Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma.
OBJECTIVE
Conventional therapies are still unsuccessful in patients with carcinoma arising from the biliary tract. Somatic mutations of the epidermal growth factor receptor (EGFR) gene and the activation of its downstream pathways predict the sensitivity to small-molecule inhibitors in non-small cell lung carcinoma. Therefore, we analyzed EGFR mutations and related pathways in gallbladder and bile duct carcinomas to consider the possible application of these alternative therapeutic strategies.


METHODS
Forty paraffin-embedded samples, including intrahepatic or extrahepatic cholangiocarcinoma and gallbladder carcinoma, were studied after tumor cell isolation by laser microdissection and sequencing of EGFR tyrosine kinase domain (exons 18-21). Activation of EGFR pathway was studied by evaluating phosphorylation of mitogen-activated protein kinase and Akt.


RESULTS
None of the 40 specimens had mutations in exon 18; one had one missense point mutation in exon 19, two in exon 20, and three in exon 21. In addition, 36 of 40 specimens had the same silent mutation at codon 787 in exon 20, which was also found in peripheral blood cells from healthy donors. Tumor samples harboring EGFR mutation had phosphorylation of one or both downstream transducers analyzed.


CONCLUSIONS
This is the first evidence of somatic mutations of the EGFR gene in bile duct carcinoma. Our findings suggest that a subgroup of patients with cholangiocarcinoma or gallbladder carcinoma exhibits somatic mutations of EGFR in the tyrosine kinase domain that can elicit cell signals sustaining survival and proliferation. These tumors might be further evaluated for their susceptibility to small-molecule inhibitor treatment.
Leone
Francesco
F
Department of Clinical Oncology, Unit of Pathology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Turin, Italy. francesco.leone@ircc.it
Cavalloni
Giuliana
G
Pignochino
Ymera
Y
Sarotto
Ivana
I
Ferraris
Renato
R
Piacibello
Wanda
W
Venesio
Tiziana
T
Capussotti
Lorenzo
L
Risio
Mauro
M
Aglietta
Massimo
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010766:Phosphorylation
D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases