Multiple K‐ras Mutations in Hyperplasia and Carcinoma in Cases of Human Pancreatic Carcinoma

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Abstract
Mucous cell hyperplasia (MCH) has been considered an important precursor of pancreatic ductal carcinoma based on histological and molecular research, although various K‐ras mutations rates are seen among cases with pancreatic carcinoma, chronic pancreatitis and normal pancreas, with a wide range of histological characters. To investigate the premalignant potential of MCH and the multicentricity of pancreatic carcinoma, we analyzed K‐ras mutation at codon 12 in carcinoma foci of 82 cases of surgically‐resected pancreatic carcinoma [67 solid‐type carcinomas (SCs) and 15 ductectatic‐type carcinomas (DCs)], as well as in both MCH and carcinoma foci in 42 cases (30 SCs and 12 DCs), using an enriched polymerase chain reaction (PCR)‐enzyme linked mini‐sequence assay (ELMA). K‐ras mutation was recognized in 85% (57/67) of SCs and 73% (11/15) of DCs, and multiple K‐ras mutations in 12% (8/67) of SCs and in 20% (3/15) of DCs. Multiple K‐ras mutations were also recognized in MCHs in 47% (14/30) of SCs and in 42% (5/12) of DCs. Moreover, the same sequence at K‐ras codon 12 in MCH and carcinoma was identified in 76% (32/42) of carcinoma cases and it was more frequently recognized in hyperplasias with histological atypia (51%, 37 of 72 foci) than those without atypia (24%, 16 of 68 foci) (P < 0.0007). These results further support the idea of multicentric carcinogenesis and premalignant potential of atypical hyperplasia in the human pancreas, although about half of the hyperplasias around carcinomas were not thought to be direct precursors.