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1. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Author

Vennin, C, Melenec, P, Rouet, R, Nobis, M, Cazet, As, Murphy, Kj, Herrmann, D, Reed, Da, Lucas, Mc, Warren, Sc, Elgundi, Z, Pinese, M, Kalna, G, Roden, D, Samuel, M, Zaratzian, A, Grey, St, Da Silva, A, Leung, W, Mathivanan, S, Wang, Yx, Braithwaite, Aw, Christ, D, Benda, A, Parkin, A, Phillips, Pa, Whitelock, Jm, Gill, Aj, Sansom, Oj, Croucher, Dr, Parker, Bl, Pajic, M, Morton, Jp, Cox, Tr, Timpson, P, Johns, Al, Chantrill, La, Chou, A, Steinmann, A, Arshi, M, Dwarte, T, Froio, D, Pereira, B, Ritchie, S, Chambers, Cr, Metcalf, X, Waddell, N, Pearson, Jv, Patch, Am, Nones, K, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Leonard, C, Wood, S, Grimmond, Sm, Hofmann, O, Christ, A, Bruxner, T, Samra, Js, Pavlakis, N, High, Ha, Asghari, R, Merrett, Nd, Pavey, D, Das, A, Cosman, Ph, Ismail, K, O'Connnor, C, Stoita, A, Williams, D, Spigellman, A, Lam, Vw, Mcleod, D, Kirk, J, Kench, Jg, Grimison, P, Cooper, Cl, Sandroussi, C, Goodwin, A, Mead, Rs, Tucker, K, Andrews, L, Texler, M, Forest, C, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Zeps, N, Beilin, M, Feeney, K, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Chen, J, Brooke-Smith, Me, Papangelis, V, Clouston, Ad, Barbour, Ap, O'Rourke, Tj, Fawcett, Jw, Slater, K, Hatzifotis, M, Hodgkinson, P, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Wolfgang, Cl, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Biankin, Av, Dixon, J, Jamieson, Nb, and Chang, Dk

Subjects
0301 basic medicine, medicine.medical_treatment, Drug Resistance, General Physics and Astronomy, 02 engineering and technology, Mice, Cancer-Associated Fibroblasts, Cell Movement, lcsh:Science, Inbred BALB C, Cancer, education.field_of_study, Mice, Inbred BALB C, Multidisciplinary, Tumor, 021001 nanoscience & nanotechnology, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, 0210 nano-technology, Pancreas, Signal Transduction, Cancer microenvironment, Cell biology, Science, Population, Perlecan, Biology, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Pancreatic cancer, Cell Line, Tumor, medicine, Humans, Animals, Neoplasm Invasiveness, education, Cell Proliferation, Neoplastic, fungi, General Chemistry, Immunotherapy, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Gene Expression Regulation, Drug Resistance, Neoplasm, Cancer cell, Cancer research, biology.protein, Neoplasm, lcsh:Q, Stromal Cells, Tumor Suppressor Protein p53, Heparan Sulfate Proteoglycans
Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer., Subtypes of cancer associated fibroblasts can both promote and suppress tumorigenesis. Here, the authors investigate how p53 status in pancreatic cancer cells affects their interaction with cancer associated fibroblasts, and report perlecan as a mediator of the pro-metastatic environment.

Published
2019

2. Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Author

Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, EM, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, UM, Jones, MD, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grützmann, R, Rahib, L, Allison, S, Bailey, PJ, Biankin, AV, Beraldi, D, Cameron, E, Chang, DK, Cooke, SL, Grimwood, P, Kelly, S, Marshall, J, Martin, S, McDade, B, McElroy, D, Musgrove, EA, Ramsay, D, Wright, D, Hair, J, Jamieson, NB, Westwood, P, Williams, N, Johns, AL, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Martyn-Smith, M, Thomas, MT, Chantrill, LA, Chin, VT, Chou, A, Cowley, MJ, Humphris, JL, Mead, RS, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, DiPietro, R, Watson, C, Steinmann, A, Lee, HC, Wong, R, Pinho, AV, Giry-Laterriere, M, Daly, RJ, Sutherland, RL, Grimmond, SM, Waddell, N, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Harliwong, I, Idrisoglu, S, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, Leonard, C, Dreyer, SB, Upstill-Goddard, R, Paulus-Hock, V, Paris, C, Lampraki, EM, Dray, E, Serrels, B, Caligiuri, G, Rebus, S, Plenker, D, Galluzzo, Z, Brunton, H, Cunningham, R, Tesson, M, Nourse, C, Bailey, UM, Jones, MD, Moran-Jones, K, Wright, DW, Duthie, F, Oien, K, Evers, L, McKay, CJ, McGregor, GA, Gulati, A, Brough, R, Bajrami, I, Pettitt, S, Dziubinski, ML, Candido, J, Balkwill, F, Barry, ST, Grützmann, R, Rahib, L, Allison, S, Bailey, PJ, Biankin, AV, Beraldi, D, Cameron, E, Chang, DK, Cooke, SL, Grimwood, P, Kelly, S, Marshall, J, Martin, S, McDade, B, McElroy, D, Musgrove, EA, Ramsay, D, Wright, D, Hair, J, Jamieson, NB, Westwood, P, Williams, N, Johns, AL, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Martyn-Smith, M, Thomas, MT, Chantrill, LA, Chin, VT, Chou, A, Cowley, MJ, Humphris, JL, Mead, RS, Nagrial, AM, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, J, Tao, J, DiPietro, R, Watson, C, Steinmann, A, Lee, HC, Wong, R, Pinho, AV, Giry-Laterriere, M, Daly, RJ, Sutherland, RL, Grimmond, SM, Waddell, N, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Harliwong, I, Idrisoglu, S, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, and Leonard, C

Abstract

Background & Aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress, and novel therapeutic response in PC to develop a biomarker-driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome, and functional characteristics of 61 novel PC patient–derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient-derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors, including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, cosegregates with response to platinum (P <.001) and PARP inhibitor therapy (P <.001) in vitro and in vivo. We generated a novel signature of replication stress that predicts response to ATR (P <.018) and WEE1 inhibitor (P <.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P <.001) but was not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR-proficient PC and after platinum therapy.

Published
2021

3. GA4GH: International policies and standards for data sharing across genomic research and healthcare

Author

Rehm, HL, Page, AJH, Smith, L, Adams, JB, Alterovitz, G, Babb, LJ, Barkley, MP, Baudis, M, Beauvais, MJS, Beck, T, Beckmann, JS, Beltran, S, Bernick, D, Bernier, A, Bonfield, JK, Boughtwood, TF, Bourque, G, Bowers, SR, Brookes, AJ, Brudno, M, Brush, MH, Bujold, D, Burdett, T, Buske, OJ, Cabili, MN, Cameron, DL, Carroll, RJ, Casas-Silva, E, Chakravarty, D, Chaudhari, BP, Chen, SH, Cherry, JM, Chung, J, Cline, M, Clissold, HL, Cook-Deegan, RM, Courtot, M, Cunningham, F, Cupak, M, Davies, RM, Denisko, D, Doerr, MJ, Dolman, LI, Dove, ES, Dursi, LJ, Dyke, SOM, Eddy, JA, Eilbeck, K, Ellrott, KP, Fairley, S, Fakhro, KA, Firth, HV, Fitzsimons, MS, Fiume, M, Flicek, P, Fore, IM, Freeberg, MA, Freimuth, RR, Fromont, LA, Fuerth, J, Gaff, CL, Gan, W, Ghanaim, EM, Glazer, D, Green, RC, Griffith, M, Griffith, OL, Grossman, RL, Groza, T, Auvil, JMG, Guigo, R, Gupta, D, Haendel, MA, Hamosh, A, Hansen, DP, Hart, RK, Hartley, DM, Haussler, D, Hendricks-Sturrup, RM, Ho, CWL, Hobb, AE, Hoffman, MM, Hofmann, OM, Holub, P, Hsu, JS, Hubaux, J-P, Hunt, SE, Husami, A, Jacobsen, JO, Jamuar, SS, Janes, EL, Jeanson, F, Jene, A, Johns, AL, Joly, Y, Jones, SJM, Kanitz, A, Kato, K, Keane, TM, Kekesi-Lafrance, K, Kelleher, J, Kerry, G, Khor, S-S, Knoppers, BM, Konopko, MA, Kosaki, K, Kuba, M, Lawson, J, Leinonen, R, Li, S, Lin, MF, Linden, M, Liu, X, Liyanage, IU, Lopez, J, Lucassen, AM, Lukowski, M, Mann, AL, Marshall, J, Mattioni, M, Metke-Jimenez, A, Middleton, A, Milne, RJ, Molnar-Gabor, F, Mulder, N, Munoz-Torres, MC, Nag, R, Nakagawa, H, Nasir, J, Navarro, A, Nelson, TH, Niewielska, A, Nisselle, A, Niu, J, Nyronen, TH, O'Connor, BD, Oesterle, S, Ogishima, S, Wang, VO, Paglione, LAD, Palumbo, E, Parkinson, HE, Philippakis, AA, Pizarro, AD, Prlic, A, Rambla, J, Rendon, A, Rider, RA, Robinson, PN, Rodarmer, KW, Rodriguez, LL, Rubin, AF, Rueda, M, Rushton, GA, Ryan, RS, Saunders, GI, Schuilenburg, H, Schwede, T, Scollen, S, Senf, A, Sheffield, NC, Skantharajah, N, Smith, AV, Sofia, HJ, Spalding, D, Spurdle, AB, Stark, Z, Stein, LD, Suematsu, M, Tan, P, Tedds, JA, Thomson, AA, Thorogood, A, Tickle, TL, Tokunaga, K, Tomroos, J, Torrents, D, Upchurch, S, Valencia, A, Guimera, RV, Vamathevan, J, Varma, S, Vears, DF, Viner, C, Voisin, C, Wagner, AH, Wallace, SE, Walsh, BP, Williams, MS, Winkler, EC, Wold, BJ, Wood, GM, Woolley, JP, Yamasaki, C, Yates, AD, Yung, CK, Zass, LJ, Zaytseva, K, Zhang, J, Goodhand, P, North, K, Birney, E, Rehm, HL, Page, AJH, Smith, L, Adams, JB, Alterovitz, G, Babb, LJ, Barkley, MP, Baudis, M, Beauvais, MJS, Beck, T, Beckmann, JS, Beltran, S, Bernick, D, Bernier, A, Bonfield, JK, Boughtwood, TF, Bourque, G, Bowers, SR, Brookes, AJ, Brudno, M, Brush, MH, Bujold, D, Burdett, T, Buske, OJ, Cabili, MN, Cameron, DL, Carroll, RJ, Casas-Silva, E, Chakravarty, D, Chaudhari, BP, Chen, SH, Cherry, JM, Chung, J, Cline, M, Clissold, HL, Cook-Deegan, RM, Courtot, M, Cunningham, F, Cupak, M, Davies, RM, Denisko, D, Doerr, MJ, Dolman, LI, Dove, ES, Dursi, LJ, Dyke, SOM, Eddy, JA, Eilbeck, K, Ellrott, KP, Fairley, S, Fakhro, KA, Firth, HV, Fitzsimons, MS, Fiume, M, Flicek, P, Fore, IM, Freeberg, MA, Freimuth, RR, Fromont, LA, Fuerth, J, Gaff, CL, Gan, W, Ghanaim, EM, Glazer, D, Green, RC, Griffith, M, Griffith, OL, Grossman, RL, Groza, T, Auvil, JMG, Guigo, R, Gupta, D, Haendel, MA, Hamosh, A, Hansen, DP, Hart, RK, Hartley, DM, Haussler, D, Hendricks-Sturrup, RM, Ho, CWL, Hobb, AE, Hoffman, MM, Hofmann, OM, Holub, P, Hsu, JS, Hubaux, J-P, Hunt, SE, Husami, A, Jacobsen, JO, Jamuar, SS, Janes, EL, Jeanson, F, Jene, A, Johns, AL, Joly, Y, Jones, SJM, Kanitz, A, Kato, K, Keane, TM, Kekesi-Lafrance, K, Kelleher, J, Kerry, G, Khor, S-S, Knoppers, BM, Konopko, MA, Kosaki, K, Kuba, M, Lawson, J, Leinonen, R, Li, S, Lin, MF, Linden, M, Liu, X, Liyanage, IU, Lopez, J, Lucassen, AM, Lukowski, M, Mann, AL, Marshall, J, Mattioni, M, Metke-Jimenez, A, Middleton, A, Milne, RJ, Molnar-Gabor, F, Mulder, N, Munoz-Torres, MC, Nag, R, Nakagawa, H, Nasir, J, Navarro, A, Nelson, TH, Niewielska, A, Nisselle, A, Niu, J, Nyronen, TH, O'Connor, BD, Oesterle, S, Ogishima, S, Wang, VO, Paglione, LAD, Palumbo, E, Parkinson, HE, Philippakis, AA, Pizarro, AD, Prlic, A, Rambla, J, Rendon, A, Rider, RA, Robinson, PN, Rodarmer, KW, Rodriguez, LL, Rubin, AF, Rueda, M, Rushton, GA, Ryan, RS, Saunders, GI, Schuilenburg, H, Schwede, T, Scollen, S, Senf, A, Sheffield, NC, Skantharajah, N, Smith, AV, Sofia, HJ, Spalding, D, Spurdle, AB, Stark, Z, Stein, LD, Suematsu, M, Tan, P, Tedds, JA, Thomson, AA, Thorogood, A, Tickle, TL, Tokunaga, K, Tomroos, J, Torrents, D, Upchurch, S, Valencia, A, Guimera, RV, Vamathevan, J, Varma, S, Vears, DF, Viner, C, Voisin, C, Wagner, AH, Wallace, SE, Walsh, BP, Williams, MS, Winkler, EC, Wold, BJ, Wood, GM, Woolley, JP, Yamasaki, C, Yates, AD, Yung, CK, Zass, LJ, Zaytseva, K, Zhang, J, Goodhand, P, North, K, and Birney, E

Abstract

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits.

Published
2021

4. Return of individual research results from genomic research: A systematic review of stakeholder perspectives

Author

Menezes, RG, Vears, DF, Minion, JT, Roberts, SJ, Cummings, J, Machirori, M, Blell, M, Budin-Ljosne, I, Cowley, L, Dyke, SOM, Gaff, C, Green, R, Hall, A, Johns, AL, Knoppers, BM, Mulrine, S, Patch, C, Winkler, E, Murtagh, MJ, Menezes, RG, Vears, DF, Minion, JT, Roberts, SJ, Cummings, J, Machirori, M, Blell, M, Budin-Ljosne, I, Cowley, L, Dyke, SOM, Gaff, C, Green, R, Hall, A, Johns, AL, Knoppers, BM, Mulrine, S, Patch, C, Winkler, E, and Murtagh, MJ

Abstract

Despite the plethora of empirical studies conducted to date, debate continues about whether and to what extent results should be returned to participants of genomic research. We aimed to systematically review the empirical literature exploring stakeholders' perspectives on return of individual research results (IRR) from genomic research. We examined preferences for receiving or willingness to return IRR, and experiences with either receiving or returning them. The systematic searches were conducted across five major databases in August 2018 and repeated in April 2020, and included studies reporting findings from primary research regardless of method (quantitative, qualitative, mixed). Articles that related to the clinical setting were excluded. Our search identified 221 articles that met our search criteria. This included 118 quantitative, 69 qualitative and 34 mixed methods studies. These articles included a total number of 118,874 stakeholders with research participants (85,270/72%) and members of the general public (40,967/35%) being the largest groups represented. The articles spanned at least 22 different countries with most (144/65%) being from the USA. Most (76%) discussed clinical research projects, rather than biobanks. More than half (58%) gauged views that were hypothetical. We found overwhelming evidence of high interest in return of IRR from potential and actual genomic research participants. There is also a general willingness to provide such results by researchers and health professionals, although they tend to adopt a more cautious stance. While all results are desired to some degree, those that have the potential to change clinical management are generally prioritized by all stakeholders. Professional stakeholders appear more willing to return results that are reliable and clinically relevant than those that are less reliable and lack clinical relevance. The lack of evidence for significant enduring psychological harm and the clear benefits to some

Published
2021

5. Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants (vol 19, 33, 2021)

Author

Murali, K, Dwarte, TM, Nikfarjam, M, Tucker, KM, Vaughan, RB, Efthymiou, M, Collins, A, Spigelman, AD, Salmon, L, Johns, AL, Williams, DB, Delatycki, MB, John, T, Stoita, A, Murali, K, Dwarte, TM, Nikfarjam, M, Tucker, KM, Vaughan, RB, Efthymiou, M, Collins, A, Spigelman, AD, Salmon, L, Johns, AL, Williams, DB, Delatycki, MB, John, T, and Stoita, A

Published
2021

6. Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants

Author

Murali, K, Dwarte, TM, Nikfarjam, M, Tucker, KM, Vaughan, RB, Efthymiou, M, Collins, A, Spigelman, AD, Salmon, L, Johns, AL, Williams, DB, Delatycki, MB, John, T, Stoita, A, Murali, K, Dwarte, TM, Nikfarjam, M, Tucker, KM, Vaughan, RB, Efthymiou, M, Collins, A, Spigelman, AD, Salmon, L, Johns, AL, Williams, DB, Delatycki, MB, John, T, and Stoita, A

Abstract

BACKGROUND: The Australian Pancreatic Cancer Screening Program (APCSP) offers endoscopic ultrasound surveillance for individuals at increased risk of pancreatic ductal adenocarcinoma (PDAC) with all participants requiring assessment by a Familial Cancer Service before or after study enrolment. METHODS: Individuals aged 40-80 years (or 10 years younger than the earliest PDAC diagnosis) were eligible for APCSP study entry if they had 1) ≥ two blood relatives with PDAC (at least one of first-degree association); 2) a clinical or genetic diagnosis of Hereditary Pancreatitis or Peutz-Jeghers syndrome irrespective of PDAC family history; or 3) a known PDAC predisposition germline pathogenic variant (BRCA2, PALB2, CDKN2A, or Lynch syndrome) with ≥one PDAC-affected first- or second-degree relative. Retrospective medical record review was conducted for APCSP participants enrolled at the participating Australian hospitals from January 2011 to December 2019. We audited the genetic investigations offered by multiple Familial Cancer Services who assessed APCSP participants according to national guidelines, local clinical protocol and/or the availability of external research-funded testing, and the subsequent findings. Descriptive statistical analysis was performed using Microsoft Excel. RESULTS: Of 189 kindreds (285 participants), 50 kindreds (71 participants) had a known germline pathogenic variant at enrolment (BRCA2 n = 35, PALB2 n = 6, CDKN2A n = 3, STK11 n = 3, PRSS1 n = 2, MLH1 n = 1). Forty-eight of 136 (35%) kindreds with no known germline pathogenic variant were offered mutation analysis; 89% was clinic-funded, with increasing self-funded testing since 2016. The relatively low rates of genetic testing performed reflects initial strict criteria for clinic-funded genetic testing. New germline pathogenic variants were detected in five kindreds (10.4%) after study enrolment (BRCA2 n = 3 kindreds, PALB2 n = 1, CDKN2A n = 1). Of note, only eight kindreds were reassessed by a

Published
2021

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

Author

Lakis, V, Lawlor, RT, Newell, F, Patch, A-M, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, M-C, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Pederzoli, P, Samra, JS, Gill, AJ, Johns, AL, Pearson, J, Biankin, A, Grimmond, SM, Waddell, N, Nones, K, Scarpa, A, Lakis, V, Lawlor, RT, Newell, F, Patch, A-M, Mafficini, A, Sadanandam, A, Koufariotis, LT, Johnston, RL, Leonard, C, Wood, S, Rusev, B, Corbo, V, Luchini, C, Cingarlini, S, Landoni, L, Salvia, R, Milella, M, Chang, D, Bailey, P, Jamieson, NB, Duthie, F, Gingras, M-C, Muzny, DM, Wheeler, DA, Gibbs, RA, Milione, M, Pederzoli, P, Samra, JS, Gill, AJ, Johns, AL, Pearson, J, Biankin, A, Grimmond, SM, Waddell, N, Nones, K, and Scarpa, A

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

8. Intravital imaging technology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status

Author

Murphy, KJ, Reed, DA, Vennin, C, Conway, JRW, Nobis, M, Yin, JX, Chambers, CR, Pereira, BA, Lee, V, Filipe, EC, Trpceski, M, Ritchie, S, Lucas, MC, Warren, SC, Skhinas, JN, Magenau, A, Metcalf, XL, Stoehr, J, Major, G, Parkin, A, Bidanel, R, Lyons, RJ, Zaratzian, A, Tayao, M, Da Silva, A, Abdulkhalek, L, Gill, AJ, Johns, AL, Biankin, A, Samra, J, Grimmond, SM, Chou, A, Goetz, JG, Samuel, MS, Lyons, JG, Burgess, A, Caldon, CE, Horvath, LG, Daly, RJ, Gadegaard, N, Wang, Y, Sansom, OJ, Morton, JP, Cox, TR, Pajic, M, Herrmann, D, Timpson, P, Murphy, KJ, Reed, DA, Vennin, C, Conway, JRW, Nobis, M, Yin, JX, Chambers, CR, Pereira, BA, Lee, V, Filipe, EC, Trpceski, M, Ritchie, S, Lucas, MC, Warren, SC, Skhinas, JN, Magenau, A, Metcalf, XL, Stoehr, J, Major, G, Parkin, A, Bidanel, R, Lyons, RJ, Zaratzian, A, Tayao, M, Da Silva, A, Abdulkhalek, L, Gill, AJ, Johns, AL, Biankin, A, Samra, J, Grimmond, SM, Chou, A, Goetz, JG, Samuel, MS, Lyons, JG, Burgess, A, Caldon, CE, Horvath, LG, Daly, RJ, Gadegaard, N, Wang, Y, Sansom, OJ, Morton, JP, Cox, TR, Pajic, M, Herrmann, D, and Timpson, P

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic, chemoresistant malignancy and is characterized by a dense, desmoplastic stroma that modulates PDAC progression. Here, we visualized transient manipulation of focal adhesion kinase (FAK), which integrates bidirectional cell-environment signaling, using intravital fluorescence lifetime imaging microscopy of the FAK-based Förster resonance energy transfer biosensor in mouse and patient-derived PDAC models. Parallel real-time quantification of the FUCCI cell cycle reporter guided us to improve PDAC response to standard-of-care chemotherapy at primary and secondary sites. Critically, micropatterned pillar plates and stiffness-tunable matrices were used to pinpoint the contribution of environmental cues to chemosensitization, while fluid flow–induced shear stress assessment, patient-derived matrices, and personalized in vivo models allowed us to deconstruct how FAK inhibition can reduce PDAC spread. Last, stratification of PDAC patient samples via Merlin status revealed a patient subset with poor prognosis that are likely to respond to FAK priming before chemotherapy.

Published
2021

9. Precision Oncology in Surgery: Patient Selection for Operable Pancreatic Cancer.

Author

Dreyer, SB, Pinese, M, Jamieson, NB, Scarlett, CJ, Colvin, EK, Pajic, M, Johns, AL, Humphris, JL, Wu, J, Cowley, MJ, Chou, A, Nagrial, AM, Chantrill, L, Chin, VT, Jones, MD, Moran-Jones, K, Carter, CR, Dickson, EJ, Samra, JS, Merrett, ND, Gill, AJ, Kench, JG, Duthie, F, Miller, DK, Cooke, S, Aust, D, Knösel, T, Rümmele, P, Grützmann, R, Pilarsky, C, Nguyen, NQ, Musgrove, EA, Bailey, PJ, McKay, CJ, Biankin, AV, Chang, DK, Australian Pancreatic Cancer Genome Initiative, Glasgow Precision Oncology Laboratory, Dreyer, SB, Pinese, M, Jamieson, NB, Scarlett, CJ, Colvin, EK, Pajic, M, Johns, AL, Humphris, JL, Wu, J, Cowley, MJ, Chou, A, Nagrial, AM, Chantrill, L, Chin, VT, Jones, MD, Moran-Jones, K, Carter, CR, Dickson, EJ, Samra, JS, Merrett, ND, Gill, AJ, Kench, JG, Duthie, F, Miller, DK, Cooke, S, Aust, D, Knösel, T, Rümmele, P, Grützmann, R, Pilarsky, C, Nguyen, NQ, Musgrove, EA, Bailey, PJ, McKay, CJ, Biankin, AV, Chang, DK, Australian Pancreatic Cancer Genome Initiative, and Glasgow Precision Oncology Laboratory

Abstract

OBJECTIVE: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection. BACKGROUND: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease. METHOD: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram. RESULTS: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables. CONCLUSIONS: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Published
2020

10. Development and validation of a targeted gene sequencing panel for application to disparate cancers

Author

McCabe, MJ, Gauthier, MEA, Chan, CL, Thompson, TJ, De Sousa, SMC, Puttick, C, Grady, JP, Gayevskiy, V, Tao, J, Ying, K, Cipponi, A, Deng, N, Swarbrick, A, Thomas, ML, Lord, RV, Johns, AL, Kohonen-Corish, M, O’Toole, SA, Clark, J, Mueller, SA, Gupta, R, McCormack, AI, Dinger, ME, Cowley, MJ, Aghmesheh, M, Amor, D, Andrews, L, Antill, Y, Armitage, S, Arnold, L, Balleine, R, Bastick, P, Beesley, J, Beilby, J, Bennett, I, Blackburn, A, Bogwitz, M, Botes, L, Brennan, M, Brown, M, Buckley, M, Burgess, M, Burke, J, Butow, P, Caldon, L, Callen, D, Campbell, I, Chauhan, D, Chauhan, M, Chenevix-Trench, G, Christian, A, Clarke, C, Cohen, P, Colley, A, Crook, A, Cui, J, Culling, B, Cummings, M, Dawson, SJ, deFazio, A, Delatycki, M, Dickson, R, Dixon, J, Dobrovic, A, Dudding, T, Edkins, T, Edwards, S, Eisenbruch, M, Farshid, G, Fellows, A, Fenton, G, Field, M, Flanagan, J, Fong, P, Forrest, L, Fox, S, French, J, Friedlander, M, Gaff, C, Ortega, DG, Gattas, M, George, P, Giles, G, Gill, G, Greening, S, Haan, E, Harris, M, Hart, S, Hayward, N, Heiniger, L, Hopper, J, Hunt, C, James, P, Jenkins, M, Kefford, R, Kidd, A, Kirk, J, Koehler, J, Kollias, J, and Lakhani, S

Abstract

© 2019, The Author(s). Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy.

Published
2019

12. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

Author

Vennin, C, Chin, VT, Warren, SC, Lucas, MC, Herrmann, D, Magenau, A, Melenec, P, Walters, SN, Del Monte-Nieto, G, Conway, JRW, Nobis, M, Allam, AH, McCloy, RA, Currey, N, Pinese, M, Boulghourjian, A, Zaratzian, A, Adam, AAS, Heu, C, Nagrial, AM, Chou, A, Steinmann, A, Drury, A, Froio, D, Giry-Laterriere, M, Harris, NLE, Phan, T, Jain, R, Weninger, W, McGhee, EJ, Whan, R, Johns, AL, Samra, JS, Chantrill, L, Gill, AJ, Kohonen-Corish, M, Harvey, RP, Biankin, AV, Australian Pancreatic Cancer Genome Initiative (APGI), Evans, TRJ, Anderson, KI, Grey, ST, Ormandy, CJ, Gallego-Ortega, D, Wang, Y, Samuel, MS, Sansom, OJ, Burgess, A, Cox, TR, Morton, JP, Pajic, M, and Timpson, P

Subjects
rho-Associated Kinases, Antineoplastic Agents, Biosensing Techniques, Deoxycytidine, Extracellular Matrix, Pancreatic Neoplasms, Actin Cytoskeleton, Mice, Treatment Outcome, src-Family Kinases, Liver, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Cell Line, Tumor, CDC2 Protein Kinase, 06 Biological Sciences, 11 Medical and Health Sciences, Disease Progression, Animals, Humans, Neoplasm Invasiveness, Collagen, Albumin-Bound Paclitaxel, Neoplasm Metastasis, Protein Kinase Inhibitors, Cell Proliferation, Signal Transduction
Abstract

The emerging standard of care for patients with inoperable pancreatic cancer is a combination of cytotoxic drugs gemcitabine and Abraxane, but patient response remains moderate. Pancreatic cancer development and metastasis occur in complex settings, with reciprocal feedback from microenvironmental cues influencing both disease progression and drug response. Little is known about how sequential dual targeting of tumor tissue tension and vasculature before chemotherapy can affect tumor response. We used intravital imaging to assess how transient manipulation of the tumor tissue, or "priming," using the pharmaceutical Rho kinase inhibitor Fasudil affects response to chemotherapy. Intravital Förster resonance energy transfer imaging of a cyclin-dependent kinase 1 biosensor to monitor the efficacy of cytotoxic drugs revealed that priming improves pancreatic cancer response to gemcitabine/Abraxane at both primary and secondary sites. Transient priming also sensitized cells to shear stress and impaired colonization efficiency and fibrotic niche remodeling within the liver, three important features of cancer spread. Last, we demonstrate a graded response to priming in stratified patient-derived tumors, indicating that fine-tuned tissue manipulation before chemotherapy may offer opportunities in both primary and metastatic targeting of pancreatic cancer.

Published
2017

14. Lost in translation: Returning germline genetic results in genome-scale cancer research

Author

Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, Musgrove, EA, Johns, AL, McKay, SH, Humphris, JL, Pinese, M, Chantrill, LA, Mead, RS, Tucker, K, Andrews, L, Goodwin, A, Leonard, C, High, HA, Nones, K, Waddell, N, Patch, AM, Merrett, ND, Pavlakis, N, Kassahn, KS, Samra, JS, Miller, DK, Chang, DK, Pajic, M, Pearson, JV, Grimmond, SM, Zeps, N, Gill, AJ, Biankin, AV, Chin, VT, Chou, A, Steinmann, A, Arshi, M, Drury, A, Froio, D, Morgan, A, Timpson, P, Hermann, D, Vennin, C, Warren, S, Wu, J, Pinho, AV, Newell, F, Mukhopadhyay, P, Addala, V, Kazakoff, S, Holmes, O, Wood, S, Xu, C, Hofmann, O, Wilson, PJ, Christ, A, Bruxner, T, Samra, S, Arena, J, Mittal, A, Asghari, R, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Williams, D, Spigellman, A, Lam, W, McLeod, D, Nagrial, AM, Kirk, J, James, V, Grimison, P, Cooper, CL, Sandroussi, C, Forest, C, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Beilin, M, Feeney, K, Nguyen, NQ, Ruszkiewicz, AR, Worthley, C, Brooke-Smith, ME, Papangelis, V, Clouston, AD, Martin, P, Barbour, AP, O'Rourke, TJ, Fawcett, JW, Slater, K, Hatzifotis, M, Hodgkinson, P, Hruban, RH, Wolfgang, CL, Hodgin, M, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Bailey, P, Martin, S, and Musgrove, EA

Abstract

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning

Published
2017

16. βIII-Tubulin: A novel mediator of chemoresistance and metastases in pancreatic cancer

Author

McCarroll, JA, Sharbeen, G, Liu, J, Youkhana, J, Goldstein, D, McCarthy, N, Limbri, LF, Dischl, D, Ceyhan, GO, Erkan, M, Johns, AL, Biankin, AV, Kavallaris, M, Phillips, PA, McCarroll, JA, Sharbeen, G, Liu, J, Youkhana, J, Goldstein, D, McCarthy, N, Limbri, LF, Dischl, D, Ceyhan, GO, Erkan, M, Johns, AL, Biankin, AV, Kavallaris, M, and Phillips, PA

Abstract

Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, β-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of β-tubulins in pancreatic cancer are unknown. We measured the expression of different β-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence βIII-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of βIII-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that βIII-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing βIII-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of βIII-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that βIII-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients.

Published
2015

17. RON is not a prognostic marker for resectable pancreatic cancer

Author

Tactacan, Carole M, Chang, David K, Cowley, Mark J, Humphrey, Emily S, Jianmin, Wu, Gill, Anthony J, Chou, Angela, Nones, Katia, Grimmond, Sean M, Sutherland, Robert L, Biankin, Andrew V, Daly, Roger J, Biankin, Av, Johns, Al, Mawson, A, Chang, Dk, Scarlett, Cj, Brancato, Ma, Rowe, Sj, Simpson, Sl, Martyn-Smith, M, Chantrill, La, Chin, Vt, Chou, A, Cowley, Mj, Caplan, W, Humphris, Jl, Jones, Md, Mead, R, Nagrial, Am, Pajic, M, Pettit, J, Pinese, M, Rooman, I, Wu, Jun, Daly, Rj, Musgrove, Ea, Sutherland, Rl, Grimmond, Sm, Waddell, N, Kassahn, Ks, Miller, Dk, Wilson, Pj, Patch, Am, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, Michela, Holmes, O, Leonard, C, Taylor, D, Wood, JOHN STEPHAN, Xu, C, Nones, K, Fink, Julika, Christ, A, Bruxner, T, Cloonan, N, Newell, F, Pearson, Jv, Samra, Js, Gill, Aj, Nickpavlakis, Guminski, A, Toon, C, Asghari, R, Merrett, Nd, Pavey, Da, Das, A, Cosman, Ph, Ismail, K, O'Connor, C, Lam, Vw, Mcleod, D, Pleass, Hc, James, V, Kench, Jg, Cooper, Cl, Joseph, D, Sandroussi, C, Crawford, M, Texler, M, Forrest, C, Laycock, A, Epari, Kp, Ballal, M, Fletcher, Dr, Mukhedkar, S, Spry, Na, Deboer, B, Chai, M, Feeney, K, Zeps, N, Beilin, M, Nguyen, Nq, Ruszkiewicz, Ar, Worthley, C, Tan, Cp, Debrencini, T, Chen, J, Brooke-Smith, Me, Papangelis, V, Tang, H, Barbour, Ap, Clouston, Ad, Martin, P, O'Rourke, Tj, Chiang, A, Fawcett, Jw, Slater, K, Yeung, S, Hatzifotis, M, Hodgkinson, P, Christophi, C, Nikfarjam, M, Eshleman, Jr, Hruban, Rh, Maitra, A, Iacobuzio-Donahue, Ca, Schulick, Rd, Wolfgang, Cl, Morgan, Ra, Scarpa, A, Lawlor, Rt, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Tempero, Ma., and Basic (bio-) Medical Sciences

Subjects
Oncology, Male, Receptor Protein-Tyrosine Kinases/analysis, Cancer Research, Receptor tyrosine kinase, Kaplan-Meier Estimate, Surgical oncology, 80 and over, Prospective cohort study, Pancreatic Neoplasms/metabolism, Biomarker, Gemcitabine, Chemotherapy, Adenocarcinoma, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Blotting, Western, Female, Humans, Immunohistochemistry, Middle Aged, Pancreatic Neoplasms, Prognosis, Proportional Hazards Models, Receptor Protein-Tyrosine Kinases, Tissue Array Analysis, Tumor, Blotting, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Adenocarcinoma/metabolism, CA19-9, Western, Research Article, medicine.drug, medicine.medical_specialty, lcsh:RC254-282, Biomarkers, Tumor/analysis, Breast cancer, Internal medicine, Pancreatic cancer, medicine, Genetics, business.industry, Cancer, medicine.disease, business, aged, 80 and over, Biomarkers
Abstract

Background The receptor tyrosine kinase RON exhibits increased expression during pancreatic cancer progression and promotes migration, invasion and gemcitabine resistance of pancreatic cancer cells in experimental models. However, the prognostic significance of RON expression in pancreatic cancer is unknown. Methods RON expression was characterized in several large cohorts, including a prospective study, totaling 492 pancreatic cancer patients and relationships with patient outcome and clinico-pathologic variables were assessed. Results RON expression was associated with outcome in a training set, but this was not recapitulated in the validation set, nor was there any association with therapeutic responsiveness in the validation set or the prospective study. Conclusions Although RON is implicated in pancreatic cancer progression in experimental models, and may constitute a therapeutic target, RON expression is not associated with prognosis or therapeutic responsiveness in resected pancreatic cancer.

Published
2012

19. Returning individual research results for genome sequences of pancreatic cancer

Author

Johns, AL, Miller, DK, Simpson, SH, Gill, AJ, Kassahn, KS, Humphris, JL, Samra, JS, Tucker, K, Andrews, L, Chang, DK, Waddell, N, Pajic, M, Pearson, JV, Grimmond, SM, Biankin, AV, Zeps, N, Johns, AL, Miller, DK, Simpson, SH, Gill, AJ, Kassahn, KS, Humphris, JL, Samra, JS, Tucker, K, Andrews, L, Chang, DK, Waddell, N, Pajic, M, Pearson, JV, Grimmond, SM, Biankin, AV, and Zeps, N

Abstract

BACKGROUND: Disclosure of individual results to participants in genomic research is a complex and contentious issue. There are many existing commentaries and opinion pieces on the topic, but little empirical data concerning actual cases describing how individual results have been returned. Thus, the real life risks and benefits of disclosing individual research results to participants are rarely if ever presented as part of this debate. METHODS: The Australian Pancreatic Cancer Genome Initiative (APGI) is an Australian contribution to the International Cancer Genome Consortium (ICGC), that involves prospective sequencing of tumor and normal genomes of study participants with pancreatic cancer in Australia. We present three examples that illustrate different facets of how research results may arise, and how they may be returned to individuals within an ethically defensible and clinically practical framework. This framework includes the necessary elements identified by others including consent, determination of the significance of results and which to return, delineation of the responsibility for communication and the clinical pathway for managing the consequences of returning results. RESULTS: Of 285 recruited patients, we returned results to a total of 25 with no adverse events to date. These included four that were classified as medically actionable, nine as clinically significant and eight that were returned at the request of the treating clinician. Case studies presented depict instances where research results impacted on cancer susceptibility, current treatment and diagnosis, and illustrate key practical challenges of developing an effective framework. CONCLUSIONS: We suggest that return of individual results is both feasible and ethically defensible but only within the context of a robust framework that involves a close relationship between researchers and clinicians.

Published
2014

20. Synoptic reporting improves histopathological assessment of pancreatic resection specimens

Author

Gill AJ, Biankin AV, Kench JG, for the NSW Pancreatic Network (incl Sitas F), Johns AL, Eckstein R, Samra JS, Kaufman A, Chang DK, Merrett ND, Cosman PH, and Smith RC

Subjects
Wales, Research, Histological Techniques, Australia, Pathology,Surgical, Cancer Control, Survivorship, and Outcomes Research - Resources and Infrastructure, Pancreaticoduodenectomy, methods, Pancreatic Neoplasms, surgery, Pancreatectomy, Cancer Type - Pancreatic Cancer, Research Design, standards, cancer, Humans, pathology, Other, New South Wales, Neoplasm Staging
Abstract

AIM: We examined whether introduction of a standardised pancreatic cancer minimum data set improved the reporting of key pathological features across multiple institutions. METHODS: From seven different pathology departments that are members of the New South Wales Pancreatic Cancer Network, 109 free text reports and 68 synoptic reports were compared. RESULTS: AJCC stage could not be inferred from 44% of free text reports, whereas stage was reported in all 68 synoptic reports. In the free text reports 28 different names were used to designate margins. All margins were reported in only 12 (11%) of the free text reports compared with 64 (94%) of the synoptic reports (p = 0.0011). The presence or absence of lymphovascular or perineural invasion was reported in 72 (66%) and 92 (84%) of free text reports, respectively. In contrast, lymphovascular space and perineural invasion were reported in all synoptic reports (p = 0.0011 and p = 0.0058). CONCLUSION: We conclude that synoptic reporting of pancreatic resections without any other intervention increases the information contained within histopathology reports. Therefore, the introduction of minimal data set synoptic reports is a simple and feasible mechanism to immediately improve reporting for pancreatectomy specimens

Published
2009

21. Clinical and molecular characterization of HER2 amplified-pancreatic cancer

Author

Chou, A, Waddell, N, Cowley, MJ, Gill, AJ, Chang, DK, Patch, AM, Nones, K, Wu, J, Pinese, M, Johns, AL, Miller, DK, Kassahn, KS, Nagrial, AM, Wasan, H, Goldstein, D, Toon, CW, Chin, V, Chantrill, L, Humphris, J, Mead, RS, Rooman, I, Samra, JS, Pajic, M, Musgrove, EA, Pearson, JV, Morey, AL, Grimmond, SM, Biankin, AV, Chou, A, Waddell, N, Cowley, MJ, Gill, AJ, Chang, DK, Patch, AM, Nones, K, Wu, J, Pinese, M, Johns, AL, Miller, DK, Kassahn, KS, Nagrial, AM, Wasan, H, Goldstein, D, Toon, CW, Chin, V, Chantrill, L, Humphris, J, Mead, RS, Rooman, I, Samra, JS, Pajic, M, Musgrove, EA, Pearson, JV, Morey, AL, Grimmond, SM, and Biankin, AV

Abstract

Background: Pancreatic cancer is one of the most lethal and molecularly diverse malignancies. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers potential for rapid improvements in outcome. Although HER2 amplification occurs in pancreatic cancer, it is inadequately characterized to exploit the potential of anti-HER2 therapies. Methods: HER2 amplification was detected and further analyzed using multiple genomic sequencing approaches. Standardized reference laboratory assays defined HER2 amplification in a large cohort of patients (n = 469) with pancreatic ductal adenocarcinoma (PDAC). Results: An amplified inversion event (1 MB) was identified at the HER2 locus in a patient with PDAC. Using standardized laboratory assays, we established diagnostic criteria for HER2 amplification in PDAC, and observed a prevalence of 2%. Clinically, HER2- amplified PDAC was characterized by a lack of liver metastases, and a preponderance of lung and brain metastases. Excluding breast and gastric cancer, the incidence of HER2-amplified cancers in the USA is >22,000 per annum. Conclusions: HER2 amplification occurs in 2% of PDAC, and has distinct features with implications for clinical practice. The molecular heterogeneity of PDAC implies that even an incidence of 2% represents an attractive target for anti-HER2 therapies, as options for PDAC are limited. Recruiting patients based on HER2 amplification, rather than organ of origin, could make trials of anti-HER2 therapies feasible in less common cancer types. © 2013 Chou et al.; licensee BioMed Central Ltd.

Published
2013

22. Somatic Point Mutation Calling in Low Cellularity Tumors

Author

Jordan, IK, Kassahn, KS, Holmes, O, Nones, K, Patch, A-M, Miller, DK, Christ, AN, Harliwong, I, Bruxner, TJ, Xu, Q, Anderson, M, Wood, S, Leonard, C, Taylor, D, Newell, F, Song, S, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Steptoe, A, Pajic, M, Cowley, MJ, Pinese, M, Chang, DK, Gill, AJ, Johns, AL, Wu, J, Wilson, PJ, Fink, L, Biankin, AV, Waddell, N, Grimmond, SM, Pearson, JV, Jordan, IK, Kassahn, KS, Holmes, O, Nones, K, Patch, A-M, Miller, DK, Christ, AN, Harliwong, I, Bruxner, TJ, Xu, Q, Anderson, M, Wood, S, Leonard, C, Taylor, D, Newell, F, Song, S, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Steptoe, A, Pajic, M, Cowley, MJ, Pinese, M, Chang, DK, Gill, AJ, Johns, AL, Wu, J, Wilson, PJ, Fink, L, Biankin, AV, Waddell, N, Grimmond, SM, and Pearson, JV

Abstract

Somatic mutation calling from next-generation sequencing data remains a challenge due to the difficulties of distinguishing true somatic events from artifacts arising from PCR, sequencing errors or mis-mapping. Tumor cellularity or purity, sub-clonality and copy number changes also confound the identification of true somatic events against a background of germline variants. We have developed a heuristic strategy and software (http://www.qcmg.org/bioinformatics/qsnp/) for somatic mutation calling in samples with low tumor content and we show the superior sensitivity and precision of our approach using a previously sequenced cell line, a series of tumor/normal admixtures, and 3,253 putative somatic SNVs verified on an orthogonal platform.

Published
2013

23. qpure: A Tool to Estimate Tumor Cellularity from Genome-Wide Single-Nucleotide Polymorphism Profiles

Author

Ting, AH, Song, S, Nones, K, Miller, D, Harliwong, I, Kassahn, KS, Pinese, M, Pajic, M, Gill, AJ, Johns, AL, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, Q, Newell, F, Cowley, MJ, Wu, J, Wilson, P, Fink, L, Biankin, AV, Waddell, N, Grimmond, SM, Pearson, JV, Ting, AH, Song, S, Nones, K, Miller, D, Harliwong, I, Kassahn, KS, Pinese, M, Pajic, M, Gill, AJ, Johns, AL, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, Q, Newell, F, Cowley, MJ, Wu, J, Wilson, P, Fink, L, Biankin, AV, Waddell, N, Grimmond, SM, and Pearson, JV

Abstract

Tumour cellularity, the relative proportion of tumour and normal cells in a sample, affects the sensitivity of mutation detection, copy number analysis, cancer gene expression and methylation profiling. Tumour cellularity is traditionally estimated by pathological review of sectioned specimens; however this method is both subjective and prone to error due to heterogeneity within lesions and cellularity differences between the sample viewed during pathological review and tissue used for research purposes. In this paper we describe a statistical model to estimate tumour cellularity from SNP array profiles of paired tumour and normal samples using shifts in SNP allele frequency at regions of loss of heterozygosity (LOH) in the tumour. We also provide qpure, a software implementation of the method. Our experiments showed that there is a medium correlation 0.42 ([Formula: see text]-value=0.0001) between tumor cellularity estimated by qpure and pathology review. Interestingly there is a high correlation 0.87 ([Formula: see text]-value [Formula: see text] 2.2e-16) between cellularity estimates by qpure and deep Ion Torrent sequencing of known somatic KRAS mutations; and a weaker correlation 0.32 ([Formula: see text]-value=0.004) between IonTorrent sequencing and pathology review. This suggests that qpure may be a more accurate predictor of tumour cellularity than pathology review. qpure can be downloaded from https://sourceforge.net/projects/qpure/.

Published
2012

24. International network of cancer genome projects

Author

Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, Wainwright, BJ, Hudson, TJ, Anderson, W, Aretz, A, Barker, AD, Bell, C, Bernabe, RR, Bhan, MK, Calvo, F, Eerola, I, Gerhard, DS, Guttmacher, A, Guyer, M, Hemsley, FM, Jennings, JL, Kerr, D, Klatt, P, Kolar, P, Kusuda, J, Lane, DP, Laplace, F, Lu, Y, Nettekoven, G, Ozenberger, B, Peterson, J, Rao, TS, Remacle, J, Schafer, AJ, Shibata, T, Stratton, MR, Vockley, JG, Watanabe, K, Yang, H, Yuen, MMF, Knoppers, M, Bobrow, M, Cambon-Thomsen, A, Dressler, LG, Dyke, SOM, Joly, Y, Kato, K, Kennedy, KL, Nicolas, P, Parker, MJ, Rial-Sebbag, E, Romeo-Casabona, CM, Shaw, KM, Wallace, S, Wiesner, GL, Zeps, N, Lichter, P, Biankin, AV, Chabannon, C, Chin, L, Clement, B, de Alava, E, Degos, F, Ferguson, ML, Geary, P, Hayes, DN, Johns, AL, Nakagawa, H, Penny, R, Piris, MA, Sarin, R, Scarpa, A, van de Vijver, M, Futreal, PA, Aburatani, H, Bayes, M, Bowtell, DDL, Campbell, PJ, Estivill, X, Grimmond, SM, Gut, I, Hirst, M, Lopez-Otin, C, Majumder, P, Marra, M, Ning, Z, Puente, XS, Ruan, Y, Stunnenberg, HG, Swerdlow, H, Velculescu, VE, Wilson, RK, Xue, HH, Yang, L, Spellman, PT, Bader, GD, Boutros, PC, Flicek, P, Getz, G, Guigo, R, Guo, G, Haussler, D, Heath, S, Hubbard, TJ, Jiang, T, Jones, SM, Li, Q, Lopez-Bigas, N, Luo, R, Pearson, JV, Quesada, V, Raphael, BJ, Sander, C, Speed, TP, Stuart, JM, Teague, JW, Totoki, Y, Tsunoda, T, Valencia, A, Wheeler, DA, Wu, H, Zhao, S, Zhou, G, Stein, LD, Lathrop, M, Ouellette, BFF, Thomas, G, Yoshida, T, Axton, M, Gunter, C, McPherson, JD, Miller, LJ, Kasprzyk, A, Zhang, J, Haider, SA, Wang, J, Yung, CK, Cross, A, Liang, Y, Gnaneshan, S, Guberman, J, Hsu, J, Chalmers, DRC, Hasel, KW, Kaan, TSH, Knoppers, BM, Lowrance, WW, Masui, T, Rodriguez, LL, Vergely, C, Cloonan, N, Defazio, A, Eshleman, JR, Etemadmoghadam, D, Gardiner, BA, Kench, JG, Sutherland, RL, Tempero, MA, Waddell, NJ, Wilson, PJ, Gallinger, S, Tsao, M-S, Shaw, PA, Petersen, GM, Mukhopadhyay, D, DePinho, RA, Thayer, S, Muthuswamy, L, Shazand, K, Beck, T, Sam, M, Timms, L, Ballin, V, Ji, J, Zhang, X, Chen, F, Hu, X, Yang, Q, Tian, G, Zhang, L, Xing, X, Li, X, Zhu, Z, Yu, Y, Yu, J, Tost, J, Brennan, P, Holcatova, I, Zaridze, D, Brazma, A, Egevad, L, Prokhortchouk, E, Banks, RE, Uhlen, M, Viksna, J, Ponten, F, Skryabin, K, Birney, E, Borg, A, Borresen-Dale, A-L, Caldas, C, Foekens, JA, Martin, S, Reis-Filho, JS, Richardson, AL, Sotiriou, C, van't Veer, L, Birnbaum, D, Blanche, H, Boucher, P, Boyault, S, Masson-Jacquemier, JD, Pauporte, I, Pivot, X, Vincent-Salomon, A, Tabone, E, Theillet, C, Treilleux, I, Bioulac-Sage, P, Decaens, T, Franco, D, Gut, M, Samuel, D, Zucman-Rossi, J, Eils, R, Brors, B, Korbel, JO, Korshunov, A, Landgraf, P, Lehrach, H, Pfister, S, Radlwimmer, B, Reifenberger, G, Taylor, MD, von Kalle, C, Majumder, PP, Pederzoli, P, Lawlor, RT, Delledonne, M, Bardelli, A, Gress, T, Klimstra, D, Zamboni, G, Nakamura, Y, Miyano, S, Fujimoto, A, Campo, E, de Sanjose, S, Montserrat, E, Gonzalez-Diaz, M, Jares, P, Himmelbaue, H, Bea, S, Aparicio, S, Easton, DF, Collins, FS, Compton, CC, Lander, ES, Burke, W, Green, AR, Hamilton, SR, Kallioniemi, OP, Ley, TJ, Liu, ET, and Wainwright, BJ

Abstract

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Published
2010

27. Index

Author

Johns, Larry C. and Johns, Alan R.

Published
2017

34. Epilogue

Author

Johns, Larry C. and Johns, Alan R.

Published
2017

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