2, Genetic Markers, Genome, Human, Genomic Instability, Genomics, Genotype, Humans, Mice, Mutation, Pancreatic Neoplasms, Platinum, Point Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays, Australian Pancreatic Cancer Genome Initiative, General Science & Technology
Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Published
2015

2. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Author

Biankin, Andrew, Waddell, Nicola, Kassahn, Karin, Gingras, Marie-Claude, Muthuswamy, Lakshmi, Johns, Amber, Miller, David, Wilson, Peter, Patch, Ann-Marie, Wu, Jianmin, Chang, David, Cowley, Mark, Gardiner, Brooke, Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Pajic, Marina, Scarlett, Christopher, Gill, Anthony, Pinho, Andreia, Rooman, Ilse, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Qinying, Nones, Katia, Fink, J, Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Kolle, Gabriel, Newell, Felicity, Pinese, Mark, Mead, R, Humphris, Jeremy, Kaplan, Warren, Jones, Marc, Colvin, Emily, Nagrial, Adnan, Humphrey, Emily, Chou, Angela, Chin, Venessa, Chantrill, Lorraine, Mawson, Amanda, Samra, Jaswinder, Kench, James, Lovell, Jessica, Daly, Roger, Merrett, Neil, Toon, Christopher, Epari, Krishna, Nguyen, Nam, Barbour, Andrew, Zeps, Nikolajs, Kakkar, Nipun, Zhao, Fengmei, Wu, Yuan, Wang, Min, Muzny, Donna, Fisher, William, Brunicardi, F, Hodges, Sally, Reid, Jeffrey, Drummond, Jennifer, Chang, Kyle, Han, Yi, Lewis, Lora, Dinh, Huyen, Buhay, Christian, Beck, Timothy, Timms, Lee, Sam, Michelle, Begley, Kimberly, Brown, Andrew, Pai, Deepa, Panchal, Ami, Buchner, Nicholas, De Borja, Richard, Denroche, Robert, Yung, Christina, Serra, Stefano, Onetto, Nicole, Mukhopadhyay, Debabrata, Tsao, Ming-Sound, Shaw, Patricia, Petersen, Gloria, Gallinger, Steven, Hruban, Ralph, Maitra, Anirban, Iacobuzio-Donahue, Christine, Schulick, Richard, Wolfgang, Christopher, and Morgan, Richard

Subjects
Animals, Axons, Carcinoma, Pancreatic Ductal, Gene Dosage, Gene Expression Regulation, Neoplastic, Genome, Humans, Kaplan-Meier Estimate, Mice, Mutation, Pancreatic Neoplasms, Proteins, Signal Transduction
Abstract

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Published
2012

3. African-specific molecular taxonomy of prostate cancer

Author

Weerachai Jaratlerdsiri, Jue Jiang, Tingting Gong, Sean M. Patrick, Cali Willet, Tracy Chew, Ruth J. Lyons, Anne-Maree Haynes, Gabriela Pasqualim, Melanie Louw, James G. Kench, Raymond Campbell, Lisa G. Horvath, Eva K. F. Chan, David C. Wedge, Rosemarie Sadsad, Ilma Simoni Brum, Shingai B. A. Mutambirwa, Phillip D. Stricker, M. S. Riana Bornman, and Vanessa M. Hayes

Subjects
Male, China, Multidisciplinary, Black People, Nuclear Proteins, Prostatic Neoplasms, Europe, Nuclear Receptor Coactivator 2, Asian People, Africa, Mutation, Ethnicity, Humans, RNA, Long Noncoding, Carrier Proteins, Africa South of the Sahara, RNA Helicases
Abstract

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages1. The contributing genetic and non-genetic factors, and associated mutational processes, are unknown2,3. Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes NCOA2, STK19, DDX11L1, PCAT1 and SETBP1. Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies.

Published
2022
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4. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Author

Balachandran, Vinod P., Łuksza, Marta, Zhao, Julia N., Makarov, Vladimir, Moral, John Alec, Remark, Romain, Herbst, Brian, Askan, Gokce, Bhanot, Umesh, Senbabaoglu, Yasin, Wells, Daniel K., Ormsby Cary, Charles Ian, Grbovic-Huezo, Olivera, Attiyeh, Marc, Medina, Benjamin, Zhang, Jennifer, Loo, Jennifer, Saglimbeni, Joseph, Abu-Akeel, Mohsen, Zappasodi, Roberta, Riaz, Nadeem, Smoragiewicz, Martin, Kelley, Larkin Z., Basturk, Olca, Johns, Amber L., Mead, Scott R., Gill, Anthony J., Chang, David K., McKay, Skye H., Chantrill, Lorraine A., Chin, Venessa T., Chou, Angela, Humphris, Jeremy L., Pajic, Marina, Steinmann, Angela, Arshi, Mehreen, Drury, Ali, Froio, Danielle, Morgan, Ashleigh, Timpson, Paul, Hermann, David, Vennin, Claire, Warren, Sean, Pinese, Mark, Wu, Jianmin, Pinho, Andreia V., Tucker, Katherine, Andrews, Lesley, Samra, Jaswinder S., Arena, Jennifer, Pavlakis, Nick, High, Hilda A., Mittal, Anubhav, Biankin, Andrew V., Bailey, Peter, Martin, Sancha, Musgrove, Elizabeth A., Jones, Marc D., Nourse, Craig, Jamieson, Nigel B., Stoita, Alina, Williams, David, Spigelman, Allan, Waddell, Nicola, Pearson, John V., Patch, Ann-Marie, Nones, Katia, Newell, Felicity, Mukhopadhyay, Pamela, Addala, Venkateswar, Kazakoff, Stephen, Holmes, Oliver, Leonard, Conrad, Wood, Scott, Xu, Christina, Grimmond, Sean M., Hofmann, Oliver, Wilson, Peter J., Christ, Angelika, Bruxner, Tim, Asghari, Ray, Merrett, Neil D., Pavey, Darren, Das, Amitabha, Goodwin, Annabel, Cosman, Peter H., Ismail, Kasim, O’Connor, Chelsie, Cooper, Caroline L., Grimison, Peter, Kench, James G., Sandroussi, Charbel, Lam, Vincent W., McLeod, Duncan, Nagrial, Adnan M., Kirk, Judy, James, Virginia, Texler, Michael, Forest, Cindy, Epari, Krishna P., Ballal, Mo, Fletcher, David R., Mukhedkar, Sanjay, Zeps, Nikolajs, Beilin, Maria, Feeney, Kynan, Nguyen, Nan Q., Ruszkiewicz, Andrew R., Worthley, Chris, Chen, John, Brooke-Smith, Mark E., Papangelis, Virginia, Clouston, Andrew D., Martin, Patrick, Barbour, Andrew P., O’Rourke, Thomas J., Fawcett, Jonathan W., Slater, Kellee, Hatzifotis, Michael, Hodgkinson, Peter, Nikfarjam, Mehrdad, Eshleman, James R., Hruban, Ralph H., Wolfgang, Christopher L., Hodgin, Mary, Scarpa, Aldo, Lawlor, Rita T., Beghelli, Stefania, Corbo, Vincenzo, Scardoni, Maria, Bassi, Claudio, Gönen, Mithat, Levine, Arnold J., Allen, Peter J., Fearon, Douglas T., Merad, Miriam, Gnjatic, Sacha, Iacobuzio-Donahue, Christine A., Wolchok, Jedd D., DeMatteo, Ronald P., Chan, Timothy A., Greenbaum, Benjamin D., Merghoub, Taha, and Leach, Steven D.

Published
2017
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5. Corrigendum: Whole-genome landscape of pancreatic neuroendocrine tumours

Author

Scarpa, Aldo, Chang, David K., Nones, Katia, Corbo, Vincenzo, Patch, Ann-Marie, Bailey, Peter, Lawlor, Rita T., Johns, Amber L., Miller, David K., Mafficini, Andrea, Rusev, Borislav, Scardoni, Maria, Antonello, Davide, Barbi, Stefano, Sikora, Katarzyna O., Cingarlini, Sara, Vicentini, Caterina, McKay, Skye, Quinn, Michael C. J., Bruxner, Timothy J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, McLean, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wilson, Peter J., Anderson, Matthew J., Fink, Lynn J., Newell, Felicity, Waddell, Nick, Holmes, Oliver, Kazakoff, Stephen H., Leonard, Conrad, Wood, Scott, Xu, Qinying, Nagaraj, Shivashankar Hiriyur, Amato, Eliana, Dalai, Irene, Bersani, Samantha, Cataldo, Ivana, Dei Tos, Angelo P., Capelli, Paola, Davì, Maria Vittoria, Landoni, Luca, Malpaga, Anna, Miotto, Marco, Whitehall, Vicki L. J., Leggett, Barbara A., Harris, Janelle L., Harris, Jonathan, Jones, Marc D., Humphris, Jeremy, Chantrill, Lorraine A., Chin, Venessa, Nagrial, Adnan M., Pajic, Marina, Scarlett, Christopher J., Pinho, Andreia, Rooman, Ilse, Toon, Christopher, Wu, Jianmin, Pinese, Mark, Cowley, Mark, Barbour, Andrew, Mawson, Amanda, Humphrey, Emily S., Colvin, Emily K., Chou, Angela, Lovell, Jessica A., Jamieson, Nigel B., Duthie, Fraser, Gingras, Marie-Claude, Fisher, William E., Dagg, Rebecca A., Lau, Loretta M. S., Lee, Michael, Pickett, Hilda A., Reddel, Roger R., Samra, Jaswinder S., Kench, James G., Merrett, Neil D., Epari, Krishna, Nguyen, Nam Q., Zeps, Nikolajs, Falconi, Massimo, Simbolo, Michele, Butturini, Giovanni, Van Buren, George, Partelli, Stefano, Fassan, Matteo, Khanna, Kum Kum, Gill, Anthony J., Wheeler, David A., Gibbs, Richard A., Musgrove, Elizabeth A., Bassi, Claudio, Tortora, Giampaolo, Pederzoli, Paolo, Pearson, John V., Waddell, Nicola, Biankin, Andrew V., and Grimmond, Sean M.

Published
2017
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6. Whole-genome landscape of pancreatic neuroendocrine tumours

Author

Scarpa, Aldo, Chang, David K., Nones, Katia, Corbo, Vincenzo, Patch, Ann-Marie, Bailey, Peter, Lawlor, Rita T., Johns, Amber L., Miller, David K., Mafficini, Andrea, Rusev, Borislav, Scardoni, Maria, Antonello, Davide, Barbi, Stefano, Sikora, Katarzyna O., Cingarlini, Sara, Vicentini, Caterina, McKay, Skye, Quinn, Michael C. J., Bruxner, Timothy J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, McLean, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wilson, Peter J., Anderson, Matthew J., Fink, Lynn J., Newell, Felicity, Waddell, Nick, Holmes, Oliver, Kazakoff, Stephen H., Leonard, Conrad, Wood, Scott, Xu, Qinying, Nagaraj, Shivashankar Hiriyur, Amato, Eliana, Dalai, Irene, Bersani, Samantha, Cataldo, Ivana, Dei Tos, Angelo P., Capelli, Paola, Davì, Maria Vittoria, Landoni, Luca, Malpaga, Anna, Miotto, Marco, Whitehall, Vicki L. J., Leggett, Barbara A., Harris, Janelle L., Harris, Jonathan, Jones, Marc D., Humphris, Jeremy, Chantrill, Lorraine A., Chin, Venessa, Nagrial, Adnan M., Pajic, Marina, Scarlett, Christopher J., Pinho, Andreia, Rooman, Ilse, Toon, Christopher, Wu, Jianmin, Pinese, Mark, Cowley, Mark, Barbour, Andrew, Mawson, Amanda, Humphrey, Emily S., Colvin, Emily K., Chou, Angela, Lovell, Jessica A., Jamieson, Nigel B., Duthie, Fraser, Gingras, Marie-Claude, Fisher, William E., Dagg, Rebecca A., Lau, Loretta M. S., Lee, Michael, Pickett, Hilda A., Reddel, Roger R., Samra, Jaswinder S., Kench, James G., Merrett, Neil D., Epari, Krishna, Nguyen, Nam Q., Zeps, Nikolajs, Falconi, Massimo, Simbolo, Michele, Butturini, Giovanni, Van Buren, George, Partelli, Stefano, Fassan, Matteo, Khanna, Kum Kum, Gill, Anthony J., Wheeler, David A., Gibbs, Richard A., Musgrove, Elizabeth A., Bassi, Claudio, Tortora, Giampaolo, Pederzoli, Paolo, Pearson, John V., Waddell, Nicola, Biankin, Andrew V., and Grimmond, Sean M.

Published
2017
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7. African-specific molecular taxonomy of prostate cancer

Author

Jaratlerdsiri, Weerachai, primary, Jiang, Jue, additional, Gong, Tingting, additional, Patrick, Sean M., additional, Willet, Cali, additional, Chew, Tracy, additional, Lyons, Ruth J., additional, Haynes, Anne-Maree, additional, Pasqualim, Gabriela, additional, Louw, Melanie, additional, Kench, James G., additional, Campbell, Raymond, additional, Horvath, Lisa G., additional, Chan, Eva K. F., additional, Wedge, David C., additional, Sadsad, Rosemarie, additional, Brum, Ilma Simoni, additional, Mutambirwa, Shingai B. A., additional, Stricker, Phillip D., additional, Bornman, M. S. Riana, additional, and Hayes, Vanessa M., additional

Published
2022
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8. Genomic analyses identify molecular subtypes of pancreatic cancer

Author

Bailey, Peter, Chang, David K., Nones, Katia, Johns, Amber L., Patch, Ann-Marie, Gingras, Marie-Claude, Miller, David K., Christ, Angelika N., Bruxner, Tim J. C., Quinn, Michael C., Nourse, Craig, Murtaugh, Charles L., Harliwong, Ivon, Idrisoglu, Senel, Manning, Suzanne, Nourbakhsh, Ehsan, Wani, Shivangi, Fink, Lynn, Holmes, Oliver, Chin, Venessa, Anderson, Matthew J., Kazakoff, Stephen, Leonard, Conrad, Newell, Felicity, Waddell, Nick, Wood, Scott, Xu, Qinying, Wilson, Peter J., Cloonan, Nicole, Kassahn, Karin S., Taylor, Darrin, Quek, Kelly, Robertson, Alan, Pantano, Lorena, Mincarelli, Laura, Sanchez, Luis N., Evers, Lisa, Wu, Jianmin, Pinese, Mark, Cowley, Mark J., Jones, Marc D., Colvin, Emily K., Nagrial, Adnan M., Humphrey, Emily S., Chantrill, Lorraine A., Mawson, Amanda, Humphris, Jeremy, Chou, Angela, Pajic, Marina, Scarlett, Christopher J., Pinho, Andreia V., Giry-Laterriere, Marc, Rooman, Ilse, Samra, Jaswinder S., Kench, James G., Lovell, Jessica A., Merrett, Neil D., Toon, Christopher W., Epari, Krishna, Nguyen, Nam Q., Barbour, Andrew, Zeps, Nikolajs, Moran-Jones, Kim, Jamieson, Nigel B., Graham, Janet S., Duthie, Fraser, Oien, Karin, Hair, Jane, Grützmann, Robert, Maitra, Anirban, Iacobuzio-Donahue, Christine A., Wolfgang, Christopher L., Morgan, Richard A., Lawlor, Rita T., Corbo, Vincenzo, Bassi, Claudio, Rusev, Borislav, Capelli, Paola, Salvia, Roberto, Tortora, Giampaolo, Mukhopadhyay, Debabrata, Petersen, Gloria M., Munzy, Donna M., Fisher, William E., Karim, Saadia A., Eshleman, James R., Hruban, Ralph H., Pilarsky, Christian, Morton, Jennifer P., Sansom, Owen J., Scarpa, Aldo, Musgrove, Elizabeth A., Bailey, Ulla-Maja Hagbo, Hofmann, Oliver, Sutherland, Robert L., Wheeler, David A., Gill, Anthony J., Gibbs, Richard A., Pearson, John V., Waddell, Nicola, Biankin, Andrew V., and Grimmond, Sean M.

Published
2016
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9. Loss of coral reef growth capacity to track future increases in sea level

Author

Perry, Chris T., Alvarez-Filip, Lorenzo, Graham, Nicholas A. J., Mumby, Peter J., Wilson, Shaun K., Kench, Paul S., and Manzello, Derek P.

Subjects
Environmental aspects, Growth, Company growth, Coral reefs -- Environmental aspects -- Growth, Sea level -- Environmental aspects, Environmental degradation, Water, Reefs
Abstract

Author(s): Chris T. Perry [sup.1] , Lorenzo Alvarez-Filip [sup.2] , Nicholas A. J. Graham [sup.3] , Peter J. Mumby [sup.4] , Shaun K. Wilson [sup.5] [sup.6] , Paul S. Kench [...], Sea-level rise (SLR) is predicted to elevate water depths above coral reefs and to increase coastal wave exposure as ecological degradation limits vertical reef growth, but projections lack data on interactions between local rates of reef growth and sea level rise. Here we calculate the vertical growth potential of more than 200 tropical western Atlantic and Indian Ocean reefs, and compare these against recent and projected rates of SLR under different Representative Concentration Pathway (RCP) scenarios. Although many reefs retain accretion rates close to recent SLR trends, few will have the capacity to track SLR projections under RCP4.5 scenarios without sustained ecological recovery, and under RCP8.5 scenarios most reefs are predicted to experience mean water depth increases of more than 0.5 m by 2100. Coral cover strongly predicts reef capacity to track SLR, but threshold cover levels that will be necessary to prevent submergence are well above those observed on most reefs. Urgent action is thus needed to mitigate climate, sea-level and future ecological changes in order to limit the magnitude of future reef submergence.Analyses of current coral reef growth rates in the tropical western Atlantic and Indian Ocean show that few reefs will have the capacity to track sea-level rise projections under Representative Concentration Pathway scenarios without sustained ecological recovery.

Published
2018
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10. Whole genomes redefine the mutational landscape of pancreatic cancer

Author

Waddell, Nicola, Pajic, Marina, Patch, Ann-Marie, Chang, David K., Kassahn, Karin S., Bailey, Peter, Johns, Amber L., Miller, David, Nones, Katia, Quek, Kelly, Quinn, Michael C. J., Robertson, Alan J., Fadlullah, Muhammad Z. H., Bruxner, Tim J. C., Christ, Angelika N., Harliwong, Ivon, Idrisoglu, Senel, Manning, Suzanne, Nourse, Craig, Nourbakhsh, Ehsan, Wani, Shivangi, Wilson, Peter J., Markham, Emma, Cloonan, Nicole, Anderson, Matthew J., Fink, Lynn J., Holmes, Oliver, Kazakoff, Stephen H., Leonard, Conrad, Newell, Felicity, Poudel, Barsha, Song, Sarah, Taylor, Darrin, Waddell, Nick, Wood, Scott, Xu, Qinying, Wu, Jianmin, Pinese, Mark, Cowley, Mark J., Lee, Hong C., Jones, Marc D., Nagrial, Adnan M., Humphris, Jeremy, Chantrill, Lorraine A., Chin, Venessa, Steinmann, Angela M., Mawson, Amanda, Humphrey, Emily S., Colvin, Emily K., Chou, Angela, Scarlett, Christopher J., Pinho, Andreia V., Giry-Laterriere, Marc, Rooman, Ilse, Samra, Jaswinder S., Kench, James G., Pettitt, Jessica A., Merrett, Neil D., Toon, Christopher, Epari, Krishna, Nguyen, Nam Q., Barbour, Andrew, Zeps, Nikolajs, Jamieson, Nigel B., Graham, Janet S., Niclou, Simone P., Bjerkvig, Rolf, Grützmann, Robert, Aust, Daniela, Hruban, Ralph H., Maitra, Anirban, Iacobuzio-Donahue, Christine A., Wolfgang, Christopher L., Morgan, Richard A., Lawlor, Rita T., Corbo, Vincenzo, Bassi, Claudio, Falconi, Massimo, Zamboni, Giuseppe, Tortora, Giampaolo, Tempero, Margaret A., Gill, Anthony J., Eshleman, James R., Pilarsky, Christian, Scarpa, Aldo, Musgrove, Elizabeth A., Pearson, John V., Biankin, Andrew V., Grimmond, Sean M., Brancato, Mary-Anne L., Rowe, Sarah J., Simpson, Skye H., Martyn-Smith, Mona, Thomas, Michelle T., Chin, Venessa T., Humphris, Jeremy L., Mead, Scott R., Pettit, Jessica, Tao, Jiang, DiPietro, Renee, Watson, Clare, Steinmann, Angela, Lee, Hong Ching, Wong, Rachel, Daly, Roger J., Sutherland, Robert L., Miller, David K., Gongora, Milena, Anderson, Matthew, Xu, Christina, Christ, Angelika, Bruxner, Tim, Quinn, Michael, Nagaraj, Shivashankar, Kazakoff, Stephen, Krisnan, Keerthana, Wood, David, Pavlakis, Nick, Guminski, Alex, Asghari, Ray, Pavey, Darren, Das, Amitabha, Cosman, Peter H., Ismail, Kasim, OʼConnnor, Chelsie, Lam Duncan McLeod, Vincent W., Pleass, Henry C., Richardson, Arthur, James, Virginia, Cooper, Caroline L., Joseph, David, Sandroussi, Charbel, Crawford, Michael, Gallagher, James, Texler, Michael, Forest, Cindy, Laycock, Andrew, Epari, Krishna P., Ballal, Mo, Fletcher, David R., Mukhedkar, Sanjay, Spry, Nigel A., DeBoer, Bastiaan, Chai, Ming, Beilin, Maria, Feeney, Kynan, Nguyen, Nan Q., Ruszkiewicz, Andrew R., Worthley, Chris, Tan, Chuan P., Debrencini, Tamara, Chen, John, Brooke-Smith, Mark E., Papangelis, Virginia, Tang, Henry, Barbour, Andrew P., Clouston, Andrew D., Martin, Patrick, OʼRourke, Thomas J., Chiang, Amy, Fawcett, Jonathan W., Slater, Kellee, Yeung, Shinn, Hatzifotis, Michael, Hodgkinson, Peter, Christophi, Christopher, Nikfarjam, Mehrdad, Mountain, Angela, Schulick, Richard D., Hodgin, Mary, Beghelli, Stefania, Scardoni, Maria, Oien, Karen, and Hair, Jane

Published
2015
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11. The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Author

Pérez-Mancera, Pedro A., Rust, Alistair G., van der Weyden, Louise, Kristiansen, Glen, Li, Allen, Sarver, Aaron L., Silverstein, Kevin A. T., Grützmann, Robert, Aust, Daniela, Rümmele, Petra, Knösel, Thomas, Herd, Colin, Stemple, Derek L., Kettleborough, Ross, Brosnan, Jacqueline A., Li, Ang, Morgan, Richard, Knight, Spencer, Yu, Jun, Stegeman, Shane, Collier, Lara S., ten Hoeve, Jelle J., de Ridder, Jeroen, Klein, Alison P., Goggins, Michael, Hruban, Ralph H., Chang, David K., Biankin, Andrew V., Grimmond, Sean M., Johns, Amber L., Mawson, Amanda, Brancato, Mary-Anne L., Rowe, Sarah J., Simpson, Skye L., Martyn-Smith, Mona, Chantrill, Lorraine A., Chin, Venessa T., Chou, Angela, Cowley, Mark J., Humphris, Jeremy L., Jones, Marc D., Mead, Scott R., Nagrial, Adnan M., Pajic, Marina, Pettit, Jessica, Pinese, Mark, Rooman, Ilse, Wu, Jianmin, Daly, Roger J., Musgrove, Elizabeth A., Sutherland, Robert L., Waddell, Nicola, Kassahn, Karin S., Miller, David K., Wilson, Peter J., Patch, Ann-Marie, Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Christina, Nones, Katia, Fink, Lynn J., Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Newell, Felicity, Pearson, John V., Samra, Jaswinder S., Gill, Anthony J., Pavlakis, Nick, Guminski, Alex, Toon, Christopher, Blankin, Andrew V., Asghari, Ray, Merrett, Neil D., Pavey, Darren A., Das, Amithabad, Cosman, Peter H., Ismail, Kasim, O’Connor, Chelsie, Lam, Vincent W., McLeod, Duncan, Pleass, Henry C., James, Virginia, Kench, James G., Cooper, Caroline L., Joseph, David, Sandroussi, Charbel, Crawford, Michael, Texler, Michael, Forrest, Cindy, Laycock, Andrew, Epari, Krishna P., Ballal, Mo, Fletcher, David R., Mukhedkar, Sanjay, Spry, Nigel A., DeBoer, Bastiaan, Chai, Ming, Feeney, Kynan, Zeps, Nikolajs, Beilin, Maria, Nguyen, Nam Q., Ruszkiewicz, Andrew R., Worthley, Chris, Tan, Chuan P., Debrencini, Tamara, Chen, John, Brooke-Smith, Mark E., Papangelis, Virginia, Tang, Henry, Barbour, Andrew P., Clouston, Andrew D., Martin, Patrick, O’Rourke, Thomas J., Chiang, Amy, Fawcett, Jonathan W., Slater, Kellee, Yeung, Shinn, Hatzifotis, Michael, Hodgkinson, Peter, Christophi, Christopher, Nikfarjam, Mehrdad, Biobank, Victorian Cancer, Eshleman, James R., Maitra, Anirban, Iacobuzio-Donahue, Christine A., Schulick, Richard D., Wolfgang, Christopher L., Morgan, Richard A., Lawlor, Rita T., Beghelli, Stefania, Corbo, Vincenzo, Scardoni, Maria, Bassi, Claudio, Tempero, Margaret A., Wessels, Lodewyk F. A., Wood, Stephen A., Pilarsky, Christian, Largaespada, David A., Adams, David J., and Tuveson, David A.

Published
2012
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12. International network of cancer genome projects

Author

Hudson, Thomas J., Anderson, Warwick, Aretz, Axel, Bell, Cindy, Bernabé, Rosa R., Bhan, M. K., Calvo, Fabien, Eerola, Iiro, Gerhard, Daniela S., Guttmacher, Alan, Guyer, Mark, Hemsley, Fiona M., Jennings, Jennifer L., Kerr, David, Klatt, Peter, Kolar, Patrik, Lane, David P., Laplace, Frank, Nettekoven, Gerd, Ozenberger, Brad, Peterson, Jane, Rao, T. S., Remacle, Jacques, Schafer, Alan J., Shibata, Tatsuhiro, Stratton, Michael R., Watanabe, Koichi, Yuen, Matthew M. F., Cambon-Thomsen, Anne, Dressler, Lynn G., Joly, Yann, Kennedy, Karen L., Parker, Michael J., Romeo-Casabona, Carlos M., Wallace, Susan, Wiesner, Georgia L., Zeps, Nikolajs, Biankin, Andrew V., Chabannon, Christian, de Alava, Enrique, Ferguson, Martin L., Geary, Peter, Hayes, Neil D., Johns, Amber L., Kasprzyk, Arek, Nakagawa, Hidewaki, Piris, Miguel A., van de Vijver, Marc, Aburatani, Hiroyuki, Bayés, Mónica, Bowtell, David D.L., Campbell, Peter J., Hirst, Martin, López-Otín, Carlos, Marra, Marco, Ning, Zemin, Puente, Xose S., Ruan, Yijun, Stunnenberg, Hendrik G., Swerdlow, Harold, Velculescu, Victor E., Xue, Hong H., Yang, Liu, Spellman, Paul T., Bader, Gary D., Boutros, Paul C., Flicek, Paul, Getz, Gad, Guigó, Roderic, Guo, Guangwu, Haussler, David, Hubbard, Tim J., Jiang, Tao, Jones, Steven M., Li, Qibin, López-Bigas, Nuria, Luo, Ruibang, Muthuswamy, Lakshmi, Ouellette, Francis B. F., Pearson, John V., Quesada, Victor, Raphael, Benjamin J., Sander, Chris, Stein, Lincoln D., Stuart, Joshua M., Teague, Jon W., Totoki, Yasushi, Tsunoda, Tatsuhiko, Valencia, Alfonso, Wheeler, David A., Wu, Honglong, Zhao, Shancen, Zhou, Guangyu, Lathrop, Mark, Axton, Myles, Dyke, Stephanie O. M., Gunter, Chris, McPherson, John D., Miller, Linda J., Zhang, Junjun, Haider, Syed A., Wang, Jianxin, Yung, Christina K., Cross, Anthony, Liang, Yong, Gnaneshan, Saravanamuttu, Guberman, Jonathan, Hsu, Jack, Bobrow, Martin, Chalmers, Don R. C., Hasel, Karl W., Kaan, Terry S. H., Knoppers, Bartha M., Lowrance, William W., Masui, Tohru, Nicolás, Pilar, Rial-Sebbag, Emmanuelle, Rodriguez, Laura Lyman, Vergely, Catherine, Grimmond, Sean M., Bowtell, David D. L., Cloonan, Nicole, deFazio, Anna, Eshleman, James R., Etemadmoghadam, Dariush, Gardiner, Brooke A., Kench, James G., Scarpa, Aldo, Sutherland, Robert L., Tempero, Margaret A., Waddell, Nicola J., Wilson, Peter J., Gallinger, Steve, Tsao, Ming-Sound, Shaw, Patricia A., Petersen, Gloria M., Mukhopadhyay, Debabrata, Chin, Lynda, DePinho, Ronald A., Thayer, Sarah, Shazand, Kamran, Beck, Timothy, Sam, Michelle, Timms, Lee, Ballin, Vanessa, Ji, Jiafu, Zhang, Xiuqing, Chen, Feng, Hu, Xueda, Yang, Qi, Tian, Geng, Zhang, Lianhai, Xing, Xiaofang, Li, Xianghong, Zhu, Zhenggang, Yu, Yingyan, Yu, Jun, Yang, Huanming, Tost, Jörg, Brennan, Paul, Holcatova, Ivana, Zaridze, David, Brazma, Alvis, Egevad, Lars, Prokhortchouk, Egor, Banks, Rosamonde Elizabeth, Uhlén, Mathias, Viksna, Juris, Ponten, Fredrik, Skryabin, Konstantin, Futreal, Andrew P., Birney, Ewan, Caldas, Carlos, Reis-Filho, Jorge S., Richardson, Andrea L., Sotiriou, Christos, Birnbaum, Daniel, Blanche, Hélène, Boucher, Pascal, Boyault, Sandrine, Masson-Jacquemier, Jocelyne D., Pauporté, Iris, Pivot, Xavier, Vincent-Salomon, Anne, Tabone, Eric, Theillet, Charles, Treilleux, Isabelle, Bioulac-Sage, Paulette, Clément, Bruno, Decaens, Thomas, Degos, Françoise, Franco, Dominique, Gut, Ivo, Gut, Marta, Heath, Simon, Samuel, Didier, Thomas, Gilles, Zucman-Rossi, Jessica, Eils, Roland, Brors, Benedikt, Korbel, Jan O., Korshunov, Andrey, Landgraf, Pablo, Lehrach, Hans, Pfister, Stefan, Radlwimmer, Bernhard, Reifenberger, Guido, Taylor, Michael D., von Kalle, Christof, Majumder, Partha P., Sarin, Rajiv, Pederzoli, Paolo, Lawlor, Rita T., Delledonne, Massimo, Bardelli, Alberto, Gress, Thomas, Klimstra, David, Zamboni, Giuseppe, Nakamura, Yusuke, Kusuda, Jun, Miyano, Satoru, Kato, Kazuto, Fujimoto, Akihiro, Yoshida, Teruhiko, Campo, Elias, Estivill, Xavier, de Sanjosé, Silvia, Montserrat, Emili, González-Díaz, Marcos, Jares, Pedro, Himmelbaue, Heinz, Bea, Silvia, Aparicio, Samuel, Borg, Ake, Børresen-Dale, Anne-Lise, Foekens, John A., vanʼt Veer, Laura, Easton, Douglas F., Martin, Sancha, Compton, Carolyn C., Lander, Eric S., Penny, Robert, Shaw, Kenna M., Speed, Terence P., Vockley, Joseph G., Lichter, Peter, Barker, Anna D., Burke, Wylie, Collins, Francis S., Green, Anthony R., Hamilton, Stanley R., Kallioniemi, Olli P., Ley, Timothy J., Liu, Edison T., Lu, Youyong, Majumder, Partha, Wainwright, Brandon J., and Wilson, Richard K.

Published
2010
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13. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Author

Conrad Leonard, Stefano Serra, Jeremy L. Humphris, J. Lynn Fink, Vincenzo Corbo, Deepa Pai, Ami Panchal, Jennifer Drummond, Anirban Maitra, Katia Nones, Mark J. Cowley, Nam Q. Nguyen, Marc D. Jones, David A. Largaespada, Karen M. Mann, Ralph H. Hruban, Nicole Cloonan, Timothy Beck, Marie-Claude Gingras, Sally E. Hodges, Darrin Taylor, Andrew V. Biankin, Angela Chou, Craig Nourse, Marina Pajic, Gloria M. Petersen, Kimberly Begley, Richard A. Morgan, Rita T. Lawlor, Senel Idrisoglu, Jessica A. Lovell, Lincoln Stein, Christina K. Yung, Lee Timms, Adnan Nagrial, Giampaolo Tortora, Shivangi Wani, Mark Pinese, Angelika N. Christ, Amanda Mawson, Neil D. Merrett, Maria Scardoni, Min Wang, Ann-Marie Patch, Steven Gallinger, Huyen Dinh, Richard A. Gibbs, John Douglas Mcpherson, Amber L. Johns, Nipun Kakkar, David A. Wheeler, Andrew Barbour, Patricia Shaw, Milena Gongora, Emily S. Humphrey, Christopher J. Scarlett, Matthew J. Anderson, Lodewyk F. A. Wessels, Andrew M.K. Brown, Christopher W. Toon, Felicity Newell, Margaret A. Tempero, Fengmei Zhao, Richard D. Schulick, Paola Capelli, Timothy J. C. Bruxner, Christine A. Iacobuzio-Donahue, Ivon Harliwong, Richard de Borja, Pedro A. Perez-Mancera, Jianmin Wu, Emily K. Colvin, Michelle Sam, Warren Kaplan, Debabrata Mukhopadhyay, John V. Pearson, Gabriel Kolle, Oliver Holmes, Lorraine A. Chantrill, Lora Lewis, Jaswinder S. Samra, Scott Wood, Lakshmi Muthuswamy, James R. Eshleman, Neal G. Copeland, Peter Wilson, David Miller, Anthony J. Gill, Qinying Xu, Nicola Waddell, Ming-Sound Tsao, Karin S. Kassahn, Venessa T. Chin, James G. Kench, David K. Chang, William E. Fisher, Kyle Chang, Aldo Scarpa, Christopher L. Wolfgang, Roger J. Daly, Alistair G. Rust, Ehsan Nourbakhsh, Jeffrey G. Reid, Nikolajs Zeps, Nicole Onetto, Donna M. Muzny, Brooke Gardiner, Robert E. Denroche, Yuan Qing Wu, Nancy A. Jenkins, Sean M. Grimmond, R. Scott Mead, David A. Tuveson, David J. Adams, Yi Han, F. Charles Brunicardi, Andreia V. Pinho, Elizabeth A. Musgrove, Sarah Song, Ilse Rooman, Thomas J. Hudson, Christian J. Buhay, Robert L. Sutherland, Suzanne Manning, Nicholas Buchner, Krishna Epari, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology

Subjects
Exome sequencing, Gene Dosage, Copy number analysis, PDAC, KRAS, Kaplan-Meier Estimate, Biology, medicine.disease_cause, Mice, CDKN2A, Pancreatic cancer, medicine, Animals, Humans, Genetics, Mutation, Genome, Multidisciplinary, Proteins, Cancer, medicine.disease, Axons, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms, Cancer research, Carcinogenesis, Carcinoma, Pancreatic Ductal, Signal Transduction
Abstract

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Published
2012
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14. Genomic analyses identify molecular subtypes of pancreatic cancer

Author

J. Lynn Fink, Jeremy L. Humphris, Katia Nones, Robert Grützmann, Anirban Maitra, Paola Capelli, Peter J. Wilson, William E. Fisher, Aldo Scarpa, Christopher J. Scarlett, Richard A. Morgan, Ann-Marie Patch, Debabrata Mukhopadhyay, Murtaugh Lc, Oliver Hofmann, Marc Giry-Laterriere, Borislav Rusev, Jennifer P. Morton, Nicole Cloonan, David A. Wheeler, Anthony J. Gill, Krishna Epari, Nam Q. Nguyen, Amber L. Johns, James G. Kench, Saadia A. Karim, Lorena Pantano, Craig Nourse, Nigel B. Jamieson, Ivon Harliwong, Stephen H. Kazakoff, Darrin Taylor, Felicity Newell, Christian Pilarsky, Giampaolo Tortora, Shivangi Wani, Nicola Waddell, Mark J. Cowley, Jaswinder S. Samra, Scott Wood, Munzy Dm, Conrad Leonard, Laura Mincarelli, Suzanne Manning, Timothy J. C. Bruxner, Mark Pinese, Michael C.J. Quinn, Hair J, Andreia V. Pinho, R. L. Sutherland, Amanda Mawson, Neil D. Merrett, Andrew Barbour, Rita T. Lawlor, Jones, Corbo, Ilse Rooman, Lorraine A. Chantrill, Marie-Claude Gingras, Christopher W. Toon, Senel Idrisoglu, Emily S. Humphrey, Kelly Quek, Sean M. Grimmond, Christopher L. Wolfgang, Oliver Holmes, Andrew V. Biankin, Fraser Duthie, Qinying Xu, Kim Moran-Jones, Gloria M. Petersen, Lisa Evers, Peter Bailey, Elizabeth A. Musgrove, Alan J. Robertson, Marina Pajic, Emily K. Colvin, John V. Pearson, Nikolajs Zeps, David K. Chang, Karin S. Kassahn, David Miller, Janet Graham, Ehsan Nourbakhsh, Ralph H. Hruban, Luis Navarro Sanchez, Ulla-Maja Bailey, Chin, Jessica A. Lovell, Angelika N. Christ, Richard A. Gibbs, Eshleman, Karin A. Oien, Christine A. Iacobuzio-Donahue, Claudio Bassi, Adnan Nagrial, Matthew J. Anderson, Owen J. Sansom, Angela Chou, Roberto Salvia, Jianmin Wu, Cell Differentiation, Basic (bio-) Medical Sciences, and Laboratory for Medical and Molecular Oncology

Subjects
0301 basic medicine, Transcription, Genetic, Receptors, Cytoplasmic and Nuclear, medicine.disease_cause, Transcriptome, Mice, 0302 clinical medicine, RNA-SEQ DATA, DUCTAL ADENOCARCINOMA, NETWORK ANALYSIS, EXPRESSION DATA, CELL FORMATION, BREAST-CANCER, MUTATIONS, PACKAGE, TUMOR, DIFFERENTIATION, Basic Helix-Loop-Helix Transcription Factors, Gene Regulatory Networks, Regulation of gene expression, Histone Demethylases, Multidisciplinary, Wnt signaling pathway, Nuclear Proteins, Genomics, Prognosis, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, 030220 oncology & carcinogenesis, DNA methylation, Hepatocyte Nuclear Factor 3-beta, PDX1, KRAS, Carcinoma, Pancreatic Ductal, Biology, 03 medical and health sciences, Downregulation and upregulation, Pancreatic cancer, Cell Line, Tumor, medicine, Animals, Humans, Homeodomain Proteins, Settore MED/06 - ONCOLOGIA MEDICA, Genome, Human, Tumor Suppressor Proteins, DNA Methylation, Zebrafish Proteins, medicine.disease, Molecular biology, Survival Analysis, Pancreatic Neoplasms, 030104 developmental biology, Mutation, Trans-Activators, Tumor Suppressor Protein p53, Hepatocyte Nuclear Factor 3-gamma, Genes, Neoplasm, Transcription Factors
Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Published
2015

15. Porphyrin formation by yeast

Author

J. E. Kench and John F. Wilkinson

Subjects
Multidisciplinary, Porphyrins, biology, Cytochrome c peroxidase, Saccharomyces cerevisiae, Porphyrin, Nervous System, Yeast, Cofactor, chemistry.chemical_compound, Pigment, Biochemistry, chemistry, Catalase, visual_art, Yeasts, biology.protein, visual_art.visual_art_medium, Protoporphyrin, Nervous System Physiological Phenomena, Peroxidase
Abstract

IN a recent communication1 a method was described by which increased yields of coproporphyrin could be obtained from yeast preparations. To secure information on the mode of production of this pigment, we examined the possibility that breakdown of preformed chromoproteins containing protoporphyrin as a component of the prosthetic group could be responsible. Such pigments occurring in yeast are cytochrome-c, catalase and peroxidase. Although the concentration of these proteins is low, it is possible that in the yeast preparations they are synthesized continuously and then rapidly degraded to porphyrin, thus reaching dynamic equilibrium under these special conditions. To test this supposition, each individual protein was added to the standard yeast preparation and the subsequent porphyrin production examined.

Published
2010

16. Changes underlying Halothane-induced Malignant Hyperpyrexia in Landrace Pigs

Author

G.G. Harrison, A. B. Bull, J. E. Kench, and Mervyn C. Berman

Subjects
Acid-Base Equilibrium, Multidisciplinary, Glycogenolysis, Fatal outcome, Fever, Inhalation, Swine, Chemistry, Water-Electrolyte Balance, Oxidative Phosphorylation, Body Temperature, Oxygen Consumption, Rapid rise, Anesthesia, Extracellular fluid, medicine, Animals, medicine.symptom, Halothane, Complication, Acidosis, medicine.drug
Abstract

MALIGNANT hyperpyrexia is a rare but often fatal complication of inhalation anaesthesia in man1. The fluorinated hydrocarbon halothane, CF3CHBrCl, is among the many anaesthetic agents which have been implicated2. A similar syndrome has been described in a pure Landrace strain of pig3. The onset of this phenomenon is rapid (10–15 min after administration of halothane) and there is extreme rigidity of skeletal muscles, a rapid rise in body temperature to 42°–45° C, severe acidosis and a fatal outcome in spite of cooling, muscle relaxants and intravenous alkalis. Once initiated, the process seems independent of the tissue concentration of halothane, which appears to act as a trigger. A few animals have recovered after brief exposure to halothane.

Published
1970
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17. Cytochrome c and in vitro formation of bile pigments

Author

C. Gardikas and J. E. Kench

Subjects
Multidisciplinary, biology, Chemistry, Cytochrome c peroxidase, Cytochrome c, Chemical structure, Cytochromes c, Bile Pigments, In Vitro Techniques, digestive system, In vitro, Pigment, Biochemistry, visual_art, biology.protein, visual_art.visual_art_medium, Cytochrome c oxidase, Cytochromes, sense organs
Abstract

THIS communication describes the attempted in vitro conversion of cytochrome c to bile pigments, using coupled oxidation with ascorbic acid1, and forms part of a systematic study of the relationship of chemical structure to bile pigment formation2,3.

Published
1952

18. Amino acid composition of Bence-Jones protein

Author

J. E. Kench, S. C. Papastamatis, and John F. Wilkinson

Subjects
chemistry.chemical_classification, Multidisciplinary, Chromatography, Methionine, Chemistry, Proteins, Photo-reactive amino acid analog, Bence Jones protein, Amino acid, chemistry.chemical_compound, Hydroxyproline, Amino acid composition, Composition (visual arts), Amino Acids, Amino acid synthesis, Bence Jones Protein
Abstract

OUR knowledge of the amino-acid composition of Bence–Jones protein is still incomplete. Recently, Dent1 has analysed a specimen of Bence–Jones protein, using paper partition chromatography, with regard to its amino-acid composition. He found that the specimen contained all the common amino-acids except methionine and hydroxyproline. Dent's findings were at variance with those of Devine2, who found methionine present in amount 0.58 per cent.

Published
1949

19. Coproporphyrin formation in yeast

Author

Kench Je

Subjects
Autolysis (biology), Coproporphyrins, Multidisciplinary, Porphyrins, biology, Cytochrome, Chemistry, fungi, Saccharomyces cerevisiae, biology.organism_classification, Porphyrin, Yeast, Microbiology, Neurospora crassa, chemistry.chemical_compound, Yeast, Dried, Yeasts, Penicillium, biology.protein, Mycelium
Abstract

IN recent articles in Nature, Keilin1 has described the occurrence of haemoglobin, in very low concentration, in certain strains of bakers' yeast, and Keilin and Tissieres2 have likewise demonstrated the presence of haemoglobin in the mycelia of the moulds Neurospora crassa and Penicillium notatum. In the latter investigation, free protohaem was also found, especially in fragments of mycelium undergoing autolysis, following their projection from the aerated nutrient on to the walls of the containing vessel. The free haem in the moulds appeared to originate from intracellular haemoglobin and from some components of cytochrome by an enzymic degradation which accompanied the autolysis of the mycelium. In old mycelia, the free haem itself was further degraded with liberation of iron and the formation of free porphyrin. These important findings are particularly relevant to the study of porphyrin formation in autolysing yeast.

Published
1954

28. Choleglobin Formation in the Erythrocyte

Author

J. E. Kench, C. Gardikas, and John F. Wilkinson

Subjects
Erythrocytes, Multidisciplinary, Biochemistry, Metalloporphyrins, Chemistry, Choleglobin, education, Bile, Bile Pigments, Pigment formation, Globins
Abstract

THE pioneer researches of Lemberg and his co-workers1 have provided a new approach to the problems of haemoglobin breakdown and bile pigment formation. Using his methods, we have recently re-examined the question of the occurrence of the intermediate choleglobin in the intact erythropyte.

Published
1948
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29. Porphyrin Metabolism in Idiopathic Porphyria

Author

J. E. Kench

Subjects
Uroporphyrin III, medicine.medical_specialty, Multidisciplinary, integumentary system, Chemistry, Urinary system, medicine.disease, Porphyrin metabolism, Excretion, chemistry.chemical_compound, Endocrinology, Porphyria, Internal medicine, polycyclic compounds, medicine, Protoporphyrin
Abstract

IDIOPATHIC porphyria is especially interesting as the urinary pigment uroporphyrin III associated with this disease resembles closely in its chemical structure the protoporphyrin of haemoglobin. Urinary uroporphyrin may provide here an index of the rate of protoporphyrin formation in the body, and it seemed important to obtain information on this point, and to observe if uroporphyrin III excretion is augmented by administration of substances which, on a theoretical basis at least, could function as protoporphyrin precursors.

Published
1944
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30. Ionophoretic Separation of Porphyrin Pigments

Author

S. C. Papastamatis and J. E. Kench

Subjects
Convection, Porphyrins, Multidisciplinary, Chromatography, Density gradient, Chemistry, Electrolyte, Gel electrophoresis of proteins, Porphyrin, Agar gel, chemistry.chemical_compound, Pigment, visual_art, Electrode, visual_art.visual_art_medium
Abstract

IN the classical Tiselius procedure for electrophoresis of proteins, convection was prevented by the density gradient of the substances under investigation; but complete separation could not thereby be obtained, and the analysis was conducted by the observation of fronts. Later the medium was stabilized by silica or agar gel for the separation of amino-acids1 and proteins2. Silica or agar gel will hold an excess of electrolyte and prevent convection currents; but it will allow substances to pass through independently and to separate into discrete bands. In addition, its use obviates contact of the moving substances with the electrodes.

Published
1952
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31. Serum Bilirubin and the Van Den Bergh Reaction

Author

John F. Wilkinson, J. E. Kench, and C. Gardikas

Subjects
Blood, Multidisciplinary, Van den Bergh reaction, Chemistry, Humans, Physiology, Bilirubin, Indirect bilirubin, Serum bilirubin
Abstract

THE problem of the nature of direct and indirect bilirubin remains obscure, in spite of many attempts to explain the phenomenon of the two types of reaction.

Published
1947
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