Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas.
BACKGROUND
Protein kinases are key regulators of cellular processes (such as proliferation, apoptosis and invasion) that are often deregulated in human cancers. Accordingly, kinase genes have been the first to be systematically analyzed in human tumors leading to the discovery that many oncogenes correspond to mutated kinases. In most cases the genetic alterations translate in constitutively active kinase proteins, which are amenable of therapeutic targeting. Tumours of the pancreas are aggressive neoplasms for which no effective therapeutic strategy is currently available.


RESULTS
We conducted a DNA-sequence analysis of a selected set of 35 kinase genes in a panel of 52 pancreatic exocrine neoplasms, including 36 pancreatic ductal adenocarcinoma, and 16 ampulla of Vater cancer. Among other changes we found somatic mutations in ATM, EGFR, EPHA3, EPHB2, and KIT, none of which was previously described in cancers.


CONCLUSIONS
Although the alterations identified require further experimental evaluation, the localization within defined protein domains indicates functional relevance for most of them. Some of the mutated genes, including the tyrosine kinases EPHA3 and EPHB2, are clearly amenable to pharmacological intervention and could represent novel therapeutic targets for these incurable cancers.
Corbo
Vincenzo
V
ARC-NET Research Center, University of Verona, Policlinico GB Rossi, Verona, Italy.
Ritelli
Rossana
R
Barbi
Stefano
S
Funel
Niccola
N
Campani
Daniela
D
Bardelli
Alberto
A
Scarpa
Aldo
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014670:Ampulla of Vater / Q000201:enzymology; D001483:Base Sequence; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D003138:Common Bile Duct Neoplasms / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism
D011494:Protein Kinases