REVIEW ARTICLE

Pancreatic Cancer Genomes: Toward Molecular Subtypingand Novel Approaches to Diagnosis and Therapy

Laura D. Wood

Published online: 12 June 2013

� Springer International Publishing Switzerland 2013

Abstract Pancreatic neoplasms represent a broad range

of clinical entities, many of which have drastic effects on

the lives of patients. Recently, high-throughput sequencing

analyses have been performed in many pancreatic neo-

plasms, providing deep insights into the underlying biology

of these neoplasms as well as novel approaches to diag-

nosis and treatment. This review discusses the molecular

alterations underlying pancreatic neoplasms as well as the

clinical impact of these alterations for diagnosis and

treatment.

1 Introduction

Pancreatic neoplasms represent a broad clinical spectrum,

ranging from benign neoplasms to deadly cancers. Until the

recent explosion in genomic research, these neoplasms

were classified largely based on morphologic features

reflective of direction of differentiation. In the past 5 years,

the exomes of common pancreatic neoplasms have been

sequenced, identifying numerous tumor-specific somatic

mutations and making pancreatic neoplasms among the

best characterized at the genetic level. High-throughput

genomic analyses have revealed the genetic alterations

underlying neoplasms of the pancreas, identifying both the

commonly mutated ‘‘mountains’’ and the rarely mutated

‘‘hills’’ in the pancreatic cancer genome landscape. These

studies have shown that genetic divisions mirror those

based on morphology. The recent genomic analyses have

deepened our understanding of tumorigenesis in the pan-

creas and have identified several promising targets for the

development of novel diagnostic and therapeutic strategies.

2 Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma is the most common

neoplasm in the pancreas and is one of the most deadly

human cancers. This aggressive cancer is almost uniformly

fatal, with a 5-year survival rate of only 5 % [1, 2]. Mean

survival for untreated patients is only 3–5 months, while

patients receiving surgical resection have a mean survival

of only 10–20 months [1]. Ductal adenocarcinoma is also

common—it is the fourth leading cause of cancer death in

the United States and accounts for more than 200,000

deaths every year worldwide [1]. Thus, the development of

better diagnosis and therapy in ductal adenocarcinoma

represents a crucial task to improve the lives of patients

with this deadly disease. Diagnostic challenges include the

distinction between cancer and chronic pancreatitis on

needle biopsy, interpretation of fine needle aspiration

specimens, and early diagnosis in patients at high risk for

pancreatic cancer. Moreover, with its current dismal

prognosis, the development of new therapeutic strategies is

of key importance.

2.1 Molecular Genetics

Numerous studies have identified frequently altered onco-

genes and tumor suppressor genes in pancreatic ductal

adenocarcinoma—these so-called mountains in the pan-

creatic cancer genome landscape are altered in the majority

of pancreatic cancers and play crucial roles in

L. D. Wood (&)

Department of Pathology, The Sol Goldman Pancreatic Cancer

Research Center, Johns Hopkins University School of Medicine,

Weinberg 2242, 401 North Broadway, Baltimore,

MD 21231, USA

e-mail: ldwood@jhmi.edu

Mol Diagn Ther (2013) 17:287–297

DOI 10.1007/s40291-013-0043-6

tumorigenesis in the pancreas (Table 1). With somatic

mutations in [90 % of ductal adenocarcinomas, KRAS is

the most frequently mutated oncogene in this tumor [3–8].

Importantly, KRAS mutations cluster at specific hotspot

residues (most commonly codon 12), confirming the role of

KRAS as an oncogene critical to the development of pan-

creatic cancer [3, 4]. In addition to this key oncogene, the

development of pancreatic cancer is driven by several

critical tumor suppressor genes. P16/CDKN2A is the most

frequently altered tumor suppressor gene, with loss of p16

protein function in[90 % of ductal adenocarcinomas [6, 9,

10]. Several mechanisms account for this frequent loss of

protein function, including homozygous gene deletion,

intragenic mutations followed by loss of heterozygosity,

and promoter methylation [6, 11, 12]. TP53 is another

frequently altered tumor suppressor gene—these muta-

tions, which usually occur through small intragenic muta-

tion followed by loss of the wild-type allele, are present in

approximately 75 % of ductal adenocarcinomas. Finally,

SMAD4/DPC4 is somatically inactivated through homo-

zygous deletion or intragenic mutation followed by loss of

heterozygosity in approximately 55 % of pancreatic can-

cers [6, 13, 14].

In addition to their presence in invasive ductal adeno-

carcinomas, mutations in these frequently altered genes are

also present in noninvasive pancreatic cancer precursors

known as pancreatic intraepithelial neoplasia or PanINs.

Intriguingly, these precursor lesions sequentially acquire

Table 1 Frequently altered

genes in pancreatic neoplasms

PDA pancreatic ductal

adenocarcinoma, IPMN

intraductal papillary mucinous

neoplasm, MCN mucinous

cystic neoplasm, SCA serous

cystadenoma, PanNET well-

differentiated pancreatic

neuroendocrine tumor, SPN

solid-pseudopapillary neoplasm,

ACC acinar cell carcinoma, PB

pancreatoblastoma, HGD high-

grade dysplasia; carcinoma:

invasive carcinoma

Neoplasm Gene(s) Alteration prevalence Gene function

PDA KRAS 95 % Cell signaling

(MAPK pathway, etc.)

P16/CDKN2A 95 % Cell cycle regulation

TP53 75 % Cellular stress response

SMAD4/DPC4 55 % Cell signaling (TGFbR pathway)

IPMN KRAS 80 % Cell signaling

(MAPK pathway, etc.)

RNF43 75 % Ubiquitin ligase

GNAS 60 % Cell signaling (adenylyl cyclase

pathway, etc.)

PIK3CA 10 % Cell signaling (PI3K pathway)

P16/CDKN2A Only in HGD/carcinoma Cell cycle regulation

TP53 Only in HGD/carcinoma Cellular stress response

SMAD4/DPC4 Only in HGD/carcinoma Cell signaling (TGFbR pathway)

MCN KRAS 80 % Cell signaling

(MAPK pathway, etc.)

RNF43 40 % Ubiquitin ligase

TP53 25 % Cellular stress response

P16/CDKN2A Only in HGD/carcinoma Cell cycle regulation

SMAD4/DPC4 Only in HGD/carcinoma Cell signaling (TGFbR pathway)

SCA VHL 50 % Ubiquitin ligase (HIF1a pathway)

SPN CTNNB1 95 % Cell signaling (WNT pathway),

cell adhesion

PanNET MEN1 45 % Unknown

DAXX/ATRX 45 % Chromatin remodeling (alternative

lengthening of telomeres)

mTOR pathway 15 % Cell signaling (PI3K pathway)

VHL 25 % Ubiquitin ligase (HIF1a pathway)

ACC CTNNB1 5 % Cell signaling (WNT pathway),

cell adhesion

APC 15 % Cell signaling (WNT pathway),

cell adhesion

PB CTNNB1 55 % Cell signaling (WNT pathway),

cell adhesion

APC 10 % Cell signaling (WNT pathway),

cell adhesion

11p loss (gene unknown) 85 % Unknown

288 L. D. Wood

the molecular changes in these key genes—while some

genetic alterations occur early in pancreatic neoplasia,

others are limited to severely dysplastic or invasive lesions.

The vast majority of early low-grade PanINs harbor alter-

ations in KRAS and P16/CDK2NA [15–21]. In contrast,

alterations in TP53 and SMAD4/DPC4 are late events and

are limited to high-grade PanINs and invasive carcinomas

[19, 22]. In addition to alterations in these mountains,

PanINs also frequently exhibit telomere shortening—this

occurs in the vast majority of the earliest PanINs (Pa-

nIN1As), making it one of the most frequently occurring

early events in pancreatic tumorigenesis [23].

Sequencing of all protein coding genes in ductal ade-

nocarcinomas provided additional insights into pancreatic

tumorigenesis—these studies identified an average of 48

nonsynonymous somatic alterations per tumor, fewer

somatic mutations than in some other epithelial malig-

nancies but more somatic mutations than in premalignant

or benign pancreatic neoplasms [6]. Intriguingly, aside

from the aforementioned frequently altered oncogenes and

tumor suppressor genes, there was marked heterogeneity in

the individual genes altered in each tumor. However, when

the alterations were analyzed on a pathway rather than

individual gene level, there was much less variability

between individual tumors—there were 12 core cellular

pathways that were altered in the majority of ductal ade-

nocarcinomas. Alterations in these 12 pathways, which

include cell adhesion, DNA damage control, KRAS sig-

naling, and TGFb signaling, represent key steps in the

transformation of a benign cell to a cancer cell in the

pancreas.

Subsequent high-throughput sequencing studies of duc-

tal adenocarcinomas confirmed these findings. Genetic

heterogeneity was also identified in a whole genome

sequencing study of three ductal adenocarcinomas. Path-

way analysis in this study highlighted the importance of

KRAS signaling, apoptosis, and cell adhesion, in agree-

ment with previous results [24]. Another study utilizing

whole-exome sequencing and copy number analyses of 99

ductal adenocarcinomas showed concordance with previ-

ous studies: it revealed frequent alterations in known

oncogenes and tumor suppressor genes, highlighted the

importance of core cellular pathways (such as DNA dam-

age control, apoptosis, and TGFb signaling), and demon-

strated marked variation in the individual genes altered in

each tumor [25]. In addition, this study identified a novel

pathway, axon guidance, that may play a role in pancreatic

tumorigenesis—mutations in genes involved in axon

guidance (including those in the SLIT/ROBO and sem-

aphorin signaling pathways) occur infrequently in human

ductal adenocarcinoma and have functional consequences

in experimental mutagenesis screens in transgenic mice

and cancer cell lines [25].

2.2 Diagnostic and Therapeutic Implications

The genes with frequent somatic alterations in ductal

adenocarcinoma represent key targets for the development

of early detection assays. Because of its role as an onco-

gene with a mutation hotspot, KRAS is a particularly

promising target—identification of these hotspot mutations

in pancreatic duct juice can differentiate patients with

cancer from those with chronic pancreatitis [26], and

improvements in technology could enable the detection of

KRAS hotspot mutations in the plasma. These assays could

represent a noninvasive screening method for patients at an

increased risk for the development of pancreatic cancer,

such as those with known hereditary syndromes (see

below) or those with a family history of pancreatic cancer,

who often lack identifiable lesions on imaging studies. In

addition, molecular analyses of multiple genes (KRAS,

TP53, and SMAD4/DPC4) can supplement morphologic

diagnosis in cytology specimens, improving the sensitivity

and specificity of fine needle aspiration of pancreatic

lesions [27]. In one study, addition of these molecular tests

to conventional cytologic evaluation improved the sensi-

tivity and specificity of fine needle aspiration to 86 % and

94 %, respectively, compared to a sensitivity of 76 % and a

specificity of 81 % for cytology alone [27].

Mutations in SMAD4/DPC4 can be utilized both diag-

nostically and prognostically. Loss of Smad4 protein

expression can be detected by immunohistochemistry, and

this loss is correlated with gene mutation [28, 29]. Thus,

this immunohistochemical assay to identify loss of Smad4

protein expression can aid in the distinction of ductal

adenocarcinoma from non-neoplastic pancreatic diseases

such as chronic pancreatitis in histologic sections. More-

over, loss of Smad4 by immunohistochemistry can be used

to suggest that a metastatic carcinoma is of pancreatic

origin in cytologic specimens, biopsies, or surgical resec-

tions. In addition, ductal adenocarcinomas with mutations

in SMAD4/DPC4 have a worse prognosis than those with

wild-type SMAD4/DPC4; therefore, assays of SMAD4/

DPC4 mutation status can aid in prognostic stratification of

patients with ductal adenocarcinoma [30].

Genomic studies of pancreatic cancer metastases and

matched primary tumors have provided profound insights

into the clonal evolution of pancreatic cancers, enabling an

estimation of evolutionary time in these tumors [31]. These

studies suggest a broad time window for early detection

and clinical intervention, with almost 15 years elapsing

between tumor initiation and acquisition of metastatic

ability. Thus, the development of novel strategies for early

detection of pancreatic neoplasms is a worthwhile endea-

vor, because there are several years in which early detec-

tion could drastically alter the clinical course of the

disease.

Pancreatic Cancer Genomes 289

Patients with hereditary predisposition to pancreatic

cancer represent a unique clinical entity with distinct

diagnostic and therapeutic considerations. Approximately

10 % of pancreatic cancer has a familial basis, and family

history of pancreatic cancer significantly increases an

individual’s risk of developing pancreatic cancer [32, 33].

Increased risk of pancreatic cancer is a feature of several

genetic syndromes, but the genetic basis for the majority

of familial pancreatic cancer remains unknown [32].

Several germline alterations predispose patients to pan-

creatic ductal adenocarcinoma. Germline mutations in

BRCA2 and its interacting protein PALB2 result in

increased risk of pancreatic cancer [34–36]. Importantly,

these genetic defects result in exquisite sensitivity to

therapies that target their specific DNA repair defect, such

as PARP inhibitors and mitomycin C [32, 37]. Therefore,

knowledge of the genetic alterations underlying a patient’s

familial pancreatic cancer is crucial for therapeutic deci-

sion making. Other germline genetic alterations that pre-

dispose to pancreatic cancer include mutations in P16/

CDKN2A (familial atypical mole and melanoma syn-

drome, leading to increased risk of melanoma and pan-

creatic cancer), STK11/LKB1 (Peutz Jeghers syndrome,

leading to hamartomatous gastrointestinal polyps as well

as increased cancer risk), PRSS1 and SPINK1 (hereditary

pancreatitis, leading to a markedly increased risk of

pancreatic cancer), and ATM [38–50]. Although these

syndromes do not yet require specific targeted therapies,

the increased risk of pancreatic cancer in these patients

carries definite implications for screening and early

diagnosis.

3 Cystic Neoplasms of the Pancreas

The category of cystic pancreatic neoplasms contains a

variety of entities with strikingly different clinical out-

comes. Some neoplasms, such as intraductal papillary

mucinous neoplasms (IPMNs) and mucinous cystic neo-

plasms (MCNs), are known precursors of pancreatic can-

cer. These neoplasms are curable if resected early but can

progress to deadly pancreatic cancer if not treated in a

timely manner. In sharp contrast, serous cystadenomas

(SCAs) are another cystic pancreatic neoplasm, but these

neoplasms are benign, and, aside from exceedingly rare

cases reported in the literature, never progress to carci-

noma. Solid pseudopapillary neoplasms (SPNs) are another

pancreatic neoplasm that can be cystic—these are consid-

ered low-grade malignant neoplasms, and, while most are

cured by resection, some progress to metastatic disease. In

addition to their unique clinical features, each of these

neoplasms possesses distinct somatic genetic alterations.

3.1 Molecular Genetics

3.1.1 Intraductal Papillary Mucinous Neoplasms

IPMNs contain frequent alterations in genes commonly

mutated in ductal adenocarcinoma (Table 1). Approxi-

mately 80 % of IPMNs harbor mutations in the KRAS

oncogene [51]. Loss of p16 expression occurs in both IP-

MNs and IPMN-associated cancers, but this loss is much

more prevalent in invasive carcinomas compared to non-

invasive IPMNs [52]. Somatic mutations in TP53 as well as

p53 overexpression have been reported in noninvasive

IPMNs but are most prevalent in IPMNs with high-grade

dysplasia [53–56]. Although Smad4 expression is retained

in the vast majority of noninvasive IPMNs, this expression

is lost in approximately one third of IPMN-associated

carcinomas [52, 57].

In addition to these genetic alterations shared with

ductal adenocarcinoma, IPMNs also contain mutations in

unique genes. Somatic mutations in GNAS occur in

approximately 60 % of IPMNs [51, 58]. Intriguingly, these

mutations all occur at an oncogenic hotspot (codon 201)

that has been previously described in other nonpancreatic

neoplasms. Although GNAS mutations have been identified

in IPMNs with low-grade, intermediate-, and high-grade

dysplasia, the prevalence of GNAS mutations increases

with degree of dysplasia, and these mutations are also

present in IPMN-associated invasive adenocarcinoma [51].

Specifically, in one study, GNAS mutations were identified

in 11 % of IPMNs with low-grade dysplasia, 34 % of IP-

MNs with intermediate-grade dysplasia, 42 % of IPMNs

with high-grade dysplasia, and 69 % of IPMNs with

associated adenocarcinoma, and the GNAS mutations were

almost always shared between the IPMNs and associated

adenocarcinomas [51]. Approximately 75 % of IPMNs

contain mutations in the RNF43 gene, the majority of

which are loss-of-function nonsense mutations [59]. The

prevalence of loss-of-function mutations as well as fre-

quent loss of heterozygosity at the RNF43 locus on chro-

mosome 17q provides strong evidence that this gene

functions as a tumor suppressor. In addition, approximately

10 % of IPMNs contain somatic mutations at previously

described oncogenic hotspots in PIK3CA [56, 60, 61], and

approximately 5 % of sporadic IPMNs contain somatic

alterations in STK11/LKB1 [62]. Thus, although IPMNs

share some genetic features with ductal adenocarcinoma,

they are in many ways genetically distinct from this neo-

plasm. They contain somatic mutations in a smaller num-

ber of total genes; whole-exome sequencing identified an

average of 26 nonsynonymous mutations per IPMN,

approximately half as many as in ductal adenocarcinoma

[59].

290 L. D. Wood

3.1.2 Mucinous Cystic Neoplasms

Like IPMNs, MCNs contain frequent alterations in genes

commonly mutated in pancreatic ductal adenocarcinoma

(Table 1), including KRAS, P16/CDKN2A, TP53, and

SMAD4/DPC4 [63–69]; these studies suggest that KRAS

mutation is an early event in the development of MCNs,

while Smad4 loss is a late event. In addition to these genes

shared with ductal adenocarcinoma, MCNs also contain

somatic mutations in genes unique to mucin-producing

cystic neoplasms—approximately 40 % of MCNs harbor

somatic mutations in RNF43 [59]. Mutations in RNF43 are

unique to IPMNs and MCNs, and do not occur in any other

pancreatic neoplasm studied to date. Whole-exome

sequencing revealed that MCNs contain fewer somatic

mutations than IPMNs and ductal adenocarcinomas—each

MCN contained an average of 16 nonsynonymous somatic

mutations [59].

3.1.3 Serous Cystadenomas

Unlike IPMNs and MCNs, SCAs lack mutations in the

genes frequently altered in ductal adenocarcinoma (KRAS,

P16/CDK2NA, TP53, and SMAD4/DPC4) [59, 65, 70, 71].

SCAs contain frequent somatic mutations in the VHL gene,

which have been reported in as many as 50 % of sporadic

SCAs (Table 1) [59, 70, 72]. Germline mutations of the

VHL gene result in von Hippel–Lindau syndrome, an

autosomal dominant neoplastic predisposition syndrome

that is characterized in part by frequent SCAs of the pan-

creas [1, 2]. In addition to somatic mutation, loss of het-

erozygosity at the VHL locus on chromosome 3p occurs in

a large proportion of sporadic SCAs [65, 72]. Recurrent

losses of other chromosomal regions, most frequently

chromosome 10p, have also been reported in SCAs, but the

target genes for these losses remain to be determined [70].

Whole-exome sequencing of SCAs identified an average of

ten nonsynonymous somatic mutations per neoplasm,

fewer than in MCNs, IPMNs, or invasive ductal adeno-

carcinoma [59]. This illustrates the correlation between the

number of somatic mutations and biologic potential of

pancreatic neoplasms, with the highest number of somatic

mutations in malignant neoplasms such as ductal adeno-

carcinoma and progressively fewer mutations in prema-

lignant and benign neoplasms.

3.1.4 Solid Pseudopapillary Neoplasms

SPNs lack alterations in genes commonly mutated in

pancreatic ductal adenocarcinoma (KRAS, P16/CDKN2A,

TP53, SMAD4/DPC4), as well as those mutated in other

cystic neoplasms of the pancreas (GNAS, RNF43, VHL)

[59, 73, 74]. SPNs contain frequent mutations in the b-

catenin gene (CTNNB1); activating mutations in this gene,

leading to nuclear accumulation of b-catenin protein, occur

in more than 95 % of SPNs (Table 1) [59, 73, 75–77].

Ductal adenocarcinomas as well as other cystic pancreatic

neoplasms (IPMNs, MCNs, SCAs) lack mutations in

CTNNB1; therefore, these mutations specifically distin-

guish SPNs from other pancreatic neoplasms. Intriguingly,

whole-exome sequencing of SPNs revealed an average of

only three nonsynonymous somatic mutations per SPN,

and only CTNNB1 was mutated in more than one SPN [59].

3.2 Diagnostic and Therapeutic Implications

Cystic neoplasms of the pancreas represent a key diag-

nostic dilemma. Each year, approximately 70 million

computed tomography scans are performed in the United

States, and in one study approximately 2.5 % of asymp-

tomatic patients had a pancreatic cyst [78]. Because some

of these cysts represent malignant or premalignant neo-

plasms requiring surgical resection (SPN, IPMN, MCN),

while others represent benign neoplasms that require no

surgical treatment (SCA), preoperative classification of

pancreatic cysts is a crucial clinical question. This dis-

tinction would allow resection of dangerous precursors,

curing patients before they develop invasive adenocarci-

noma, and would also avoid surgery and its potential

complications in patients with benign cysts. Current tech-

niques used to analyze pancreatic cysts, including endo-

scopic ultrasound (EUS) morphology, cytology, and

chemical analysis of cyst fluid, lack adequate diagnostic

accuracy—the accuracy of EUS morphology and cytology

is only approximately 50 % and that of cyst fluid carci-

noembryonic antigen is only approximately 80 % [79].

Therefore, molecular analysis of pancreatic cyst fluid rep-

resents a promising tool for improved preoperative diag-

nosis, because mutations from neoplastic cells can be

efficiently detected in cyst fluid [51, 80]. Considering that

more than 95 % of IPMNs contain a somatic mutation in

either KRAS or GNAS, a molecular assay for mutations in

these two genes would be a highly sensitive assay for the

identification of IPMNs, the most common premalignant

pancreatic cyst [51]. Moreover, the lack of KRAS and

GNAS mutations in SCAs and SPNs demonstrates that

assays for these mutations are also specific for premalig-

nant pancreatic cysts [51, 59]. Independent studies have

shown that KRAS mutation followed by allelic loss has

sensitivity and specificity [90 % in the diagnosis of

mucinous cysts, and the presence of KRAS mutations

identified malignancies that were missed by cytologic

evaluation [81, 82]. In addition, although they have not

been specifically validated in studies of clinical cyst fluid

samples, genetic data suggest that the addition of assays for

RNF43, VHL, and CTNNB1 could further improve the

Pancreatic Cancer Genomes 291

diagnostic accuracy of cyst fluid analyses in the classifi-

cation of cystic neoplasms of the pancreas [59]. Moreover,

because the prevalence of GNAS mutations increases with

degree of dysplasia, identification of these mutations could

help to identify IPMNs with a higher risk of malignant

transformation [51]. Importantly, until their sensitivities

and specificities have been extensively validated in clinical

specimens, these molecular techniques should be used as

an adjunct to, rather than a replacement for, currently

employed cyst fluid analysis techniques.

4 Pancreatic Neuroendocrine Tumors

Pancreatic neuroendocrine tumors (PanNETs) are uncom-

mon pancreatic neoplasms with differentiation resembling

the endocrine compartment of the pancreas, accounting for

1–2 % of all pancreatic neoplasms [1]. They are classified

as well-differentiated PanNETs or high-grade neuroendo-

crine carcinomas, the latter being very rare and accounting

for \1 % of pancreatic carcinomas and 2–3 % of pancre-

atic neuroendocrine tumors [1]. Although prognosis varies

based on size, grade, and stage, all PanNETs except tiny

microadenomas are regarded as having malignant potential

[1]. Although not as aggressive as ductal adenocarcinomas,

the 5-year survival for even well-differentiated PanNETs is

only 65 %, and high-grade neuroendocrine carcinomas

have a mortality of almost 100 % [1].

4.1 Molecular Genetics

PanNETs are genetically distinct from other pancreatic

neoplasms (Table 1). Somatic mutations in MEN1 occur in

approximately 45 % of sporadic PanNETs, and loss of

heterozygosity at this locus is also common [83–88].

Germline mutations in the MEN1 gene on chromosome 11q

cause multiple endocrine neoplasia syndrome, type 1

(MEN1), a clinical syndrome characterized by neuroen-

docrine neoplasms in multiple organs, including the pan-

creas [89]. PanNETs also contain frequent inactivating

somatic mutations in DAXX and ATRX, genes whose pro-

tein products function in a chromatin remodeling com-

plex—mutations in these genes are mutually exclusive and

occur in a total of 45 % of PanNETs [83]. The proteins

encoded by DAXX and ATRX are part of a complex that

plays a key role in telomere maintenance, and mutational

inactivation of these genes in PanNETs is associated with

the alternative lengthening of telomeres (ALT) phenotype,

a telomerase-independent mechanism of telomere mainte-

nance [90]. The prevalence of the ALT phenotype in

PanNETs highlights a fundamental difference from ductal

adenocarcinomas, which exhibit telomere shortening and

reactivation of telomerase [23, 91]. Mutations in DAXX and

ATRX, and thus the ALT phenotype, are late events in the

development of PanNETs, because they occur only in large

tumors ([3 cm) and are absent from microadenomas [92].

A subset of PanNETs contain alterations in components of

a specific cell signaling pathway—approximately 15 % of

sporadic PanNETs have alterations in components of the

mammalian target of rapamycin (mTOR) pathway

(including PIK3CA, PTEN, and TSC2) [83]. In addition to

these somatic mutations, loss of heterozygosity at the TSC2

locus on chromosome 16p is a frequent occurrence in

sporadic PanNETs, and was reported in 30 % of cases in

one study [93].

Whole-exome sequencing of PanNETs revealed fewer

somatic alterations than in ductal adenocarcinoma—each

PanNET contained an average of 16 nonsynonymous

somatic mutations [83]. Although rare alterations in some

genes have been reported, PanNETs lack frequent muta-

tions in the commonly altered genes in ductal adenocar-

cinoma, including KRAS, P16/CDKN2A, TP53, and

SMAD4/DPC4 [74, 83]. No mutations in KRAS, SMAD4/

DPC4, or P16/CDKN2A have been identified in PanNETs,

and mutations in TP53 occur in only approximately 3 % of

PanNETs [83, 94]. No mutations have been reported in

PanNETs in genes frequently altered in cystic neoplasms,

including GNAS, RNF43, and CTNNB1, although promoter

methylation and deletion of VHL occurs in up to 25 % of

sporadic PanNETs [95]. These findings highlight that, in

addition to their unique morphology and clinical features,

PanNETs are genetically unique from other pancreatic

neoplasms.

4.2 Diagnostic and Therapeutic Implications

Somatic alterations in PanNETs have prognostic and

therapeutic implications. Somatic mutations in MEN1 and

ATRX/DAXX are associated with improved prognosis—

patients with mutations in both pathways had a median

survival of 13.0 years, compared to 5.2 years for patients

without mutations in either pathway [83]. Alterations in the

mTOR pathway may carry profound therapeutic signifi-

cance, because drugs targeting this pathway have already

been developed for clinical use and may be specifically

efficacious against tumors with somatic mutations in

mTOR pathway components [96]. Although studies on

these mutations to date have utilized tumor tissue from

resection specimens, the rapid improvement of genetic

techniques for analysis of plasma suggests that mutations

in key pathways could be identified in plasma as well as

tumor samples. Future trials of these drugs in PanNETs

should incorporate mutation status (as assayed in tumor

tissue or possibly patient plasma) into their analyses of

therapeutic efficacy.

292 L. D. Wood

5 Other Rare Pancreatic Neoplasms

Acinar cell carcinoma and pancreatoblastoma are both rare

pancreatic neoplasms that exhibit acinar differentiation, but

they occur in very different clinical situations. Acinar cell

carcinomas occur mostly in older adults with a male pre-

dominance and have a relatively poor prognosis, with a

5-year survival of only 25 % [1]. In contrast, pancreat-

oblastomas mostly occur in children less than 10 years old

and account for 25 % of pancreatic neoplasms in the first

decade of life—the prognosis is poor with overall survival

of only 50 % [1, 97]. In both neoplasms, pathologic stage is

the best predictor of survival.

5.1 Molecular Genetics

5.1.1 Acinar Cell Carcinoma

Acinar cell carcinomas are characterized by striking

genomic instability—a subset exhibit microsatellite insta-

bility, leading to the accumulation of numerous missense

mutations [98]. In addition, most acinar cell carcinomas

show chromosomal instability, with numerous chromo-

somal gains and losses [99–101]. This genomic instability

complicates the identification of mutations that drive

tumorigenesis in acinar cell carcinoma. However, the APC/

b-catenin pathway likely plays a crucial role, because

somatic alterations in this pathway are present in 20–25 %

of acinar cell carcinomas, including inactivating mutations

in APC as well as activating mutations in CTNNB1

(Table 1) [99–101]. Although acinar cell carcinomas lack

frequent alterations in genes commonly mutated in ductal

adenocarcinoma, rare mutations in TP53, SMAD4/DPC4,

and KRAS have been reported [74, 98, 100, 102–104].

5.1.2 Pancreatoblastoma

The majority of pancreatoblastomas have somatic inactiva-

tion of the APC/b-catenin pathway with somatic mutation of

APC or CTNNB1 (Table 1) [105]. In addition, pancreatobl-

astomas frequently show allelic loss of chromosome 11p.

This allelic loss has been reported in other embryonal tumors

such as hepatoblastoma and Wilm’s tumor, suggesting the

possibility of a common genetic pathway in embryonal

tumors [105, 106]. Pancreatoblastomas lack frequent alter-

ations in genes commonly mutated in ductal adenocarci-

noma, including KRAS, TP53, and SMAD4/DPC4 (although

rare loss of Smad4 expression has been reported) [105].

5.2 Diagnostic and Therapeutic Implications

Because acinar cell carcinoma and pancreatoblastoma are

rare neoplasms, less is known about their underlying genetic

alterations than other neoplasms in the pancreas. However,

with the data available, it is clear that each of these is a

genetically distinct entity, paralleling their clinical and

morphological separation from other pancreatic neoplasms.

6 Conclusions

The neoplasms of the pancreas encompass a broad range of

clinical entities, from benign tumors to deadly cancers.

These neoplasms have been extensively characterized on the

genomic level, leading to profound insights into their

underlying biology as well as novel approaches to diagnosis

and treatment. As we enter the era of genomic medicine,

analysis of molecular alterations in pancreatic neoplasms

will likely become part of the standard of care, and the results

will be used to guide treatment and follow-up. Moreover,

molecular diagnostic tests for pancreatic neoplasms are also

likely to be developed, leading to earlier diagnosis and pre-

operative classification of pancreatic neoplasms. Rather than

remaining in the domain of basic science, molecular analyses

will become part of everyday workflow for surgeons, on-

cologists, gastroenterologists, and pathologists, leading to

diagnosis and treatment based on the specific genetic alter-

ations in an individual patient’s tumor.

Acknowledgments The author has no conflicts of interest that are

directly relevant to the content of this article.

References

1. Bosman FT, Carneiro F, Hruban RH, Theise ND. WHO Clas-

sification of Tumours of the Digestive System. 4th ed. World

Health Organization Classification of Tumours. Lyon: Interna-

tional Agency for Research on Cancer; 2010.

2. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas.

Fourth Series, Fascicle 6 ed. AFIP Atlas of Tumor Pathology.

Washington, D.C.: American Registry of Pathology; 2007.

3. Smit VT, Boot AJ, Smits AM, Fleuren GJ, Cornelisse CJ, Bos JL.

KRAS codon 12 mutations occur very frequently in pancreatic

adenocarcinomas. Nucleic Acids Res. 1988;16(16):7773–82.

4. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N,

Perucho M. Most human carcinomas of the exocrine pancreas

contain mutant c-K-ras genes. Cell. 1988;53(4):549–54.

5. Caldas C, Kern SE. K-ras mutation and pancreatic adenocarci-

noma. Int J Pancreatol. 1995;18(1):1–6.

6. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P,

et al. Core signaling pathways in human pancreatic cancers

revealed by global genomic analyses. Science. 2008;321

(5897):1801–6. doi:10.1126/science.1164368.

7. Pellegata NS, Sessa F, Renault B, Bonato M, Leone BE, Solcia

E, et al. K-ras and p53 gene mutations in pancreatic cancer:

ductal and nonductal tumors progress through different genetic

lesions. Cancer Res. 1994;54(6):1556–60.

8. Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH,

Allison DC, Goodman SN, et al. K-ras oncogene activation in

adenocarcinoma of the human pancreas. A study of 82 carci-

nomas using a combination of mutant-enriched polymerase

Pancreatic Cancer Genomes 293

chain reaction analysis and allele-specific oligonucleotide

hybridization. Am J Pathol. 1993;143(2):545–54.

9. Maitra A, Hruban RH. Pancreatic cancer. Annu Rev Pathol.

2008;3:157–88. doi:10.1146/annurev.pathmechdis.3.121806.

154305.

10. Attri J, Srinivasan R, Majumdar S, Radotra BD, Wig J. Alter-

ations of tumor suppressor gene p16INK4a in pancreatic ductal

carcinoma. BMC Gastroenterol. 2005;5:22. doi:10.1186/1471-

230x-5-22.

11. Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M,

Seymour AB, et al. Frequent somatic mutations and homozygous

deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

Nat Genet. 1994;8(1):27–32. doi:10.1038/ng0994-27.

12. Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W,

Rabindran SK, et al. Abrogation of the Rb/p16 tumor-suppres-

sive pathway in virtually all pancreatic carcinomas. Cancer Res.

1997;57(15):3126–30.

13. Hahn SA, Hoque AT, Moskaluk CA, da Costa LT, Schutte M,

Rozenblum E, et al. Homozygous deletion map at 18q21.1 in

pancreatic cancer. Cancer Res. 1996;56(3):490–4.

14. Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT,

Rozenblum E, et al. DPC4, a candidate tumor suppressor gene at

human chromosome 18q21.1. Science. 1996;271(5247):350–3.

15. Lohr M, Kloppel G, Maisonneuve P, Lowenfels AB, Luttges J.

Frequency of K-ras mutations in pancreatic intraductal neopla-

sias associated with pancreatic ductal adenocarcinoma and

chronic pancreatitis: a meta-analysis. Neoplasia. 2005;7(1):

17–23. doi:10.1593/neo.04445.

16. Goggins M, Hruban RH, Kern SE. BRCA2 is inactivated late in

the development of pancreatic intraepithelial neoplasia: evi-

dence and implications. Am J Pathol. 2000;156(5):1767–71. doi:

10.1016/s0002-9440(10)65047-x.

17. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene

mutations in the intraductal precursors of human pancreatic

adenocarcinoma. Cancer Res. 1997;57(11):2140–3.

18. Shi C, Hong SM, Lim P, Kamiyama H, Khan M, Anders RA,

et al. KRAS2 mutations in human pancreatic acinar-ductal

metaplastic lesions are limited to those with PanIN: implications

for the human pancreatic cancer cell of origin. Mol Cancer Res.

2009;7(2):230–6. doi:10.1158/1541-7786.mcr-08-0206.

19. Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De

Marzo A, Cameron JL, et al. Multicomponent analysis of the

pancreatic adenocarcinoma progression model using a pancre-

atic intraepithelial neoplasia tissue microarray. Mod Pathol.

2003;16(9):902–12. doi:10.1097/01.mp.0000086072.56290.fb.

20. Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M,

Goggins M, et al. Inactivation of the p16 (INK4A) tumor-sup-

pressor gene in pancreatic duct lesions: loss of intranuclear

expression. Cancer Res. 1998;58(20):4740–4.

21. Kanda M, Matthaei H, Wu J, Hong SM, Yu J, Borges M, et al.

Presence of somatic mutations in most early-stage pancreatic

intraepithelial neoplasia. Gastroenterology. 2012;142(4):730–3

e9. doi:10.1053/j.gastro.2011.12.042.

22. Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM,

Parsons JL, Yeo CJ, et al. Loss of expression of Dpc4 in pan-

creatic intraepithelial neoplasia: evidence that DPC4 inactiva-

tion occurs late in neoplastic progression. Cancer Res.

2000;60(7):2002–6.

23. van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD,

Cameron JL, et al. Telomere shortening is nearly universal in

pancreatic intraepithelial neoplasia. Am J Pathol. 2002;

161(5):1541–7. doi:10.1016/s0002-9440(10)64432-x.

24. Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ,

Weiss GJ, et al. Genome-wide characterization of pancreatic

adenocarcinoma patients using next generation sequencing. PloS

ONE. 2012;7(10):e43192. doi:10.1371/journal.pone.0043192.

25. Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthusw-

amy LB, Johns AL, et al. Pancreatic cancer genomes reveal

aberrations in axon guidance pathway genes. Nature.

2012;491(7424):399–405. doi:10.1038/nature11547.

26. Shi C, Fukushima N, Abe T, Bian Y, Hua L, Wendelburg BJ,

et al. Sensitive and quantitative detection of KRAS2 gene

mutations in pancreatic duct juice differentiates patients with

pancreatic cancer from chronic pancreatitis, potential for early

detection. Cancer Biol Therapy. 2008;7(3):353–60.

27. van Heek T, Rader AE, Offerhaus GJ, McCarthy DM, Goggins

M, Hruban RH, et al. K-ras, p53, and DPC4 (MAD4) alterations

in fine-needle aspirates of the pancreas: a molecular panel cor-

relates with and supplements cytologic diagnosis. Am J Clin

Pathol. 2002;117(5):755–65. doi:10.1309/5rq0-jcqu-5xf2-51lq.

28. Tascilar M, Offerhaus GJ, Altink R, Argani P, Sohn TA, Yeo

CJ, et al. Immunohistochemical labeling for the Dpc4 gene

product is a specific marker for adenocarcinoma in biopsy

specimens of the pancreas and bile duct. Am J Clin Pathol.

2001;116(6):831–7. doi:10.1309/wf03-nfce-7brh-7c26.

29. Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA,

et al. Immunohistochemical labeling for dpc4 mirrors genetic

status in pancreatic adenocarcinomas: a new marker of DPC4

inactivation. Am J Pathol. 2000;156(1):37–43. doi:10.1016/

s0002-9440(10)64703-7.

30. Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S,

Zhang X, et al. SMAD4 gene mutations are associated with poor

prognosis in pancreatic cancer. Clin Cancer Res. 2009;

15(14):4674–9. doi:10.1158/1078-0432.ccr-09-0227.

31. Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B, et al.

Distant metastasis occurs late during the genetic evolution of

pancreatic cancer. Nature. 2010;467(7319):1114–7. doi:10.

1038/nature09515.

32. Hruban RH, Canto MI, Goggins M, Schulick R, Klein AP. Update

on familial pancreatic cancer. Adv Surg. 2010;44:293–311.

33. Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC,

Offerhaus GJ, et al. Prospective risk of pancreatic cancer in

familial pancreatic cancer kindreds. Cancer Res. 2004;64(7):

2634–8.

34. Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B,

et al. BRCA2 germline mutations in familial pancreatic carci-

noma. J Natl Cancer Inst. 2003;95(3):214–21.

35. Couch FJ, Johnson MR, Rabe KG, Brune K, de Andrade M,

Goggins M, et al. The prevalence of BRCA2 mutations in

familial pancreatic cancer. Cancer Epidemiol Biomarkers Prev.

2007;16(2):342–6. doi:10.1158/1055-9965.epi-06-0783.

36. Jones S, Hruban RH, Kamiyama M, Borges M, Zhang X, Par-

sons DW, et al. Exomic sequencing identifies PALB2 as a

pancreatic cancer susceptibility gene. Science. 2009;324(5924):

217. doi:10.1126/science.1171202.

37. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M,

et al. Inhibition of poly(ADP-ribose) polymerase in tumors from

BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.

doi:10.1056/NEJMoa0900212.

38. Whelan AJ, Bartsch D, Goodfellow PJ. Brief report: a familial

syndrome of pancreatic cancer and melanoma with a mutation in

the CDKN2 tumor-suppressor gene. N Engl J Med. 1995;

333(15):975–7. doi:10.1056/nejm199510123331505.

39. Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ra-

nade K, Zametkin DP, et al. Increased risk of pancreatic cancer

in melanoma-prone kindreds with p16INK4 mutations. N Engl J

Med. 1995;333(15):970–4. doi:10.1056/nejm199510123331504.

40. de Snoo FA, Bishop DT, Bergman W, van Leeuwen I, van der

Drift C, van Nieuwpoort FA, et al. Increased risk of cancer other

than melanoma in CDKN2A founder mutation (p16-Leiden)-

positive melanoma families. Clin Cancer Res. 2008;14(21):

7151–7. doi:10.1158/1078-0432.ccr-08-0403.

294 L. D. Wood

41. McWilliams RR, Wieben ED, Rabe KG, Pedersen KS, Wu Y,

Sicotte H, et al. Prevalence of CDKN2A mutations in pancreatic

cancer patients: implications for genetic counseling. Eur J Hum

Genet. 2011;19(4):472–8. doi:10.1038/ejhg.2010.198.

42. Bartsch DK, Sina-Frey M, Lang S, Wild A, Gerdes B, Barth P,

et al. CDKN2A germline mutations in familial pancreatic can-

cer. Ann Surg. 2002;236(6):730–7. doi:10.1097/01.sla.00000

36393.89509.4e.

43. Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittel-

sohn AM, Booker SV, et al. Increased risk of cancer in the

Peutz–Jeghers syndrome. N Engl J Med. 1987;316(24):1511–4.

doi:10.1056/nejm198706113162404.

44. Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher

MC, et al. Germline and somatic mutations of the STK11/LKB1

Peutz–Jeghers gene in pancreatic and biliary cancers. Am J

Pathol. 1999;154(6):1835–40. doi:10.1016/s0002-9440(10)654

40-5.

45. Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer

MJ, Ulrich CD, et al. Hereditary pancreatitis is caused by a

mutation in the cationic trypsinogen gene. Nat Genet.

1996;14(2):141–5. doi:10.1038/ng1096-141.

46. Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, et al.

Mutations in the gene encoding the serine protease inhibitor,

Kazal type 1 are associated with chronic pancreatitis. Nat Genet.

2000;25(2):213–6. doi:10.1038/76088.

47. de las Heras-Castano G, Castro-Senosiain B, Fontalba A, Lopez-

Hoyos M, Sanchez-Juan P. Hereditary pancreatitis: clinical

features and inheritance characteristics of the R122C mutation

in the cationic trypsinogen gene (PRSS1) in six Spanish fami-

lies. JOP. 2009;10(3):249–55.

48. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW,

Lankisch PG, Andersen JR, et al. Pancreatitis and the risk of

pancreatic cancer. International Pancreatitis Study Group.

N Engl J Med. 1993;328(20):1433–7. doi:10.1056/nejm19

9305203282001.

49. Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates

LK Jr, Perrault J, et al. Hereditary pancreatitis and the risk of

pancreatic cancer. International Hereditary Pancreatitis Study

Group. J Natl Cancer Inst. 1997;89(6):442–6.

50. Roberts NJ, Jiao Y, Yu J, Kopelovich L, Petersen GM, Bondy

ML, et al. ATM mutations in patients with hereditary pancreatic

cancer. Cancer Discov. 2012;2(1):41–6. doi:10.1158/2159-8290.

cd-11-0194.

51. Wu J, Matthaei H, Maitra A, Dal Molin M, Wood LD, Eshleman

JR, et al. Recurrent GNAS mutations define an unexpected

pathway for pancreatic cyst development. Sci Transl Med.

2011;3(92):92ra66. doi:10.1126/scitranslmed.3002543.

52. Biankin AV, Biankin SA, Kench JG, Morey AL, Lee CS, Head

DR, et al. Aberrant p16(INK4A) and DPC4/Smad4 expression

in intraductal papillary mucinous tumours of the pancreas is

associated with invasive ductal adenocarcinoma. Gut.

2002;50(6):861–8.

53. Kawahira H, Kobayashi S, Kaneko K, Asano T, Ochiai T. p53

protein expression in intraductal papillary mucinous tumors

(IPMT) of the pancreas as an indicator of tumor malignancy.

Hepatogastroenterology. 2000;47(34):973–7.

54. Satoh K, Shimosegawa T, Moriizumi S, Koizumi M, Toyota T.

K-ras mutation and p53 protein accumulation in intraductal

mucin-hypersecreting neoplasms of the pancreas. Pancreas.

1996;12(4):362–8.

55. Chadwick B, Willmore-Payne C, Tripp S, Layfield LJ, Hir-

schowitz S, Holden J. Histologic, immunohistochemical, and

molecular classification of 52 IPMNs of the pancreas. Appl

Immunohistochem Mol Morphol. 2009;17(1):31–9. doi:

10.1097/PAI.0b013e31817c02c6.

56. Lubezky N, Ben-Haim M, Marmor S, Brazowsky E, Rechavi G,

Klausner JM, et al. High-throughput mutation profiling in

intraductal papillary mucinous neoplasm (IPMN). J Gastrointest

Surg. 2011;15(3):503–11. doi:10.1007/s11605-010-1411-8.

57. Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE,

Argani P, Sohn TA, et al. Dpc-4 protein is expressed in virtually

all human intraductal papillary mucinous neoplasms of the

pancreas: comparison with conventional ductal adenocarcino-

mas. Am J Pathol. 2000;157(3):755–61. doi:10.1016/s0002-

9440(10)64589-0.

58. Furukawa T, Kuboki Y, Tanji E, Yoshida S, Hatori T, Ya-

mamoto M, et al. Whole-exome sequencing uncovers frequent

GNAS mutations in intraductal papillary mucinous neoplasms of

the pancreas. Sci Rep. 2011;1:161. doi:10.1038/srep00161.

59. Wu J, Jiao Y, Dal Molin M, Maitra A, de Wilde RF, Wood LD,

et al. Whole-exome sequencing of neoplastic cysts of the pan-

creas reveals recurrent mutations in components of ubiquitin-

dependent pathways. Proc Natl Acad Sci USA. 2011;

108(52):21188–93. doi:10.1073/pnas.1118046108.

60. Schonleben F, Allendorf JD, Qiu W, Li X, Ho DJ, Ciau NT,

et al. Mutational analyses of multiple oncogenic pathways in

intraductal papillary mucinous neoplasms of the pancreas.

Pancreas. 2008;36(2):168–72. doi:10.1097/MPA.0b013e3181

58a4d2.

61. Schonleben F, Qiu W, Remotti HE, Hohenberger W, Su GH.

PIK3CA, KRAS, and BRAF mutations in intraductal papillary

mucinous neoplasm/carcinoma (IPMN/C) of the pancreas.

Langenbecks Arch Surg. 2008;393(3):289–96. doi:10.1007/

s00423-008-0285-7.

62. Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, et al.

STK11/LKB1 Peutz–Jeghers gene inactivation in intraductal

papillary-mucinous neoplasms of the pancreas. Am J Pathol.

2001;159(6):2017–22. doi:10.1016/s0002-9440(10)63053-2.

63. Yanagisawa A, Kato Y, Ohtake K, Kitagawa T, Ohashi K, Hori

M, et al. c-Ki-ras point mutations in ductectatic-type mucinous

cystic neoplasms of the pancreas. Jpn J Cancer Res.

1991;82(10):1057–60.

64. Jimenez RE, Warshaw AL, Z’Graggen K, Hartwig W, Taylor

DZ, Compton CC, et al. Sequential accumulation of K-ras

mutations and p53 overexpression in the progression of pan-

creatic mucinous cystic neoplasms to malignancy. Ann Surg.

1999;230(4):501–9 (discussion 9–11).

65. Kim SG, Wu TT, Lee JH, Yun YK, Issa JP, Hamilton SR, et al.

Comparison of epigenetic and genetic alterations in mucinous

cystic neoplasm and serous microcystic adenoma of pancreas.

Mod Pathol. 2003;16(11):1086–94. doi:10.1097/01.mp.000009

4088.37888.a6.

66. Yoshizawa K, Nagai H, Sakurai S, Hironaka M, Morinaga S,

Saitoh K, et al. Clonality and K-ras mutation analyses of epi-

thelia in intraductal papillary mucinous tumor and mucinous

cystic tumor of the pancreas. Virchows Arch. 2002;

441(5):437–43. doi:10.1007/s00428-002-0645-6.

67. Sorio C, Capelli P, Lissandrini D, Moore PS, Balzarini P, Falconi

M, et al. Mucinous cystic carcinoma of the pancreas: a unique

cell line and xenograft model of a preinvasive lesion. Virchows

Arch. 2005;446(3):239–45. doi:10.1007/s00428-004-1167-1.

68. Luttges J, Feyerabend B, Buchelt T, Pacena M, Kloppel G. The

mucin profile of noninvasive and invasive mucinous cystic

neoplasms of the pancreas. Am J Surg Pathol. 2002;26(4):

466–71.

69. Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cam-

eron JL, Kern SE, et al. Dpc4 protein in mucinous cystic neo-

plasms of the pancreas: frequent loss of expression in invasive

carcinomas suggests a role in genetic progression. Am J Surg

Pathol. 2000;24(11):1544–8.

Pancreatic Cancer Genomes 295

70. Moore PS, Zamboni G, Brighenti A, Lissandrini D, Antonello D,

Capelli P, et al. Molecular characterization of pancreatic serous

microcystic adenomas: evidence for a tumor suppressor gene on

chromosome 10q. Am J Pathol. 2001;158(1):317–21. doi:

10.1016/s0002-9440(10)63971-5.

71. Ishikawa T, Nakao A, Nomoto S, Hosono J, Harada A, Nonami

T, et al. Immunohistochemical and molecular biological studies

of serous cystadenoma of the pancreas. Pancreas. 1998;16(1):

40–4.

72. Vortmeyer AO, Lubensky IA, Fogt F, Linehan WM, Khettry U,

Zhuang Z. Allelic deletion and mutation of the von Hippel–

Lindau (VHL) tumor suppressor gene in pancreatic microcystic

adenomas. Am J Pathol. 1997;151(4):951–6.

73. Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K,

Brennan M, et al. Solid-pseudopapillary tumors of the pancreas

are genetically distinct from pancreatic ductal adenocarcinomas

and almost always harbor beta-catenin mutations. Am J Pathol.

2002;160(4):1361–9.

74. Moore PS, Orlandini S, Zamboni G, Capelli P, Rigaud G, Fal-

coni M, et al. Pancreatic tumours: molecular pathways impli-

cated in ductal cancer are involved in ampullary but not in

exocrine nonductal or endocrine tumorigenesis. Br J Cancer.

2001;84(2):253–62. doi:10.1054/bjoc.2000.1567.

75. Min Kim S, Sun CD, Park KC, Kim HG, Lee WJ, Choi SH.

Accumulation of beta-catenin protein, mutations in exon-3 of

the beta-catenin gene and a loss of heterozygosity of 5q22 in

solid pseudopapillary tumor of the pancreas. J Surg Oncol.

2006;94(5):418–25. doi:10.1002/jso.20509.

76. Tanaka Y, Kato K, Notohara K, Hojo H, Ijiri R, Miyake T, et al.

Frequent beta-catenin mutation and cytoplasmic/nuclear accu-

mulation in pancreatic solid-pseudopapillary neoplasm. Cancer

Res. 2001;61(23):8401–4.

77. Audard V, Cavard C, Richa H, Infante M, Couvelard A, Sau-

vanet A, et al. Impaired E-cadherin expression and glutamine

synthetase overexpression in solid pseudopapillary neoplasm of

the pancreas. Pancreas. 2008;36(1):80–3. doi:10.1097/mpa.0b

013e318137a9da.

78. Laffan TA, Horton KM, Klein AP, Berlanstein B, Siegelman SS,

Kawamoto S, et al. Prevalence of unsuspected pancreatic cysts

on MDCT. Am J Roentgenol. 2008;191(3):802–7. doi:10.2214/

ajr.07.3340.

79. Brugge WR, Lewandrowski K, Lee-Lewandrowski E, Centeno

BA, Szydlo T, Regan S, et al. Diagnosis of pancreatic cystic

neoplasms: a report of the cooperative pancreatic cyst study.

Gastroenterology. 2004;126(5):1330–6.

80. Schoedel KE, Finkelstein SD, Ohori NP. K-Ras and microsat-

ellite marker analysis of fine-needle aspirates from intraductal

papillary mucinous neoplasms of the pancreas. Diagn Cytopa-

thol. 2006;34(9):605–8. doi:10.1002/dc.20511.

81. Khalid A, McGrath KM, Zahid M, Wilson M, Brody D, Swalsky

P, et al. The role of pancreatic cyst fluid molecular analysis in

predicting cyst pathology. Clin Gastroenterol Hepatol.

2005;3(10):967–73.

82. Khalid A, Zahid M, Finkelstein SD, LeBlanc JK, Kaushik N,

Ahmad N, et al. Pancreatic cyst fluid DNA analysis in evalu-

ating pancreatic cysts: a report of the PANDA study. Gastro-

intest Endosc. 2009;69(6):1095–102. doi:10.1016/j.gie.2008.

07.033.

83. Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A,

et al. DAXX/ATRX, MEN1, and mTOR pathway genes are

frequently altered in pancreatic neuroendocrine tumors. Science.

2011;331(6021):1199–203. doi:10.1126/science.1200609.

84. Hessman O, Lindberg D, Skogseid B, Carling T, Hellman P,

Rastad J, et al. Mutation of the multiple endocrine neoplasia

type 1 gene in nonfamilial, malignant tumors of the endocrine

pancreas. Cancer Res. 1998;58(3):377–9.

85. Gortz B, Roth J, Krahenmann A, de Krijger RR, Muletta-Feurer

S, Rutimann K, et al. Mutations and allelic deletions of the

MEN1 gene are associated with a subset of sporadic endocrine

pancreatic and neuroendocrine tumors and not restricted to

foregut neoplasms. Am J Pathol. 1999;154(2):429–36. doi:

10.1016/s0002-9440(10)65289-3.

86. Zhuang Z, Vortmeyer AO, Pack S, Huang S, Pham TA, Wang C,

et al. Somatic mutations of the MEN1 tumor suppressor gene in

sporadic gastrinomas and insulinomas. Cancer Res. 1997;

57(21):4682–6.

87. Toliat MR, Berger W, Ropers HH, Neuhaus P, Wiedenmann B.

Mutations in the MEN I gene in sporadic neuroendocrine

tumours of gastroenteropancreatic system. Lancet. 1997;

350(9086):1223. doi:10.1016/s0140-6736(05)63453-8.

88. Wang EH, Ebrahimi SA, Wu AY, Kashefi C, Passaro E Jr,

Sawicki MP. Mutation of the MENIN gene in sporadic pan-

creatic endocrine tumors. Cancer Res. 1998;58(19):4417–20.

89. Bassett JH, Forbes SA, Pannett AA, Lloyd SE, Christie PT,

Wooding C, et al. Characterization of mutations in patients with

multiple endocrine neoplasia type 1. Am J Hum Genet.

1998;62(2):232–44. doi:10.1086/301729.

90. Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C,

et al. Altered telomeres in tumors with ATRX and DAXX

mutations. Science. 2011;333(6041):425. doi:10.1126/science.

1207313.

91. Hiyama E, Kodama T, Shinbara K, Iwao T, Itoh M, Hiyama K,

et al. Telomerase activity is detected in pancreatic cancer but not

in benign tumors. Cancer Res. 1997;57(2):326–31.

92. de Wilde RF, Heaphy CM, Maitra A, Meeker AK, Edil BH,

Wolfgang CL, et al. Loss of ATRX or DAXX expression and

concomitant acquisition of the alternative lengthening of telo-

meres phenotype are late events in a small subset of MEN-1

syndrome pancreatic neuroendocrine tumors. Mod Pathol.

2012;. doi:10.1038/modpathol.2012.53.

93. Chung DC, Brown SB, Graeme-Cook F, Tillotson LG, Warshaw

AL, Jensen RT, et al. Localization of putative tumor suppressor

loci by genome-wide allelotyping in human pancreatic endo-

crine tumors. Cancer Res. 1998;58(16):3706–11.

94. Tannapfel A, Vomschloss S, Karhoff D, Markwarth A, Hengge

UR, Wittekind C, et al. BRAF gene mutations are rare events in

gastroenteropancreatic neuroendocrine tumors. Am J Clin

Pathol. 2005;123(2):256–60.

95. Schmitt AM, Schmid S, Rudolph T, Anlauf M, Prinz C, Kloppel

G, et al. VHL inactivation is an important pathway for the

development of malignant sporadic pancreatic endocrine

tumors. Endocr Relat Cancer. 2009;16(4):1219–27. doi:

10.1677/erc-08-0297.

96. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E,

et al. Everolimus for advanced pancreatic neuroendocrine

tumors. N Engl J Med. 2011;364(6):514–23. doi:10.1056/NEJM

oa1009290.

97. Klimstra DS, Wenig BM, Adair CF, Heffess CS. Pancreato-

blastoma. A clinicopathologic study and review of the literature.

Am J Surg Pathol. 1995;19(12):1371–89.

98. Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K,

et al. Genetic and immunohistochemical analysis of pancreatic

acinar cell carcinoma: frequent allelic loss on chromosome 11p

and alterations in the APC/beta-catenin pathway. Am J Pathol.

2002;160(3):953–62.

99. Taruscio D, Paradisi S, Zamboni G, Rigaud G, Falconi M,

Scarpa A. Pancreatic acinar carcinoma shows a distinct pattern

of chromosomal imbalances by comparative genomic hybrid-

ization. Genes Chromosomes Cancer. 2000;28(3):294–9.

100. Rigaud G, Moore PS, Zamboni G, Orlandini S, Taruscio D,

Paradisi S, et al. Allelotype of pancreatic acinar cell carcinoma.

Int J Cancer. 2000;88(5):772–7.

296 L. D. Wood

101. Dewald GW, Smyrk TC, Thorland EC, McWilliams RR, Van

Dyke DL, Keefe JG, et al. Fluorescence in situ hybridization to

visualize genetic abnormalities in interphase cells of acinar cell

carcinoma, ductal adenocarcinoma, and islet cell carcinoma of

the pancreas. Mayo Clin Proc. 2009;84(9):801–10. doi:

10.4065/84.9.801.

102. Hoorens A, Lemoine NR, McLellan E, Morohoshi T, Kamisawa

T, Heitz PU, et al. Pancreatic acinar cell carcinoma. An analysis

of cell lineage markers, p53 expression, and Ki-ras mutation.

Am J Pathol. 1993;143(3):685–98.

103. de Wilde RF, Ottenhof NA, Jansen M, Morsink FH, de Leng

WW, Offerhaus GJ, et al. Analysis of LKB1 mutations and other

molecular alterations in pancreatic acinar cell carcinoma. Mod

Pathol. 2011;24(9):1229–36. doi:10.1038/modpathol.2011.83.

104. Terhune PG, Memoli VA, Longnecker DS. Evaluation of p53

mutation in pancreatic acinar cell carcinomas of humans and

transgenic mice. Pancreas. 1998;16(1):6–12.

105. Abraham SC, Wu TT, Klimstra DS, Finn LS, Lee JH, Yeo CJ,

et al. Distinctive molecular genetic alterations in sporadic and

familial adenomatous polyposis-associated pancreatoblastomas:

frequent alterations in the APC/beta-catenin pathway and

chromosome 11p. Am J Pathol. 2001;159(5):1619–27.

106. Kerr NJ, Fukuzawa R, Reeve AE, Sullivan MJ. Beckwith–Wi-

edemann syndrome, pancreatoblastoma, and the wnt signaling

pathway. Am J Pathol. 2002;160(4):1541–2 (author reply 2).

Pancreatic Cancer Genomes 297