K-RAS AND P53 GENE-MUTATIONS IN PANCREATIC-CANCER - DUCTAL AND NONDUCTAL TUMORS PROGRESS THROUGH DIFFERENT GENETIC LESIONS

We studied K-ras and p53 gene mutations in a panel of 57 primary pancr eatic cancers including ductal and nonductal tumors. DNAs were obtaine d from formalin fixed, paraffin-embedded material. Target sequences we re amplified by polymerase chain reaction and analyzed by denaturing g radient gel electrophoresis and sequencing. Both K-ras and p53 genes w ere frequently mutated in ductal cancers (25 of 35, 71.4%; 18 of 35, 5 1.4%, respectively). K-ras mutations were confined to the second posit ion of codon 12 where base transitions and transversions were equally observed. p53 changes were mainly missense mutations. Transitions and transversions were found equally with a prevalence of G:C --> A:T chan ges among transitions. No gene alterations were present in the 6 exocr ine nonductal tumors and (with one exception) in the 12 endocrine tumo rs analyzed. Our results indicate that mutated K-ras and p53 genes can cooperate in the establishment of ductal pancreatic cancers, whereas other genetic events have to be present in nonductal tumors. Moreover, K-ras alterations may represent an early event in ductal tumorigenesi s, as suggested both by the high gene mutation frequency and by the pr esence of mutations in low-grade tumors. On the contrary, p53 gene cha nges seem to represent an event required for the malignancy progressio n of ductal tumors from lower to higher grades.