Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.

2.50
Hdl Handle:
http://hdl.handle.net/2436/29452
Title:
Epidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.
Authors:
Kwak, Eunice L.; Jankowski, Janusz; Thayer, Sarah P.; Lauwers, Gregory Y.; Brannigan, Brian W.; Harris, Patricia L.; Okimoto, Ross A.; Haserlat, Sara M.; Driscoll, David R.; Ferry, David R.; Muir, Beth; Settleman, Jeff; Fuchs, Charles S.; Kulke, Matthew H.; Ryan, David P.; Clark, Jeff W.; Sgroi, Dennis C.; Haber, Daniel A.; Bell, Daphne W.
Abstract:
PURPOSE: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. RESULTS: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. CONCLUSION: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.
Citation:
Clinical Cancer Research, 12: 4283-4287
Publisher:
American Association for Cancer Research
Journal:
Clinical Cancer Research
Issue Date:
2006
URI:
http://hdl.handle.net/2436/29452
DOI:
10.1158/1078-0432.CCR-06-0189
PubMed ID:
16857803
Additional Links:
http://clincancerres.aacrjournals.org/cgi/content/full/12/14/4283
Type:
Article
Language:
en
ISSN:
1078-0432
Appears in Collections:
Cancer Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorKwak, Eunice L.-
dc.contributor.authorJankowski, Janusz-
dc.contributor.authorThayer, Sarah P.-
dc.contributor.authorLauwers, Gregory Y.-
dc.contributor.authorBrannigan, Brian W.-
dc.contributor.authorHarris, Patricia L.-
dc.contributor.authorOkimoto, Ross A.-
dc.contributor.authorHaserlat, Sara M.-
dc.contributor.authorDriscoll, David R.-
dc.contributor.authorFerry, David R.-
dc.contributor.authorMuir, Beth-
dc.contributor.authorSettleman, Jeff-
dc.contributor.authorFuchs, Charles S.-
dc.contributor.authorKulke, Matthew H.-
dc.contributor.authorRyan, David P.-
dc.contributor.authorClark, Jeff W.-
dc.contributor.authorSgroi, Dennis C.-
dc.contributor.authorHaber, Daniel A.-
dc.contributor.authorBell, Daphne W.-
dc.date.accessioned2008-06-04T09:11:45Z-
dc.date.available2008-06-04T09:11:45Z-
dc.date.issued2006-
dc.identifier.citationClinical Cancer Research, 12: 4283-4287en
dc.identifier.issn1078-0432-
dc.identifier.pmid16857803-
dc.identifier.doi10.1158/1078-0432.CCR-06-0189-
dc.identifier.urihttp://hdl.handle.net/2436/29452-
dc.description.abstractPURPOSE: Specific activating mutations within the epidermal growth factor receptor (EGFR) identify a subset of non-small cell lung cancers with dramatic sensitivity to the specific tyrosine kinase inhibitors (TKI), gefitinib and erlotinib. Despite the abundant expression of EGFR protein in a broad range of epithelial cancers, EGFR mutations have not been reported in a substantial fraction of other cancers. Given recent reports of TKI-responsive cases of esophageal and pancreatic cancer, this study was designed to determine the prevalence of EGFR mutations in these gastrointestinal cancers. EXPERIMENTAL DESIGN: We sequenced exons 18 to 21 of EGFR from 21 cases of Barrett's esophagus, 5 cases of high-grade esophageal dysplasia, 17 cases of esophageal adenocarcinoma, and 55 cases of pancreatic adenocarcinoma. Subsets of esophageal (n = 7) and pancreatic cancer cases (n = 5) were obtained from patients who were subsequently treated with gefitinib or erlotinib-capecitabine, respectively. RESULTS: Mutations of EGFR were identified in two esophageal cancers (11.7%), three cases of Barrett's esophagus (14.2%), and two pancreatic cancers (3.6%). The mutations consisted of the recurrent missense L858R and in-frame deletion delE746-A750, previously characterized as activating EGFR mutations in non-small cell lung cancer. We also identified the TKI drug resistance-associated EGFR T790M mutation in an untreated case of Barrett's esophagus and the corresponding adenocarcinoma. CONCLUSION: The presence of activating mutations within EGFR in both esophageal and pancreatic adenocarcinomas defines a previously unrecognized subset of gastrointestinal tumors in which EGFR signaling may play an important biological role. EGFR mutations in premalignant lesions of Barrett's esophagus also point to these as an early event in transformation of the esophageal epithelium. The role of genotype-directed TKI therapy should be tested in prospective clinical trials.en
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.relation.urlhttp://clincancerres.aacrjournals.org/cgi/content/full/12/14/4283en
dc.subject.meshAdenocarcinomaen
dc.subject.meshAntineoplastic Agentsen
dc.subject.meshCell Transformation, Neoplasticen
dc.subject.meshDNA Mutational Analysisen
dc.subject.meshEsophageal Neoplasmsen
dc.subject.meshExonsen
dc.subject.meshGenotypeen
dc.subject.meshHumansen
dc.subject.meshMutationen
dc.subject.meshPancreatic Neoplasmsen
dc.subject.meshProtein Structure, Tertiaryen
dc.subject.meshReceptor, Epidermal Growth Factoren
dc.titleEpidermal growth factor receptor kinase domain mutations in esophageal and pancreatic adenocarcinomas.en
dc.typeArticleen
dc.identifier.journalClinical Cancer Researchen

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