Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

Marie Claude Gingras, Kyle R. Covington, David K. Chang, Lawrence A. Donehower, Anthony J. Gill, Michael M. Ittmann, Chad J. Creighton, Amber L. Johns, Eve Shinbrot, Ninad Dewal, William E. Fisher, Christian Pilarsky, Robert Grützmann, Michael J. Overman, Nigel B. Jamieson, George Van Buren, Jennifer Drummond, Kimberly Walker, Oliver A. Hampton, Liu Xi & 158 others Donna M. Muzny, Harsha Doddapaneni, Sandra L. Lee, Michelle Bellair, Jianhong Hu, Yi Han, Huyen H. Dinh, Mike Dahdouli, Jaswinder S. Samra, Peter Bailey, Nicola Waddell, John V. Pearson, Ivon Harliwong, Huamin Wang, Daniela Aust, Karin A. Oien, Ralph H. Hruban, Sally E. Hodges, Amy McElhany, Charupong Saengboonmee, Fraser R. Duthie, Sean M. Grimmond, Andrew V. Biankin, David A. Wheeler, Richard A. Gibbs, Marc D. Jones, Amanda Mawson, Christopher J. Scarlett, Mary Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Smith Martyn, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Chou Angela, Mark J. Cowley, Jeremy L. Humphris, Scott Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann Marie Patch, Sarah Song, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, Lynn J. Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Queelly, David Wood, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O'Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O'Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Greater Glasgow, Janet S. Graham

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

LanguageEnglish
Pages907-919
Number of pages13
JournalCell Reports
Volume14
Issue number4
DOIs
Publication statusPublished - 2 Feb 2016
Externally publishedYes

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Genetic Suppression
Ports and harbors
Tumor Suppressor Genes
Tumors
Adenocarcinoma
Genes
Neoplasms
Ampulla of Vater
Microsatellite Instability
Mutation
beta Catenin
Mutation Rate
Bile Ducts
Microsatellite Repeats
Ducts
Amplification
Clinical Trials
Molecules

Bibliographical note

Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Cite this

Gingras, M. C., Covington, K. R., Chang, D. K., Donehower, L. A., Gill, A. J., Ittmann, M. M., ... Graham, J. S. (2016). Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Reports, 14(4), 907-919. https://doi.org/10.1016/j.celrep.2015.12.005
Gingras, Marie Claude ; Covington, Kyle R. ; Chang, David K. ; Donehower, Lawrence A. ; Gill, Anthony J. ; Ittmann, Michael M. ; Creighton, Chad J. ; Johns, Amber L. ; Shinbrot, Eve ; Dewal, Ninad ; Fisher, William E. ; Pilarsky, Christian ; Grützmann, Robert ; Overman, Michael J. ; Jamieson, Nigel B. ; Van Buren, George ; Drummond, Jennifer ; Walker, Kimberly ; Hampton, Oliver A. ; Xi, Liu ; Muzny, Donna M. ; Doddapaneni, Harsha ; Lee, Sandra L. ; Bellair, Michelle ; Hu, Jianhong ; Han, Yi ; Dinh, Huyen H. ; Dahdouli, Mike ; Samra, Jaswinder S. ; Bailey, Peter ; Waddell, Nicola ; Pearson, John V. ; Harliwong, Ivon ; Wang, Huamin ; Aust, Daniela ; Oien, Karin A. ; Hruban, Ralph H. ; Hodges, Sally E. ; McElhany, Amy ; Saengboonmee, Charupong ; Duthie, Fraser R. ; Grimmond, Sean M. ; Biankin, Andrew V. ; Wheeler, David A. ; Gibbs, Richard A. ; Jones, Marc D. ; Mawson, Amanda ; Scarlett, Christopher J. ; Brancato, Mary Anne L. ; Rowe, Sarah J. ; Simpson, Skye H. ; Smith Martyn, Mona ; Thomas, Michelle T. ; Chantrill, Lorraine A. ; Chin, Venessa T. ; Angela, Chou ; Cowley, Mark J. ; Humphris, Jeremy L. ; Mead, Scott ; Nagrial, Adnan M. ; Pajic, Marina ; Pettit, Jessica ; Pinese, Mark ; Rooman, Ilse ; Wu, Jianmin ; Tao, Jiang ; DiPietro, Renee ; Watson, Clare ; Steinmann, Angela ; Lee, Hong Ching ; Wong, Rachel ; Pinho, Andreia V. ; Giry-Laterriere, Marc ; Daly, Roger J. ; Musgrove, Elizabeth A. ; Sutherland, Robert L. ; Kassahn, Karin S. ; Miller, David K. ; Wilson, Peter J. ; Patch, Ann Marie ; Song, Sarah ; 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 ; Quinn, Michael ; Nagaraj, Shivashankar ; Kazakoff, Stephen ; Waddell, Nick ; Krisnan, Keerthana ; Queelly ; Wood, David ; Pavlakis, Nick ; Guminski, Alex ; Toon, Christopher ; Asghari, Ray ; Merrett, Neil D. ; Pavey, Darren ; Das, Amitabha ; Cosman, Peter H. ; Ismail, Kasim ; O'Connnor, Chelsie ; Lam, Vincent W. ; McLeod, Duncan ; 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 ; Spry, Nigel A. ; DeBoer, Bastiaan ; Chai, Ming ; Zeps, Nikolajs ; 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. ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Hodgin, Mary ; Scarpa, Aldo ; Lawlor, Rita T. ; Beghelli, Stefania ; Corbo, Vincenzo ; Scardoni, Maria ; Bassi, Claudio ; Tempero, Margaret A. ; Glasgow, Greater ; Graham, Janet S. / Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. In: Cell Reports. 2016 ; Vol. 14, No. 4. pp. 907-919.
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title = "Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation",
abstract = "The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.",
author = "Gingras, {Marie Claude} and Covington, {Kyle R.} and Chang, {David K.} and Donehower, {Lawrence A.} and Gill, {Anthony J.} and Ittmann, {Michael M.} and Creighton, {Chad J.} and Johns, {Amber L.} and Eve Shinbrot and Ninad Dewal and Fisher, {William E.} and Christian Pilarsky and Robert Gr{\"u}tzmann and Overman, {Michael J.} and Jamieson, {Nigel B.} and {Van Buren}, George and Jennifer Drummond and Kimberly Walker and Hampton, {Oliver A.} and Liu Xi and Muzny, {Donna M.} and Harsha Doddapaneni and Lee, {Sandra L.} and Michelle Bellair and Jianhong Hu and Yi Han and Dinh, {Huyen H.} and Mike Dahdouli and Samra, {Jaswinder S.} and Peter Bailey and Nicola Waddell and Pearson, {John V.} and Ivon Harliwong and Huamin Wang and Daniela Aust and Oien, {Karin A.} and Hruban, {Ralph H.} and Hodges, {Sally E.} and Amy McElhany and Charupong Saengboonmee and Duthie, {Fraser R.} and Grimmond, {Sean M.} and Biankin, {Andrew V.} and Wheeler, {David A.} and Gibbs, {Richard A.} and Jones, {Marc D.} and Amanda Mawson and Scarlett, {Christopher J.} and Brancato, {Mary Anne L.} and Rowe, {Sarah J.} and Simpson, {Skye H.} and {Smith Martyn}, Mona and Thomas, {Michelle T.} and Chantrill, {Lorraine A.} and Chin, {Venessa T.} and Chou Angela and Cowley, {Mark J.} and Humphris, {Jeremy L.} and Scott Mead and Nagrial, {Adnan M.} and Marina Pajic and Jessica Pettit and Mark Pinese and Ilse Rooman and Jianmin Wu and Jiang Tao and Renee DiPietro and Clare Watson and Angela Steinmann and Lee, {Hong Ching} and Rachel Wong and Pinho, {Andreia V.} and Marc Giry-Laterriere and Daly, {Roger J.} and Musgrove, {Elizabeth A.} and Sutherland, {Robert L.} and Kassahn, {Karin S.} and Miller, {David K.} and Wilson, {Peter J.} and Patch, {Ann Marie} and Sarah Song and Senel Idrisoglu and Craig Nourse and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Milena Gongora and Matthew Anderson and Oliver Holmes and Conrad Leonard and Darrin Taylor and Scott Wood and Christina Xu and Katia Nones and Fink, {Lynn J.} and Angelika Christ and Tim Bruxner and Nicole Cloonan and Felicity Newell and Michael Quinn and Shivashankar Nagaraj and Stephen Kazakoff and Nick Waddell and Keerthana Krisnan and Queelly and David Wood and Nick Pavlakis and Alex Guminski and Christopher Toon and Ray Asghari and Merrett, {Neil D.} and Darren Pavey and Amitabha Das and Cosman, {Peter H.} and Kasim Ismail and Chelsie O'Connnor and Lam, {Vincent W.} and Duncan McLeod and Pleass, {Henry C.} and Arthur Richardson and Virginia James and Kench, {James G.} and Cooper, {Caroline L.} and David Joseph and Charbel Sandroussi and Michael Crawford and James Gallagher and Michael Texler and Cindy Forest and Andrew Laycock and Epari, {Krishna P.} and Mo Ballal and Fletcher, {David R.} and Sanjay Mukhedkar and Spry, {Nigel A.} and Bastiaan DeBoer and Ming Chai and Nikolajs Zeps and Maria Beilin and Kynan Feeney and Nguyen, {Nan Q.} and Ruszkiewicz, {Andrew R.} and Chris Worthley and Tan, {Chuan P.} and Tamara Debrencini and John Chen and Brooke-Smith, {Mark E.} and Virginia Papangelis and Henry Tang and Barbour, {Andrew P.} and Clouston, {Andrew D.} and Patrick Martin and O'Rourke, {Thomas J.} and Amy Chiang and Fawcett, {Jonathan W.} and Kellee Slater and Shinn Yeung and Michael Hatzifotis and Peter Hodgkinson and Christopher Christophi and Mehrdad Nikfarjam and Angela Mountain and Eshleman, {James R.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Schulick, {Richard D.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Mary Hodgin and Aldo Scarpa and Lawlor, {Rita T.} and Stefania Beghelli and Vincenzo Corbo and Maria Scardoni and Claudio Bassi and Tempero, {Margaret A.} and Greater Glasgow and Graham, {Janet S.}",
note = "Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",
year = "2016",
month = "2",
day = "2",
doi = "10.1016/j.celrep.2015.12.005",
language = "English",
volume = "14",
pages = "907--919",
journal = "Cell Reports",
issn = "2211-1247",
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Gingras, MC, Covington, KR, Chang, DK, Donehower, LA, Gill, AJ, Ittmann, MM, Creighton, CJ, Johns, AL, Shinbrot, E, Dewal, N, Fisher, WE, Pilarsky, C, Grützmann, R, Overman, MJ, Jamieson, NB, Van Buren, G, Drummond, J, Walker, K, Hampton, OA, Xi, L, Muzny, DM, Doddapaneni, H, Lee, SL, Bellair, M, Hu, J, Han, Y, Dinh, HH, Dahdouli, M, Samra, JS, Bailey, P, Waddell, N, Pearson, JV, Harliwong, I, Wang, H, Aust, D, Oien, KA, Hruban, RH, Hodges, SE, McElhany, A, Saengboonmee, C, Duthie, FR, Grimmond, SM, Biankin, AV, Wheeler, DA, Gibbs, RA, Jones, MD, Mawson, A, Scarlett, CJ, Brancato, MAL, Rowe, SJ, Simpson, SH, Smith Martyn, M, Thomas, MT, Chantrill, LA, Chin, VT, Angela, C, Cowley, MJ, Humphris, JL, Mead, S, 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, Musgrove, EA, Sutherland, RL, Kassahn, KS, Miller, DK, Wilson, PJ, Patch, AM, Song, S, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, C, Nones, K, Fink, LJ, Christ, A, Bruxner, T, Cloonan, N, Newell, F, Quinn, M, Nagaraj, S, Kazakoff, S, Waddell, N, Krisnan, K, Queelly, Wood, D, Pavlakis, N, Guminski, A, Toon, C, Asghari, R, Merrett, ND, Pavey, D, Das, A, Cosman, PH, Ismail, K, O'Connnor, C, Lam, VW, McLeod, D, Pleass, HC, Richardson, A, James, V, Kench, JG, Cooper, CL, Joseph, D, Sandroussi, C, Crawford, M, Gallagher, J, Texler, M, Forest, C, Laycock, A, Epari, KP, Ballal, M, Fletcher, DR, Mukhedkar, S, Spry, NA, DeBoer, B, Chai, M, Zeps, N, Beilin, M, Feeney, K, 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, Mountain, A, Eshleman, JR, Maitra, A, Iacobuzio-Donahue, CA, Schulick, RD, Wolfgang, CL, Morgan, RA, Hodgin, M, Scarpa, A, Lawlor, RT, Beghelli, S, Corbo, V, Scardoni, M, Bassi, C, Tempero, MA, Glasgow, G & Graham, JS 2016, 'Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation', Cell Reports, vol. 14, no. 4, pp. 907-919. https://doi.org/10.1016/j.celrep.2015.12.005

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. / Gingras, Marie Claude; Covington, Kyle R.; Chang, David K.; Donehower, Lawrence A.; Gill, Anthony J.; Ittmann, Michael M.; Creighton, Chad J.; Johns, Amber L.; Shinbrot, Eve; Dewal, Ninad; Fisher, William E.; Pilarsky, Christian; Grützmann, Robert; Overman, Michael J.; Jamieson, Nigel B.; Van Buren, George; Drummond, Jennifer; Walker, Kimberly; Hampton, Oliver A.; Xi, Liu; Muzny, Donna M.; Doddapaneni, Harsha; Lee, Sandra L.; Bellair, Michelle; Hu, Jianhong; Han, Yi; Dinh, Huyen H.; Dahdouli, Mike; Samra, Jaswinder S.; Bailey, Peter; Waddell, Nicola; Pearson, John V.; Harliwong, Ivon; Wang, Huamin; Aust, Daniela; Oien, Karin A.; Hruban, Ralph H.; Hodges, Sally E.; McElhany, Amy; Saengboonmee, Charupong; Duthie, Fraser R.; Grimmond, Sean M.; Biankin, Andrew V.; Wheeler, David A.; Gibbs, Richard A.; Jones, Marc D.; Mawson, Amanda; Scarlett, Christopher J.; Brancato, Mary Anne L.; Rowe, Sarah J.; Simpson, Skye H.; Smith Martyn, Mona; Thomas, Michelle T.; Chantrill, Lorraine A.; Chin, Venessa T.; Angela, Chou; Cowley, Mark J.; Humphris, Jeremy L.; Mead, Scott; Nagrial, Adnan M.; Pajic, Marina; Pettit, Jessica; Pinese, Mark; Rooman, Ilse; Wu, Jianmin; Tao, Jiang; DiPietro, Renee; Watson, Clare; Steinmann, Angela; Lee, Hong Ching; Wong, Rachel; Pinho, Andreia V.; Giry-Laterriere, Marc; Daly, Roger J.; Musgrove, Elizabeth A.; Sutherland, Robert L.; Kassahn, Karin S.; Miller, David K.; Wilson, Peter J.; Patch, Ann Marie; Song, Sarah; 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; Quinn, Michael; Nagaraj, Shivashankar; Kazakoff, Stephen; Waddell, Nick; Krisnan, Keerthana; Queelly; Wood, David; Pavlakis, Nick; Guminski, Alex; Toon, Christopher; Asghari, Ray; Merrett, Neil D.; Pavey, Darren; Das, Amitabha; Cosman, Peter H.; Ismail, Kasim; O'Connnor, Chelsie; Lam, Vincent W.; McLeod, Duncan; 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; Spry, Nigel A.; DeBoer, Bastiaan; Chai, Ming; Zeps, Nikolajs; 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.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Hodgin, Mary; Scarpa, Aldo; Lawlor, Rita T.; Beghelli, Stefania; Corbo, Vincenzo; Scardoni, Maria; Bassi, Claudio; Tempero, Margaret A.; Glasgow, Greater; Graham, Janet S.

In: Cell Reports, Vol. 14, No. 4, 02.02.2016, p. 907-919.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

AU - Gingras, Marie Claude

AU - Covington, Kyle R.

AU - Chang, David K.

AU - Donehower, Lawrence A.

AU - Gill, Anthony J.

AU - Ittmann, Michael M.

AU - Creighton, Chad J.

AU - Johns, Amber L.

AU - Shinbrot, Eve

AU - Dewal, Ninad

AU - Fisher, William E.

AU - Pilarsky, Christian

AU - Grützmann, Robert

AU - Overman, Michael J.

AU - Jamieson, Nigel B.

AU - Van Buren, George

AU - Drummond, Jennifer

AU - Walker, Kimberly

AU - Hampton, Oliver A.

AU - Xi, Liu

AU - Muzny, Donna M.

AU - Doddapaneni, Harsha

AU - Lee, Sandra L.

AU - Bellair, Michelle

AU - Hu, Jianhong

AU - Han, Yi

AU - Dinh, Huyen H.

AU - Dahdouli, Mike

AU - Samra, Jaswinder S.

AU - Bailey, Peter

AU - Waddell, Nicola

AU - Pearson, John V.

AU - Harliwong, Ivon

AU - Wang, Huamin

AU - Aust, Daniela

AU - Oien, Karin A.

AU - Hruban, Ralph H.

AU - Hodges, Sally E.

AU - McElhany, Amy

AU - Saengboonmee, Charupong

AU - Duthie, Fraser R.

AU - Grimmond, Sean M.

AU - Biankin, Andrew V.

AU - Wheeler, David A.

AU - Gibbs, Richard A.

AU - Jones, Marc D.

AU - Mawson, Amanda

AU - Scarlett, Christopher J.

AU - Brancato, Mary Anne L.

AU - Rowe, Sarah J.

AU - Simpson, Skye H.

AU - Smith Martyn, Mona

AU - Thomas, Michelle T.

AU - Chantrill, Lorraine A.

AU - Chin, Venessa T.

AU - Angela, Chou

AU - Cowley, Mark J.

AU - Humphris, Jeremy L.

AU - Mead, Scott

AU - Nagrial, Adnan M.

AU - Pajic, Marina

AU - Pettit, Jessica

AU - Pinese, Mark

AU - Rooman, Ilse

AU - Wu, Jianmin

AU - Tao, Jiang

AU - DiPietro, Renee

AU - Watson, Clare

AU - Steinmann, Angela

AU - Lee, Hong Ching

AU - Wong, Rachel

AU - Pinho, Andreia V.

AU - Giry-Laterriere, Marc

AU - Daly, Roger J.

AU - Musgrove, Elizabeth A.

AU - Sutherland, Robert L.

AU - Kassahn, Karin S.

AU - Miller, David K.

AU - Wilson, Peter J.

AU - Patch, Ann Marie

AU - Song, Sarah

AU - Idrisoglu, Senel

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Wani, Shivangi

AU - Gongora, Milena

AU - Anderson, Matthew

AU - Holmes, Oliver

AU - Leonard, Conrad

AU - Taylor, Darrin

AU - Wood, Scott

AU - Xu, Christina

AU - Nones, Katia

AU - Fink, Lynn J.

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Cloonan, Nicole

AU - Newell, Felicity

AU - Quinn, Michael

AU - Nagaraj, Shivashankar

AU - Kazakoff, Stephen

AU - Waddell, Nick

AU - Krisnan, Keerthana

AU - Queelly,

AU - Wood, David

AU - Pavlakis, Nick

AU - Guminski, Alex

AU - Toon, Christopher

AU - Asghari, Ray

AU - Merrett, Neil D.

AU - Pavey, Darren

AU - Das, Amitabha

AU - Cosman, Peter H.

AU - Ismail, Kasim

AU - O'Connnor, Chelsie

AU - Lam, Vincent W.

AU - McLeod, Duncan

AU - Pleass, Henry C.

AU - Richardson, Arthur

AU - James, Virginia

AU - Kench, James G.

AU - Cooper, Caroline L.

AU - Joseph, David

AU - Sandroussi, Charbel

AU - Crawford, Michael

AU - Gallagher, James

AU - Texler, Michael

AU - Forest, Cindy

AU - Laycock, Andrew

AU - Epari, Krishna P.

AU - Ballal, Mo

AU - Fletcher, David R.

AU - Mukhedkar, Sanjay

AU - Spry, Nigel A.

AU - DeBoer, Bastiaan

AU - Chai, Ming

AU - Zeps, Nikolajs

AU - Beilin, Maria

AU - Feeney, Kynan

AU - Nguyen, Nan Q.

AU - Ruszkiewicz, Andrew R.

AU - Worthley, Chris

AU - Tan, Chuan P.

AU - Debrencini, Tamara

AU - Chen, John

AU - Brooke-Smith, Mark E.

AU - Papangelis, Virginia

AU - Tang, Henry

AU - Barbour, Andrew P.

AU - Clouston, Andrew D.

AU - Martin, Patrick

AU - O'Rourke, Thomas J.

AU - Chiang, Amy

AU - Fawcett, Jonathan W.

AU - Slater, Kellee

AU - Yeung, Shinn

AU - Hatzifotis, Michael

AU - Hodgkinson, Peter

AU - Christophi, Christopher

AU - Nikfarjam, Mehrdad

AU - Mountain, Angela

AU - Eshleman, James R.

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Schulick, Richard D.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Hodgin, Mary

AU - Scarpa, Aldo

AU - Lawlor, Rita T.

AU - Beghelli, Stefania

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Bassi, Claudio

AU - Tempero, Margaret A.

AU - Glasgow, Greater

AU - Graham, Janet S.

N1 - Copyright the Author(s) 2016. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2016/2/2

Y1 - 2016/2/2

N2 - The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

AB - The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

UR - http://www.scopus.com/inward/record.url?scp=84958103886&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2015.12.005

DO - 10.1016/j.celrep.2015.12.005

M3 - Article

VL - 14

SP - 907

EP - 919

JO - Cell Reports

T2 - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 4

ER -

Gingras MC, Covington KR, Chang DK, Donehower LA, Gill AJ, Ittmann MM et al. Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Reports. 2016 Feb 2;14(4):907-919. https://doi.org/10.1016/j.celrep.2015.12.005