molecular pathogenesis of pancreatic cancer

Molecular pathogenesis of pancreatic cancer

Werner Hilgers, MDa,*, Christophe Rosty, MDb,Stephan A. Hahn, MDc

aDepartment of Medical Oncology, Hopital Saint Louis, 1 Avenue Claude Vellefaux,

75475 Paris, Cedex 10, FrancebDepartment of Pathology, Johns Hopkins School of Medicine, 720 Rutland Avenue,

Baltimore, MD, 21205, USAcLaboratory of Molecular Oncology, Department of Internal Medicine, University of Bochum,

In der Schornau 23-25, 44892 Bochum, Germany

The poor prognosis of pancreatic carcinoma has remained unchanged for

several decades. It is a premise of research of the molecular mechanism under-

lying this disease that the findings might aide the development of new tools and

strategies of defeating this deadly disease. Recent years have led to a major

progress in our understanding of pancreatic carcinoma biology, advancing this

tumor type to one of the best genetically characterized tumors. The aim of this

review is to give an overview of the different genes involved in the pathogenesis

of pancreatic carcinoma and to describe their functions within the biological

pathways that lead to pancreatic carcinogenesis. Furthermore, it will give an

introduction to the current understanding of molecular tumor progression of

pancreatic carcinoma, as well as highlighting familial pancreatic carcinoma.

Chromosomal alterations

In the past, methodological approaches describing gross chromosomal

changes involved in various tumor types including pancreatic carcinoma have

formed an important basis for the discovery of many cancer genes. Today, with

the help of karyotyping, microsatellite analysis and comparative genomic hybrid-

ization (CGH), a wealth of information about chromosomal changes frequently

found in pancreatic carcinoma is available.

Karyotypic alterations in pancreatic adenocarcinoma include both numerical

and structural changes. In a series of 62 primary pancreatic carcinomas studied at

0889-8588/02/$ - see front matter D 2002, Elsevier Science (USA). All rights reserved.

PII: S0889 -8588 (01 )00005 -3

* Corresponding author.

E-mail address: [email protected] (W. Hilgers).

Hematol Oncol Clin N Am

16 (2002) 17–35

the Johns Hopkins Hospital [26], frequent losses were reported for chromosomes

18, 13, 12, 17 and 6. The most frequent whole chromosome gains were found for

chromosomes 20 and 7. Recurrent structural abnormalities involved the chro-

mosomal arms 1p, 3p, 11p, 17p, 1q, 6q and 19q. Double minute chromosomes

were reported in six pancreatic carcinomas suggesting the existence of gene

amplification. A comparative study in pancreatic carcinomas using microsatellite

analysis and karyotyping has shown that two-thirds of the allelic losses identified

with microsatellite analysis are associated with karyotypic structural abnormal-

ities, whereas most homozygous deletions are below the detection limit of

conventional karyotypic analyses [6].

Using high-resolution microsatellite analysis and CGH it was found that in

each pancreatic tumor an average of more than one third of chromosomal arms

harbor allelic losses [30,82]. The chromosomal arms with the highest frequency

of allelic loss (>60%) were 9p, 17p, and 18q, which are known to carry major

tumor suppressor genes involved in pancreatic carcinogenesis [30]. Moderately

frequent allelic loss (40–60%) was seen at 1p [35], 3p, 6p, 6q, 8p, 10q, 12q, 13q,

18p, 21q, and 22q [30].

Examining allelic loss patterns in sporadic pancreatic and almost all other

sporadic cancer types has been one of the most widely used tools, helping to

identify chromosomal regions which could potentially harbor tumor suppressor

genes involved in the given tumor type. Unfortunately, allelic loss analyses

rarely produced small enough consensus regions of common deletions, which

Table 1

Genes involved in sporadic pancreatic carcinoma

Chromosomal locus

Gene Tumor suppressor genes Frequencies

p16 9p21 >90%

p53 17p31 50–75%

DPC4 18q21 50%

ALK5 9q21 1%

ACVR1B 12q13 2%

TGF-b-RII 3p22 4%

MKK4 17p13 4%

FHIT 3p14.2 4%

STK11/LKB1 19p13.3 4–5%

DCC 18q21 6%

MMR a genes b 3–13%

Oncogenes

K-ras 12p12 >90%

AKT2 19q13.1 10–20%

MYB 6q24 10%

AIB1 20q12 66%c

a MMR mismatch repair.b Mutational analyses for MMR genes are not yet available.c Only cell lines.

W. Hilgers et al / Hematol Oncol Clin N Am 16 (2002) 17–3518

could be used as a starting point for positional cloning efforts. Successful

strategies for tumor suppressor gene cloning from sporadic carcinomas were

rather based on the identification of homozygous deletions leading to the

identification, among others, of the DPC4 and PTEN tumor suppressor genes

[28,29,50].

Tumor suppressor genes

In-depth genetic analyses of pancreatic carcinomas have proved that the

‘‘multi-hit’’ model of carcinogenesis also applies to this tumor type (Table 1).

Mutations in up to five different genes have so far been reported in a single

pancreatic carcinoma [70]. Three tumor suppressor genes play a prominent role in

pancreatic carcinoma formation since alterations in these genes are found in the

majority of tumors (>70%), severely compromising important pathways, such as

the p16-CDK4-cyclinD-Rb pathway of cell cycle control, the p53 tumor sup-

pressor pathway, and the DPC4/Smad4 pathway.

Additional genes are likely to be inactivated in virtually all pancreatic

carcinomas but the majority of these genes are targeted only in a minor fraction

(< 10%) of tumors reflecting the high degree of heterogeneity typical for

neoplastic cell growth. Only a few of these ‘‘low frequency’’ tumor suppressor

genes are currently known and new genes are awaited to be identified, including

genes of yet unexplored pathways.

The p16-CDK4-cyclinD-Rb pathway of cell cycle control

Genes regulating cell cycle control are frequently targeted in carcinogenesis

[79]. Cells committed towards cell division need to pass beyond an important

checkpoint (restriction point or START) in late G1 phase where positive and

negative external signals are integrated. The cyclin-dependant kinases (CDKs)

are the key kinases regulating progression of a cell through the cell division cycle

at several defined checkpoints [39]. In their active state CDKs generally form a

complex with different regulatory subunits, the cyclins. The activation of CDK4

by cyclin D drives the cell through the restriction point. For further progression

towards the G1/S border [77], hyperphosphorylation of the retinoblastoma

protein Rb (inactive form of Rb) seems to be a prerequisite [83]. Rb can be

phosphorylated by the CDK4/cyclin D complex or the CDK2/cyclin E complex.

Phosphorylated Rb releases transcription factors such as E2F, and thereby

allowing transactivation of genes important for S-phase entry. CyclinD-CDK4

and cyclinD-CDK6 activities can be blocked by the p16INK4a, CDKN2A tumor-

suppressor gene encoding for a cyclin dependent kinase inhibitor causing

G1-phase arrest [43].

The p16-CDK4-cyclinD-Rb pathway of cell cycle control was found to be

deregulated in almost all pancreatic carcinomas [9,62,71,72]. Ninety-five percent

of the pancreatic cancers inactivated the p16 gene by either homozygous deletion

W. Hilgers et al / Hematol Oncol Clin N Am 16 (2002) 17–35 19

or a combination of loss of one allele and point mutation of the other allele. In the

remaining cases p16 transcription was silenced by methylation of its promoter

region [72]. CDK4/cyclinD amplification or Rb inactivation was seldom reported

[4,72]. An alteration of more than one gene of the p16-Rb pathway was never

found in pancreatic carcinoma, consistent with the notion that these genes are

involved in the same pathway.

The p53 tumor suppressor gene

The p53 tumor suppressor gene is inactivated in 50–75% of pancreatic

carcinomas [42,65,68,70]. The p53 protein has been shown to have a multitude

of functions. It can induce temporary growth arrest and DNA repair, irreversible

growth arrest, terminal differentiation, or apoptosis in response to DNA damage.

Wild-type p53 normally has a short half-life when it is targeted by Mdm2 for its

degradation, whereas mutant p53 proteins escape this negative feedback loop and

accumulate in cancer cells [49].

p53 is almost exclusively inactivated by missense mutations while nonsense

and frameshift mutations are only rarely observed. Homozygous deletions, while

common for other tumor suppressor genes, are not observed at the p53 locus in

pancreatic carcinoma.

Mutant p53 proteins have lost their tumor suppressor function and have

oncogenic properties [81]. Mutant p53 can still bind to its wild-type form and

thereby impair the DNA-binding properties of the p53 complex [45], also referred

to as dominant-negative effect. In addition, mutant p53 can interfere with

p53-independent apoptosis by a yet unknown mechanism that may involve

transactivation [81]. These oncogenic effects may provide the p53-mutant cells

with a selective growth advantage even before the loss of the second allele

occurs, which is frequently observed in pancreatic carcinoma [30].

DPC4, SMADs and TGF-b signaling

Inactivating mutations in the DPC4 (Deleted in Pancreatic Carcinoma,

Locus 4) gene (SMAD4, MADH4) were first demonstrated in approximately

50% of pancreatic carcinomas [29]. Subsequent studies of a variety of cancer

types suggest that DPC4 may also contribute albeit to a lesser degree to the

formation of colon cancer, biliary cancer and non-functioning neuroendocrine

tumors playing only a minor role in other tumor types including head and

neck cancer, lung cancer, ovarian cancer, breast cancer and bladder cancer

[27,59,73,89,92]. Germline mutations of the DPC4 gene have been identified

in patients affected with familial juvenile polyposis [36], an autosomal

dominant disorder characterized by predisposition to hamartomatous polyps

and an increased risk for gastrointestinal carcinomas. Although DPC4 is

frequently altered in ‘‘sporadic’’ pancreatic carcinoma to date no germline

mutations have been found in families with an increased rate of this

carcinoma type.


DPC4 belongs to the highly conserved family of SMAD genes whose founding

member Mad (Mothers against decapentaplegic) was identified in Drosophila

melanogaster [76]. To date, nine human Smad-family members have been

described all involved at different levels in the SMAD signaling cascade

(Fig. 1). This cascade is initiated upon ligand-induced TGFb-receptor stimulation

(binding of a TGFb superfamily member to its appropriate TGFb type I/II

receptor complex) [58]. This leads to a transient interaction of receptor regulated

Smads (also called R-Smads or class-I Smad) with the type I receptor (Fig. 1).

R-Smads thereby become C-terminally phosphorylated through the receptor

kinase. Once phosphorylated they change their folding pattern enabling them

to form a hetero oligomeric complex with a ‘‘common-mediator Smad’’ (also

called co-Smad or class-II Smad) such as DPC4. This Smad complex is then

translocated into the nucleus. There it regulates the transcription of target genes

Fig. 1. Steps in the TGF-b–Smad signaling cascade (see text for details). BMP = bone morpho-

genetic protein.


through interaction with other nuclear factors and recruitment of transcriptional

co-activators or co-repressors (Fig. 1) [3,32].

Recently inhibitory Smads (also called I-Smads or class-III Smads) have been

identified (Fig. 1). According to the current model they compete with the

R-Smads for the type I receptor binding and therefore interfere with the activation

of R-Smads through receptor mediated phosphorylation. Another mechanism is

thought to be the direct binding of I-Smads to R-Smads, yielding R-Smads

inactive [3].

Presently, it seems unique to DPC4 that it is the common partner employed for

signaling by different TGF-b-family members. This central role of DPC4 is

further highlighted by the fact that most somatic and germ line mutations reported

to date affect the DPC4 gene.

In pancreatic carcinoma no mutations in one of the other known SMAD family

members were detected. On the other hand, a low mutation frequency of one to

four per cent was reported for the type I TGF-b receptor (ALK5), the type II

TGF-b receptor and the activin type I receptor (ACVR1B) [24,84], genes that are

involved in the TGF-b-signaling ‘‘upstream’’ of DPC4. The coexistence of DPC4

inactivation and mutations of TGF-b family receptors has been observed in

pancreatic and other cancer types, thus it can be speculated that overlapping

signaling cascades are targeted by these mutations.

The majority of DPC4 mutations identified to date are located within a highly

conserved C-terminal region (also called MH2-domain). Functional studies have

shown that the MH2 domain provides the binding properties to R-Smads, an

important prerequisite to generate a functionally active Smad complex [3]. In

addition, a few mutations have been identified within the N-terminal conserved

region (MH1 domain). This domain has been shown to mediate direct DNA

binding of DPC4 to promoter sequences [40,80].

Our knowledge of how loss of DPC4 function may contribute to tumor

formation is still limited. Based on few recent studies, it was proposed that loss of

DPC4 function may either directly affect tumor cell growth rate [104] or support

tumor invasion and metastasis via alteration of extracellular matrix components

[74]. Furthermore, it was shown that loss of DPC4 expression might promote

tumor angiogenesis by increasing the concentration of angiogenic factors and/or

decreasing corresponding inhibitors [75].

Genes inactivated in a minority of pancreatic carcinomas

MKK4

The MKK4 (MAP kinase kinase 4) protein is a component of a stress and

cytokine-induced signal transduction pathway involving MAPK (Mitogen-

activated protein kinase) proteins [13]. The MKK4 protein has been implicated

in activation of JNK1 and p38 MAPK by phosphorylation of conserved kinase

pathways. MKK4 is mutated in 4% of pancreatic carcinomas [85,90]. Since


pancreatic carcinomas can harbor mutations in MKK4 as well as in p16, p53

and DPC4 genes, MKK4 is probably part of a distinct pathway of tumor

suppression [85].

FHIT

FHIT is a candidate tumor suppressor gene, which is found at the fragile site

FRA3B, at chromosome 3p14.2. The exact function of FHIT remains unclear but

it has been shown that FHIT could induce apoptosis and retard tumor cell

proliferation [16]. In pancreatic carcinoma, homozygous deletions inside the

FRA3B fragile site were found in four percent of tumors without microsatellite

instability, but only half affected the FHIT coding region. In contrast, FHIT

alterations were found in all three pancreatic carcinomas showing high-frequency

microsatellite instability. Since no inactivating intragenic mutations were reported

in pancreatic carcinoma, the tumor suppressor role of FHIT in pancreatic

carcinoma remains unclear [33].

STK11

The STK11/LKB1 gene maps to chromosome subband 19p13.3 and encodes

for a serine/threonine kinase. Germline mutations are responsible for the Peutz-

Jeghers syndrome (PJS). In sporadic pancreatic carcinoma, STK11 is mutated in

4–5% of cases [86].

DCC

DCC (deleted in colorectal cancer) is a candidate tumor suppressor gene

localized at chromosome 18q21.2, within 2 Mb to the DPC4 tumor suppressor

gene locus, a site of more than 90% allelic loss rate in pancreatic carcinoma. DCC

encodes a netrin-1 receptor component implicated in cell migration and apoptosis

[44]. Reduced or absent expression of DCC without inactivating mutations have

been reported in many tumor types. In pancreatic carcinoma the DCC gene was

found inactivated by homozygous deletion in 6% of cases [34]. Among those

cases, the homozygous deletion of two did not encompass the DPC4 locus, which

raises the hypothesis of the presence of putative tumor suppressor genes distal to

the DPC4 locus.

Microsatellite instability

The microsatellite instability (MSI) phenotype results from mutations in DNA

mismatch repair genes: hMLH1, located on chromosome 3p21, hMSH2, located

on chromosome 2p22, hPMS1, located on chromosome 2q31, hPMS2, located on

chromosome 7p22, hMLH3, located on chromosome 14q24, and hMSH6, located

on chromosome 2p16 [66]. High-frequency microsatellite instability (MSI-H)

occur in 3% to 13% of pancreatic carcinoma [22,102]. In a limited number of

pancreatic carcinomas with microsatellite instability loss of hMLH1 expression


could be demonstrated [99]. Mutation analyses of MMR genes are currently not

available for pancreatic carcinoma.

MSI-H pancreatic carcinoma show a distinct histology and are part of a

subgroup of pancreatic tumors characterized by a medullary phenotype and poor

differentiation [22]. Furthermore, they are almost diploid and generally lack

mutations of the K-ras oncogene and the p53 tumor suppressor gene [22,99,102].

The medullary phenotype is a strong indicator of a family history of cancer but no

further clinicopathological differences have yet been identified [99].

Oncogenes

K-ras

K-ras encodes for a membrane-associated protein binding guanine nucleotides

with GTPase activity and is a key mediator in signal transduction pathways

regulating cell proliferation and differentiation. Mutations in the K-ras oncogene

are present in more than 90% of pancreatic adenocarcinoma [2,10,38], the highest

rate of K-ras mutation in any human tumor type. Mutations have been mainly

reported at codons 12, 13 and 61 leading to activation of the transduction signal

by loss of its GTPase activity. Notably, K-ras mutations are not exclusive to

cancer and have been detected in normal pancreatic ductal cells as well as in

precursor lesions identified in organs with either carcinoma or chronic pancrea-

titis [10,15,53,88].

Low frequency oncogenes

Amplification is a common mechanism by which oncogenes can be activated

in several human cancers. Amplified regions generally involve large chromo-

somal regions and are therefore not restricted to single genes. This causes

significant difficulties in identifying the target gene potentially responsible for

the clonal growth advantage in a given tumor. To date no amplified region has

been identified which would involve a major fraction of pancreatic carcinomas.

Amplification in a minor fraction of pancreatic tumors have been reported at the

following sites: the chromosomal band 19q13, containing the signal transducer

AKT2 amplified in 10–20% of the cases [11], and the chromosome 6q24

mapping the MYB oncogene amplified in 10% of the cases [96]. Furthermore,

significant copy number changes were reported for the nuclear receptor coac-

tivator AIB1 at chromosome 20q12 in six out of nine pancreatic carcinoma cell

lines analyzed [18].

Mitochondrial DNA

Recent investigations have focused on mitochondrial DNA (mtDNA) as a

potential site of mutations in cancer [67]. Interestingly, almost all tumors


examined to date (including pancreatic carcinoma) carry homoplasmic somatic

mutations of mitochondrial DNA not prevalent in normal tissue [41]. The

majority of mutations observed do not cause relevant functional alterations of

mitochondrial proteins. Therefore, the question remains unsolved if these

mutations provide a growth advantage to the tumor cell leading to clonal

selection. A hypothesis based on a mathematical model suggests rather a random

drift to homoplasmy based on the assumption of a several magnitude higher

mutation rate in tumor mtDNA [41].

Nevertheless, a recent study has demonstrated the feasibility to detect

mutant mtDNA in several kinds of body fluid of cancer patients as a

consequence of an up to 200 times higher abundance of mtDNA in tumor

cells in comparison to normal cells [17]. Therefore, a known somatic mtDNA

mutation in an individual tumor specimen could serve as a highly specific

tumor marker for surveillance.

Negative genetic findings in pancreatic carcinoma

The knowledge of cancer genes not altered in pancreatic carcinoma is also

broadening our understanding of this tumor type.

APC (adenomatous polyposis coli) [78] and b-catenin [21] mutations are found

in the vast majority of colorectal carcinoma. APC is considered the gatekeeper

gene in colorectal tumorigenesis [46]. Neither APC [78], nor b-catenin [21],

mutations were detected in primary pancreatic carcinomas, indicating a funda-

mental difference between the two tumor types starting already at the first step of

tumorigenesis. One b-catenin mutation has so far been reported in a pancreatic

carcinoma cell line [8]. Furthermore, most members of the TGF-b family signal-

ing pathway do not have mutations in pancreatic carcinomas (SMAD1, 2 [69], 3,5

and 6; ALK1, 2,3 and 6 [24]; Endoglin [101]), as well as a number of genes

involved in cell cycle control ( p18INK4c [71], p19INK4d [71], p15INK4b [71],

p14ARF [9,70]). Finally, PTEN [63], a candidate tumor suppressor gene which is

mutated in sporadic brain, breast, and prostate cancer and in the germ line of

patients with hereditary Cowden’s disease, was not found to be inactivated in

pancreatic carcinoma.

Genetic tumor progression model of pancreatic carcinoma

Ductal lesions of various morphological appearances have frequently been

recognized within and close to infiltrating ductal adenocarcinomas of the

pancreas as well as within non-cancerous pancreatic tissue and are likely to

represent the precursor lesions of pancreatic ductal adenocarcinoma [12,48,51].

Recently, an international expert committee has classified these lesions by

histomorphological criteria in four categories of Pancreatic Intraepithelial Neo-

plasia (PanIN, Fig. 2) [37]. PanIN-1A lesions are those with a flat mucinous


Fig. 2. Genetic progression model of pancreatic tumorigenesis (see text for details). PanIN = pancreatic intraepithelial neoplasia; CIS = carcinoma in situ; LOH = loss

of heterozygosity.

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epithelium without any sign of atypia, whereas lesions with a papillary archi-

tecture without atypia are categorized PanIN-1B. Lesions with increasing signs

of atypia and a prevalence of papillary architecture are categorized as PanIN-2

(low to moderate grade dysplasia) or PanIN-3 (high-grade dysplasia), respec-

tively. This classification is somewhat different from the earlier WHO classifi-

cation. The WHO classification distinguishes low (WHO-1), moderate (WHO-2)

and high-grade dysplasia (WHO-3), whereas the PanIN classification unifies

low to moderate dysplastic lesions as PanIN-2 and severe dysplastic lesions are

typed as PanIN-3 [47]. It is expected that this new nomenclature will improve

the reproducibility of histopathological and genetic studies on pancreatic pre-

cursor lesions.

A major challenge of current molecular PanIN studies is the identification

of genetic alterations, which could indicate the actual risk of a precursor

lesion to develop into an invasive cancer. In this context detailed knowledge

of the timing of emergence of characteristic genetic changes in these PanIN

lesions will likely prove important for the development of new sensitive early

diagnostic strategies as well as chemoprevention. Mutations in the K-ras

oncogene have been identified in PanINs of all grades [53,54,61,87,88], and

are therefore not useful in discriminating PanINs according to their grade and

malignant potential. In a small series of lesions, p16 gene mutations were

almost exclusively identified in PanIN-3 lesions [61], whereas loss of p16

protein expression was already found at the PanIN-2 stage [98]. Furthermore,

abnormal expression of the p53 protein and lack of DPC4 protein expression

were frequently seen in PanIN-3 lesions but rarely in PanIN-1 or PanIN-2

lesions [5,14,31,100,103], suggesting that monitoring the expression of p53

and DPC4 would provide additional criteria to identify PanIN-3 lesions.

Three recently published studies reported low to moderate frequencies of

allelic losses at 9p, 17p and 18q in PanIN-1 lesions and moderate to high

allelic loss frequencies of these regions for PanIN-3 lesions [31,52,103]. One

study combining genetic and immunohistochemical analysis of PanINs

suggested that allelic loss precedes the mutational event in the biallelic

inactivation of the p53 and DPC4 tumor suppressor genes [52]. Moreover,

it was proposed that allelic loss analysis might be useful in separating

PanIN-2 lesions with low-grade dysplasia from those PanIN-2 lesions with

moderate grade dysplasia, each potentially representing a distinct progression

step towards invasive carcinoma.

Taken together, the genetic PanIN data available show that the successive

accumulation of genetic changes parallel the severity of ductal dysplasia and

thus support the previously suggested precursor nature of the ductal lesions and

the proposed pathomorphological tumor progression model for pancreatic

carcinogenesis. In addition, the genetic data support the idea that K-ras

mutations occur early during pancreatic tumor progression, chromosomal

deletions of 9p, 17p and 18q occur at an intermediate stage, and the biallelic

inactivation of DPC4 and p53 at a late stage of the carcinoma development.

Further investigation will be necessary to identify those PanIN stage-specific


gene/protein alterations which would lend high sensitivity and specificity to an

early diagnostic test. The detection of such genes or proteins for example in

pancreatic or duodenal juice could help to identify incipient pancreatic

carcinoma in risk patients. Furthermore, an improved understanding of the

PanIN biology should help to devise future chemoprevention strategies.

Familial pancreatic carcinoma

As many as 10% of pancreatic carcinoma cases occur in patients with a family

history of pancreatic carcinoma, some related to known genetic syndromes

(Table 2), some that remain without known genetic basis [56]. The age of onset

of pancreatic carcinomas in those families is the same as that of sporadic

pancreatic carcinoma, about 63 years [55]. A first report from the National

Familial Pancreatic Tumor Registry (NFPTR) at The Johns Hopkins Medical

Institutions demonstrated an increased 18-fold risk of pancreatic carcinoma

among first-degree relatives in familial pancreatic carcinoma kindreds [91].

When three or more members are affected in a kindred, the risk is increased to

57-fold. So far, five genetic syndromes associated with familial aggregation of

pancreatic carcinoma have been characterized, involving genes that are also

targeted in sporadic pancreatic carcinomas.

Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome

FAMMM is a rare hereditary syndrome that predisposes affected patients to

the development of multiple nevi, melanomas, and a 22-fold increased risk of

developing pancreatic carcinoma [25]. It is caused by germline mutations of the

p16 gene and is inherited in an autosomal dominant pattern. Interestingly, a

mutation affecting the C-terminus of p16 was recently identified in a kindred

meeting only the criteria of familial pancreatic carcinoma, but not those of

familial melanoma [60].

Peutz-Jeghers syndrome (PJS)

PJS is an autosomal dominant disease with variable expression and incomplete

penetrance. PJS is caused by germline mutations of the STK11/LKB1 gene. The

Table 2

Familial pancreatic carcinoma

Genetic syndrome Gene Frequencies

Familial atypical multiple mole melanoma p16 < 1%

Peutz-Jeghers syndrome LKB1/STK11 < 1%

Breast cancer familial syndrome BRCA2 5–7%

Hereditary nonpolyposis colorectal cancer MMR a genes < 3%

Hereditary pancreatitis PRSS1 < 1%

a MMR mismatch repair.


diagnosis is based on the occurrence of hamartomatous gastrointestinal polyps

and perioral pigmented spots. Those patients also have an overall increased risk

of cancers, including cancers form the esophagus, stomach, small intestine,

pancreas, lung, breast, uterus, and ovary [20]. The relative risk of developing

pancreatic carcinoma in PJS patients has been estimated to 132 when compared

to the general population [19].

Early-onset familial breast cancer syndrome due to BRCA2 germline mutation

An increased risk for developing pancreatic carcinoma has been observed in

families of patients with an aggregation of breast cancers [94]. The BRCA2 gene,

linked to familial breast and ovarian cancers, is involved in the fundamental

cellular processes of maintaining genomic integrity and transcriptional regulation.

BRCA2 germline mutations were detected in about 7% of an unselected group

of patients with pancreatic carcinoma and are the most frequent described cause

of an inherited predisposition to pancreatic carcinoma [23]. Interestingly, only

one of the patients with a BRCA2 germline mutation had a family history of

breast cancer and no patient had a family history of pancreatic cancer. This

discrepancy may be in part explained by a low penetrance of BRCA2 germline

mutations for pancreatic carcinoma. The estimated lifetime risk for pancreatic

carcinoma may be as low as 5% [23,93]. The pattern of an inherited disease in

these families can therefore be easily missed.

Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome

An increased risk of pancreatic carcinoma is observed in kindreds affected by

the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome [1,57]. The

HNPCC syndrome is caused by a germline mutation of one of the DNA

mismatch repair genes. Cancers, which develop in patients affected by the

syndrome, are associated with high frequency microsatellite instability (MSI-H)

and can be located in the colon, the uterus, the stomach, the small intestine, the

ovary, the urinary tract, and the pancreas.

Hereditary pancreatitis

Hereditary pancreatitis is an autosomal dominant disorder caused by germline

mutations in the cationic trypsinogen protein PRSS1, located on chromosome

7q35 [97]. As a result of this abnormality, the cationic trypsinogen protein is

resistant to auto-inactivation, ultimately resulting in autodigestion of the pan-

creas. Germline PRSS1 mutations show the highest penetrance of inherited

pancreatic carcinoma of all yet known familial pancreatic carcinoma syndromes.

Patients with hereditary pancreatitis have a cumulative risk for the development

of pancreatic carcinoma that approaches 40% by the age of 70. They have an

estimated 50-fold relative risk for the development of pancreatic carcinoma with

an average age of onset of 39 years [55].


Perspectives in pancreatic carcinoma research

The majority of genes implicated in pancreatic carcinoma development might

have been already identified. More knowledge has to be obtained about

inherited susceptibility responsible for familial pancreatic carcinoma. Small

kindreds and low penetrance of the disease are currently important obstacles

of successful linkage studies. It is hoped that growing family registries like the

NFPTR at Johns Hopkins University will help to identify families with a

Mendelian pattern of inheritance, not explained by any of the known genes. The

availability of the human genome project data and the development of new

high-throughput techniques will accelerate the process of gene mapping and will

be of enormous aid in identifying new genes related to cancer susceptibility.

So far, the rather descriptive field of molecular genetics has had the major

contributions to our current knowledge of the molecular biology of pancreatic

carcinoma. Today, there is a growing interest into a better understanding of

mRNA and protein expression related to cancer development. A better knowl-

edge of differentially regulated genes and proteins found in pancreatic carcinoma

will provide the basis for translational research to identify biomarkers for early

detection, new prognostic factors, new therapeutic targets, or help for the

classification of tumors. Strategies toward early detection of pancreatic cancer

and precancerous lesions incorporating these genetic and proteomic insights

are detailed later in this edition of the Clinics. How the emerging understanding

of molecular biologly of pancreatic cancer is being incorporated into novel

therapies also is discussed.

Transcriptomics refers to the study of messenger RNA expression profiles in a

population of cells applying a variety of technologies. cDNA microarrays,

currently most widely used for differential expression profiling, allows the

simultaneous and rapid detection of expression levels of tens of thousands of

genes [7]. Another approach utilizes the serial analysis of gene expression

(SAGE), a technique that permits generation of a quantitative and comprehensive

profile of cellular gene expression [95]. The comparison of gene expression

profiles in pancreatic carcinoma and normal samples can thus lead to the

discovery of differentially expressed genes in cancer cells.

The comprehensive analysis of cellular proteins is termed proteomics [64].

Proteins are more complex to analyze and more numerous than genes and

messenger RNAs, because of multiple post-translational modifications. However,

proteins are the ultimate effectors of any genetic alterations or gene expression

dysregulation. Therefore, it is hoped that the access to differential transcriptomics

and proteomics data will give a better insight into cancer biology and will

generate new rational tools for diagnosis and treatment of pancreatic carcinoma.

References

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