Establishment of efficient treatment strategies for the pancreatic cancer based on its molecular characteristics

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To know molecular characteristics of the pancreatic cancer for establishment of novel diagnostic procedure and efficient therapy to make prognosis better, we investigated loss of heterozygosity (LOH) of autosomes in the pancreatic cancer specimens and their relationships with clinicopathological features of the patients, microsatellite instability (MSI) and possible alterations of its candidate target genes including TGFβRII, IGFIIR, BAX, and PTEN, putative tumor suppressor gene-loci on 6q and 12q, FISH analysis in the pancreatic juice samples to evaluate its implication for diagnosis of the pancreatic cancer, and alterations of TP53-related genes, p73 and p33/ING1. Results were shown as follows : A poor prognosis was significantly associated with LOHs of 12q, 17p, and 18q. MSI-H showing MSI in 40% and more markers was observed in 15% of primary pancreatic cancers, however, none of the candidate target genes altered. Detailed analysis revealed frequent allelic losses at 6q21, 6q23-q24, … More 6q26, 12q21 and 12q22-q23.1. Human bacterial artificial chromosomes were constructed in contig to cover the deleted regions. DUSP6 and TDG were identified as candidate tumor suppressor genes whose expressions were reduced in vast majority of pancreatic cancer cell lines analyzed. The pancreatic juice-FISH-analysis revealed none of copy number-abnormalities in 13 non neoplastic samples while the abnormalities in 12 out of 19 neoplastic samples. The abnormality involving 2 or more markers was significantly associated with malignant phenotype. p73 was not altered in various cancer tissues except in one breast cancer tissue. p24/ING1-ALT1 and p47/INGI-ALT2 were identified as alternative transcripts of p33/ING1. These results led us to conclude that detecting allelic loss is quite useful for diagnosis and predicting prognosis, an exclusive pathway for development and progression involving unidentified MSI-target genes possibly exist, novel candidate tumor suppressor genes like DUSP6 and TDG may play a role in pancreatic carcinogenesis and progression. Less