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cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the western population with a five - year survival rate under 5% . because of the few treatment options , understanding of the molecular pathology is prerequisite to identify potential molecular targets for drug therapy .
the panin ( pancreatic intraepithelial neoplasia ) classification describes various changes in the pancreatic duct system distinguishing three panin grades ( panin 1  panin 3 ) according to the degree of structural dysplasia and cytological atypia present in the lesions .
microdissection techniques revealed genetic alteration in cancer - causing genes in the putative premalignant lesions similar to pancreatic carcinomas ( see table 1 ) .
the combination of morphological and genetic observations leads to a tumor progression model for pancreatic carcinoma , comparable to the adenoma - carcinoma sequence in colorectal carcinomas .
the sequential acquisition of mutations in the proto - oncogene k - ras and the tumor suppressors ink4a , tp53 and dpc4/smad4 leads to a profound disturbance in cell cycle regulation , a hallmark of pancreatic cancer .
mutations in k - ras , ink4a , tp53 and dpc4/smad4 are frequent , whereas mutations in the tumor suppressor brca2 , mismatch repair genes and the serine - threonine kinases akt2 and lkb1/stk11 are rare genetic events .
table 1 summarizes the reported frequencies of major genetic alterations in the pancreatic tumor progression model .
pancreatic cancer has the highest incidence of ras mutations in human tumors identified to date .
the mutations of the k - ras gene , h - ras and n - ras are not affected , are generally found in codon 12 .
dependent on the used technique the frequencies of codon 12 mutations reported range from 20 to 100% and occur early in the tumor progression model .
the ras family proteins encode small gtp - binding cytoplasmic proteins that mediate pleiotropic effects including cell proliferation , survival and migration .
mutation of codon 12 in k - ras results in a gain of function , because the ras protein remains trapped in the activated state .
in contrast primary murine fibroblasts can be efficiently transformed by mutated ras in concert with a second oncogene or loss of a tumor suppressor , like p53 or p16 .
the sole expression of oncogenic ras in primary rodent and human cells results in a permanent g1 arrest accompanied by accumulation of p53 , p16and p21 .
this senescence is thought to be a defense mechanism against oncogenic stress . whether the observed overexpression of p21 , whose frequency parallels that of k - ras mutation in the pancreatic tumor progression model , is part of this defense mechanism or directly linked to the cell cycle by working as an assembly factor for the cyclin d1/cdk4 complex , is not known . placing p21 in a defence program
is speculative but attractive , because it could explain in part the observation that oncogenic k - ras mutations are not specific for malignancy , being present in benign diseases of the pancreas and in early clonal lesions .
moreover , the risk of progression to malignancy is low in the absence of co - operating genetic events [ 11 - 14 ] . despite the high mutation frequency in human pancreatic carcinoma , mice which harbor a latent allele of k - ras g12d capable of spontaneous activation in vivo ,
develop multiple early onset lung tumors but not pancreatic cancer , further demonstrating the species differences of ras function .
the complexity of ras function is amplified through recent data suggesting tumor suppressor properties of ras .
transfection of wildtype ras into rat fibroblasts inhibits anchorage - independent growth and colony formation , induced by the oncogenic ras gene .
loss of the wildtype k - ras allele was observed in some pancreatic carcinoma cell lines with mutation in k - ras ( aspc1 , capan1 and miapaca ) and there was underexpression of the mutanted allele in comparison to the wildtype allele in two other cell lines ( su8686 and panc1 ) .
a further species difference affects the signaling pathway utilized by oncogenic ras . whereas in rodent cells
the raf / mapk and the pi3k are thought to mediate many effects of oncogenic ras , there are hints that in human cells the guanine nucleotide exchange factor ral is sufficient for ras transformation .
therefore , the net outcome of ras activation in a specific setting is not easy to predict and further studies , including primary cultures of epithelial pancreas cells , are needed .
homozygous deletion of p16/p14locus is a characteristic genetic alteration observed in 80%  95% of human pancreatic cancer and usually occurs in later stages of the tumor progression model [ 19 - 21 ] .
this locus on chromosom 9q21 encodes the two related tumor suppressor genes ink4a and arf , who 's coding sequence partially overlap .
are generated by the use of a different first exon and an alternative reading frame in exon 2 .
whereas ink4a regulates cell cycle progression as an inhibitor of the cyclin d / cdk 4/6 kinase complex , arf directly interacts with mdm 2/hdm 2 to block the interaction with p53 by localizing mdm 2/hdm 2 to the nucleolus and by inhibiting directly mdm 2/hdm 2 's e3 ubiquitin ligase activity , contributing to p53 activation ( figure 1 ) .
gene deficient mice for p19 , the mouse homologue of human p14 , strongly suggest that arf is the major tumor suppressor in mice .
the specific mutation of the ink4a gene in mice also etablishes p16as a tumor suppressor in mice .
germline mutations in the exon 1 of ink4a are associated with the familial atypical mole - malignant melanoma syndrome , implicating ink4a in human tumor susceptibility .
this mutation also predispose to pancreatic cancer , but in contrast to very high penetrance and early onset of melanoma , the penetrance of pancreatic cancer is very low and displays latency similar to the sporadic disease [ 28 - 30 ] . in humans
ink4a seems to be the more important tumor suppressor for pancreatic cancer development , because germline and sporadic mutations have been identified that target ink4a , but omit arf .
ink4a is inactivated by homozygous deletions and intragenic mutation and in the remaining cases the ink4a gene is turned off through promoter methylation . the ink4a / arf locus .
the two products of the ink4a / arf locus encodes for p16and p14(p19 in mice ) .
the tp53 tumor suppressor gene is mutated , especially by missense mutations in sequences coding for the dna binding domain , in greater than 50% of pancreatic adenocarcinomas .
the mutations are often accompanied by loss of the wildtyp allele and occur late in the progression model [ 21,35 - 39 ] .
the transcription factor p53 regulates an essential growth checkpoint that both protects against genomic rearrangement or the accumulation of mutations , and suppresses cellular transformation caused by oncogene activation or the loss of tumor suppressor pathways .
p53 is stabilized and activated by extracellular stress including  irradiation and intracellular stress such as deregulation of cellular oncogenes .
loss of p53 is associated with aneuploidy , an outstanding feature of pancreatic cancer , indicating that p53 function maintains genomic stability .
germline mutations in tp53 have been described as li - fraumeni syndrome , predisposing to several neoplasms , but pancreatic carcinomas are rare findings .
smad4 , which was initially named dpc4 , deleted in pancreatic carcinoma , was originally identified as a candidate tumor suppressor that is frequently inactivated in pancreatic tumors .
the transcription factor smad4 is an important regulator of the transforming growth factor  ( tgf- ) signaling pathway . upon receptor activation smad proteins
get phosphorylated and heterodimerize with smad4 to transmit upstream signals to the nucleus and transactivate transcription of specific target genes .
the smad4 gene is deleted or mutated in over 50% of pancreatic carcinoma , an event occurring late in the tumor progression model .
the most prominent biological activity of tgf- is its potent inhibition of cell growth , mediated by a cell cycle g1 arrest , in a wide variety of cells .
it is assumed that the growth - inhibitory function of tgf- is important for smad4 tumor suppressor activity .
restoration of smad4 in human pancreatic carcinoma cells suppressed tumor formation in vivo and did not restore tgf- sensitivity .
furthermore a decrease in pro - angiogenic vegf expression and an increase in the angiogenesis inhibitor tsp-1 was observed , so that regulation of an angiogenic switch might contribute to the tumor suppressor function of smad4 .
epigenetic inactivation of the tgf-/smad4 pathway occurs in the presence of activated ras , whereby explaining the reduced selection pressure for loh at the smad4 locus .
brca2 on chromosome 13q encodes for a protein that is needed for the maintenance of genomic stability by regulating dna repair processes .
normal cells , deficient for brca2 , accumulate lethal chromosomal aberrations . inherited brca2 mutation predispose to early onset familiar breast and ovarian cancer .
albeit with lower penetrance and equal age of onset , inherited brca2 mutations also increase the risk for pancreatic cancer . in sporadic pancreatic cancer brca2 is inactivated in 7 to 10% and lately the biallelic inactivation in a high - grade duct lesion was demonstrated , so that it is assumed that brca2 mutation occur late in the neoplastic progression in the pancreas .
the autosomal dominant inherited peutz - jeghers syndrome , caused by mutation of the serine - threonine kinase lkb1/stk11 that maps to chromosom 19p13 , is associated with an increased incidence of pancreatic carcinoma [ 57 - 60 ] .
the signaling pathway of lkb1/stk1 is so far unknown , but this gene was shown to be inactivated in 5% of sporadic pancreatic cancer , suggesting a possible role in tumor suppression .
the serine - treonine kinase akt2 is a candidate oncogene for human pancreatic cancer and was found to be amplified and overexpressed in pancreatic adenocarcinoma and cell lines in up to 20% [ 63 - 65 ] .
akt2 is a downstream effector of the pi3 kinase and can be activated by epidermal growth factor , platelet - derived growth factor and basic fibroblast growth factor , all known to be overexpressed in pancreatic carcinoma .
recently akt signaling was linked to enforced insulin - like growth factor i receptor expression , promoting invasiveness of pancreatic cancer cells .
autosomal dominant inherited lynch syndrome is characterized by an increased risk of developing colorectal , endometrial , ovarian and breast cancers , transitional carcinoma of the ureter and renal pelvis .
mutations in the dna mismatch repair genes , including hmlh1 , hmsh2 and hmsh6 , cause this syndrome .
pancreatic cancer is included in the tumor spectrum , however , it seems to be a rare finding .
pancreatic cancers occurring in context of the lynch syndrome are different compared to sporadic pancreatic carcinomas in terms of the superior clinical course , histopathology and distinct molecular genetic profiles , including retention of wildtyp ras [ 72 - 74 ] .
furthermore , microsattellite instability is unlikely to participate in the oncogenesis of spontaneous pancreatic cancer [ 75 - 77 ] .
molecular investigations of pancreatic cancer are complicated by the restricted accessibility of the organ for biopsies .
the findings in molecular research on pancreatic carcinoma of the last years is now integrated in a pancreatic tumor progression model , with genetically , epigenetically and morphological defined precursor lesions .
pancreatic cancer is a genetic disease , but the transition between cancer and non - cancer is not regulated by a simple switch activated by a single gene .
in fact , multiple mutations must accumulate in a single cell , including overexpression of receptor - ligand systems , oncogene activation and loss of tumor suppressor genes , to develop pancreatic carcinoma .
deregulated cell cycle is the hallmark of many human tumors , including pancreatic carcinoma , and therefore the cell cycle could be placed into the center of pancreatic oncogenesis . as figure 2 illustrates , each of the major genetic alteration mentioned above is involved in cell cycle regulation and leads together to the acceleration of the cell cycle progression and continuous growth .
all four major genetic alteration , k - ras , ink4a , tp53 and the tgf-/smad4 tumor suppressor pathway , observed in pancreatic carcinoma , regulate directly or indirectly g1 progression , leading to e2f dependent s phase entry .
further analysis of the underlying molecular mechanism will offer new diagnostic and therapeutic options and , hopefully improve the outcome of this dismal disease in the future .
cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the western population with an average survival after diagnosis of 3 to 6 months and a five - year survival rate under 5% . 
 our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques . 
 pancreatic cancer is a multi - stage process resulting from the accumulation of genetic changes in the somatic dna of normal cells . in this article 
 we describe major genetic alterations of pancreatic cancer , mutations in the proto - oncogene k - ras and the tumor suppressors ink4a , tp53 and dpc4/smad4 . 
 the accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth . 
 the knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease .