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

Marie-Claude Gingras; Kyle R. Covington; David K. Chang; Lawrence A. Donehower; Anthony J. Gill; Michael M. Ittman; Chad J. Creighton; Amber L. Johns; Eve Shinbrot; Ninad Dewal; William E. Fisher; null Australian Pancreatic Cancer Genome Initiative; Neil D. Merrett; Christian Pilarsky; Robert Grutzmann; Michael J. Overman; Nigel B. Jamieson; George Van Buren II; Jennifer Drummond; Kimberly Walker; Oliver A. Hamptom; Liu Xi; 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

doi:10.1016/j.celrep.2015.12.005

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

Marie-Claude Gingras, Kyle R. Covington, David K. Chang, Lawrence A. Donehower, Anthony J. Gill, Michael M. Ittman, Chad J. Creighton, Amber L. Johns, Eve Shinbrot, Ninad Dewal, William E. Fisher, Australian Pancreatic Cancer Genome Initiative, Neil D. Merrett, Christian Pilarsky, Robert Grutzmann, Michael J. Overman, Nigel B. Jamieson, George Van Buren II, Jennifer Drummond, Kimberly WalkerOliver A. Hamptom, Liu Xi, 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

Western Sydney University

Research output: Contribution to journal › Article › peer-review

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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 b-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	14
Journal	Cell Reports
Volume	14
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2015.12.005
Publication status	Published - 2016

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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10.1016/j.celrep.2015.12.005

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Gingras, M.-C., Covington, K. R., Chang, D. K., Donehower, L. A., Gill, A. J., Ittman, M. M., Creighton, C. J., Johns, A. L., Shinbrot, E., Dewal, N., Fisher, W. E., Australian Pancreatic Cancer Genome Initiative, Merrett, N. D., Pilarsky, C., Grutzmann, R., Overman, M. J., Jamieson, N. B., Van Buren II, G., Drummond, J., ... Gibbs, R. A. (2016). Ampullary cancers harbor the tumor suppressor gene ELF3 and exhibit frequent WNT dysregulation. Cell Reports, 14(4), 907-919. https://doi.org/10.1016/j.celrep.2015.12.005

@article{c4ac392ce4bc44bc987cd9608d2884c4,

title = "Ampullary cancers harbor the tumor suppressor gene ELF3 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 b-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.",

author = "Marie-Claude Gingras and Covington, {Kyle R.} and Chang, {David K.} and Donehower, {Lawrence A.} and Gill, {Anthony J.} and Ittman, {Michael M.} and Creighton, {Chad J.} and Johns, {Amber L.} and Eve Shinbrot and Ninad Dewal and Fisher, {William E.} and {Australian Pancreatic Cancer Genome Initiative} and Merrett, {Neil D.} and Christian Pilarsky and Robert Grutzmann and Overman, {Michael J.} and Jamieson, {Nigel B.} and {Van Buren II}, George and Jennifer Drummond and Kimberly Walker and Hamptom, {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.}",

year = "2016",

doi = "10.1016/j.celrep.2015.12.005",

language = "English",

volume = "14",

pages = "907--919",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "4",

}

Gingras, M-C, Covington, KR, Chang, DK, Donehower, LA, Gill, AJ, Ittman, MM, Creighton, CJ, Johns, AL, Shinbrot, E, Dewal, N, Fisher, WE, Australian Pancreatic Cancer Genome Initiative, , Merrett, ND, Pilarsky, C, Grutzmann, R, Overman, MJ, Jamieson, NB, Van Buren II, G, Drummond, J, Walker, K, Hamptom, 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 2016, 'Ampullary cancers harbor the tumor suppressor gene ELF3 and exhibit frequent WNT dysregulation', Cell Reports, vol. 14, no. 4, pp. 907-919. https://doi.org/10.1016/j.celrep.2015.12.005

TY - JOUR

T1 - Ampullary cancers harbor the tumor suppressor gene ELF3 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 - Ittman, Michael M.

AU - Creighton, Chad J.

AU - Johns, Amber L.

AU - Shinbrot, Eve

AU - Dewal, Ninad

AU - Fisher, William E.

AU - Australian Pancreatic Cancer Genome Initiative, null

AU - Merrett, Neil D.

AU - Pilarsky, Christian

AU - Grutzmann, Robert

AU - Overman, Michael J.

AU - Jamieson, Nigel B.

AU - Van Buren II, George

AU - Drummond, Jennifer

AU - Walker, Kimberly

AU - Hamptom, 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.

PY - 2016

Y1 - 2016

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 b-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 b-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

UR - https://hdl.handle.net/1959.7/uws:61404

U2 - 10.1016/j.celrep.2015.12.005

DO - 10.1016/j.celrep.2015.12.005

M3 - Article

SN - 2211-1247

VL - 14

SP - 907

EP - 919

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

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

Abstract

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