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.
| Original language | English |
|---|---|
| Pages (from-to) | 907-919 |
| Number of pages | 13 |
| Journal | Cell Reports |
| Volume | 14 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 2 Feb 2016 |
| Externally published | Yes |
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.Access to Document
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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 journal › Article › peer-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
C2 - 26804919
AN - SCOPUS:84958103886
VL - 14
SP - 907
EP - 919
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 4
ER -