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3 results on '"Worthley, Chris"'

1. DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association

Author

Lakis, Vanessa, Lawlor, Rita T., Newell, Felicity, Patch, Ann-Marie, Mafficini, Andrea, Sadanandam, Anguraj, Koufariotis, Lambros T., Johnston, Rebecca L., Leonard, Conrad, Wood, Scott, Rusev, Borislav, Corbo, Vincenzo, Luchini, Claudio, Cingarlini, Sara, Landoni, Luca, Salvia, Roberto, Milella, Michele, Chang, David, Bailey, Peter, Jamieson, Nigel B., Duthie, Fraser, Gingras, Marie-Claude, Muzny, Donna M., Wheeler, David A., Gibbs, Richard A., Milione, Massimo, Pederzoli, Paolo, Samra, Jaswinder S., Gill, Anthony J., Johns, Amber L., Pearson, John V., Biankin, Andrew V., Grimmond, Sean M., Waddell, Nicola, Nones, Katia, Scarpa, Aldo, Chantrill, Lorraine A., Timpson, Paul, Chou, Angela, Pajic, Marina, Murphy, Angela, Dwarte, Tanya, Hermann, David, Vennin, Claire, Cox, Thomas R., Pereira, Brooke, Ritchie, Shona, Reed, Daniel A., Chambers, Cecilia R., Metcalf, Xanthe, Nobis, Max, Mukhopadhyay, Pamela, Addala, Venkateswar, Kazakoff, Stephen, Holmes, Oliver, Xu, Qinying, Hofmann, Oliver, Pavlakis, Nick, Arena, Jennifer, High, Hilda A., Asghari, Ray, Merrett, Neil D., Pavey, Darren, Das, Amitabha, Cosman, Peter H., Ismail, Kasim, O’Connnor, Chelsie, Stoita, Alina, Williams, David, Spigellman, Allan, Lam, Vincent W., McLeod, Duncan, Kirk, Judy, Kench, James G., Grimison, Peter, Sandroussi, Charbel, Goodwin, Annabel, Mead, R. Scott, Tucker, Katherine, Andrews, Lesley, Texler, Michael, Forest, Cindy, Ballal, Mo, Fletcher, David R., Zeps, Nikolajs, Nguyen, Nan Q., Ruszkiewicz, Andrew R., Worthley, Chris, Chen, John, Brooke-Smith, Mark E., Papangelis, Virginia, Clouston, Andrew D., 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., Dixon, Judith, Scardoni, Maria, Bassi, Claudio, Grimaldi, Sonia, Cantù, Cinzia, Bonizzato, Giada, Bersani, Samantha, Antonello, Davide, Piredda, Liliana, Sperandio, Nicola, Barbi, Stefano, and Merlini, Paola

Abstract

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.

Published
2021

2. 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., Cary, Charles Ian Ormsby, Grbovic-Huezo, Olivera, Attiyeh, Marc, Medina, Benjamin, Zhang, Jennifer, Loo, Jennifer, Saglimbeni, Joseph, Abu-Akeel, Mohsen, Zappasodi, Roberta, Riaz, Nadeem, Smoragiewicz, Martin, Kelley, Z. Larkin, Basturk, Olca, Johns, Amber L., Mead, R. Scott, 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.

Subjects
integumentary system
Abstract

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Published
2017

3. 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, J. Lynn, 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., Biankin, Andrew V., Brancato, Mary-Anne L., Rowe, Sarah J., Simpson, Skye H., Martyn-Smith, Mona, Thomas, Michelle T., Chin, Venessa T., Humphris, Jeremy L., Scott Mead, R., Pettit, Jessica, Tao, Jiang, DiPietro, Renee, Watson, Clare, Steinmann, Angela, Ching Lee, Hong, Wong, Rachel, Daly, Roger J., Musgrove, Elizabeth A., Sutherland, Robert L., Grimmond, Sean M., Miller, David K., Gongora, Milena, Anderson, Matthew, Xu, Christina, Lynn Fink, J., Christ, Angelika, Bruxner, Tim, Pearson, John V., Quinn, Michael, Nagaraj, Shivashankar, Kazakoff, Stephen, Krisnan, Keerthana, Wood, David, Gill, Anthony J., Pavlakis, Nick, Guminski, Alex, Asghari, Ray, Pavey, Darren, Das, Amitabha, Cosman, Peter H., Ismail, Kasim, O’Connnor, 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, O’Rourke, Thomas J., Chiang, Amy, Fawcett, Jonathan W., Slater, Kellee, Yeung, Shinn, Hatzifotis, Michael, Hodgkinson, Peter, Christophi, Christopher, Nikfarjam, Mehrdad, Mountain, Angela, Eshleman, James R., Schulick, Richard D., Morgan, Richard A, Hodgin, Mary, Scarpa, Aldo, Beghelli, Stefania, Scardoni, Maria, Oien, Karin, Hair, Jane, and Pilarsky, Christian

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

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