Molecular pathogenesis of exocrine pancreatic cancer (Uptodate, 2016)


Carcinoma of the exocrine pancreas is a genetic disease that is caused by inherited and acquired mutations in specific cancer-associated genes. The sequencing of the protein-coding exons from 20,661 genes in 24 advanced ductal adenocarcinomas of the pancreas provided the foundation for a more complete understanding of the key signaling pathways that are dysregulated in pancreatic tumorigenesis [1-3]. Progress in our understanding of the genes involved in the molecular pathogenesis of pancreatic cancer has provided insight into the familial aggregation of the disease, the progression of normal pancreatic ductal cells to noninvasive precursor lesions and to invasive carcinoma, and led to a new classification system of pancreatic neoplasms that encompasses both morphology and genetics [4-8].

As a general rule, multiple combinations of genetic mutations are commonly found in pancreatic adenocarcinomas [1-3]. These can be divided into three broad categories [9]:

  • Mutational activation of oncogenes such as KRAS
  • Inactivation of tumor suppressor genes such as TP53, p16/CDKN2A, and SMAD4
  • Inactivation of genome maintenance genes, such as hMLH1and MSH2, which control the repair of DNA damage

Although most of these genetic aberrations represent somatic mutations, others are present in the germline of kindreds who carry a familial predisposition to pancreatic cancer [10,11].

Specific gene abnormalities involved in molecular pathogenesis

Overall, there are four major driver genes in pancreatic ductal adenocarcinoma (one oncogene [KRAS] and three tumor suppressor genes [CDKN2ATP53, and SMAD4]).

KRAS mutations  

The KRAS gene, located on chromosome 12p, is one of the most frequently mutated genes in pancreatic cancer. This gene is the human homolog of a transforming gene isolated from the Kirsten rat sarcoma virus, hence the name, KRAS. As noted earlier, KRAS is an oncogene. Mutations in this gene, the vast majority of which are at codon 12, are activating, leading to activation of the protein product of the gene [12].

Over 90% of pancreatic cancers harbor a KRAS gene mutation [1,12,13]. Furthermore, these mutations appear to occur very early in pancreatic carcinogenesis, as indicated by their presence in noninvasive precursors. KRAS gene mutations have been identified in noninvasive intraductal papillary mucinous neoplasms (IPMNs), in pancreatic intraepithelial neoplasia (PanIN), and in noninvasive mucinous cystic neoplasms (MCNs), and the prevalence of mutations increases with increasing degrees of dysplasia in these noninvasive precursor lesions [14-18]. Mouse studies provide compelling evidence that oncogenic KRAS is required for the formation of PanIN, the most common precursor lesion to pancreatic cancer, as well as for the initiation and maintenance of invasive pancreatic cancers [19-21].

Since KRAS mutations are both common and early events in pancreatic neoplasia, the KRAS gene is an attractive target for the development of an early detection test.

Tumor suppressor genes 

Loss of function of several postulated tumor suppressor genes has been documented in pancreatic carcinomas. In order to abrogate gene function, both copies (both the maternal and paternal alleles) of the gene need to be inactivated. This can occur by one of three mechanisms:

  • Inactivation of one copy of the gene by an intragenic mutation coupled with loss of the second allele (called loss of heterozygosity)
  • Homozygous deletion (deletion of both copies of the gene)
  • Hypermethylation of the promoter of the gene

Tumor suppressor genes that are inactivated in more than one-half of all pancreatic cancers are p16/CDKN2A, TP53, and SMAD4 (previously known as DPC4) [22].


The p16/CDKN2A gene on chromosome 9p is somatically inactivated in almost all pancreatic cancers (approximately 95%) [23,24]. Most of these inactivating mutations lead to loss of function of p16, the protein product of the CDKN2A gene. In 40% of the cancers, the gene is inactivated by homozygous deletion; in 40%, there is an intragenic mutation coupled with deletion of the second allele; and in 15%, gene inactivation is through hypermethylation of the p16/CDKN2A gene promoter.

Inactivation of the p16/CDKN2A gene in pancreatic cancer is important for several reasons:

  • Loss of gene function abrogates an important control of the cell cycle in these tumors.
  • Inherited mutations in the p16/CDKN2A gene are one of the causes of the Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome [10]. Patients with the FAMMM syndrome have an increased risk of developing melanoma and a 20- to 34-fold increased risk of developing pancreatic cancer. Screening for pancreatic cancer in these kindreds is discussed in detail elsewhere.
  • The homozygous deletions that inactivate the p16/CDKN2A gene frequently also inactivate an adjacent gene, the methylthioadenosine phosphorylase (MTAP) gene [25,26]. Data from cell lines suggest that inactivation of the MTAP gene in some pancreatic cancers could theoretically be exploited therapeutically [25,27].


The TP53 gene on chromosome 17p is one of the most frequently targeted genes in human cancer, including pancreatic cancer. The TP53 gene is inactivated in 75 to 85% of pancreatic cancers, almost always by an intragenic mutation (which is most often somatically acquired) coupled with loss of the second allele [1,28]. Genetic inactivation of TP53 abrogates two important cell functions: regulation of cellular proliferation and cell death (apoptosis) in response to DNA damage.


The SMAD4 gene (formerly known as DPC4), located on chromosome 18q, is inactivated in approximately 50% of pancreatic cancers [1,29]. In 30% of tumors, the gene is inactivated by homozygous deletion, and in another 20% of cases, there is an intragenic mutation coupled with loss of the second allele.

The protein product of the SMAD4 gene functions in the transmission of intracellular signals from transforming growth factor beta (TGFb) receptors within the cell membrane to the nucleus [30]. Mutations in genes coding for other components of the TGFb signaling pathway, such as SMAD3, TGFbR1, and TGFbR2, have also been reported in pancreatic cancer [1,31], underscoring the importance of this signaling pathway to the development of pancreatic cancer [1,31].

The inactivation of SMAD4 in pancreatic cancer is important for the following reasons:

  • An immunostain for the Smad4 protein has been developed, and the results of immunohistochemical labeling (IHC) of tissue sections using this antibody strongly correlate with SMAD4 gene status [32]. This means that IHC for the presence of absence of Smad4 protein can be used diagnostically, as an adjunct to the interpretation of difficult tissue biopsies, and to suggest the pancreas as a possible primary in patients with metastatic adenocarcinoma of unknown primary site [32,33].

As an example, if a patient had a pancreatic cancer in which SMAD4 is genetically inactivated and later developed an adenocarcinoma in the lung, which showed intact Smad4 expression, it could be deduced that the tumor in the lung was a separate primary.

  • Pancreatic cancers with loss of Smad4 expression have higher rates of distant metastases and a poorer prognosis [34,35]. While further studies are needed, these data suggest that SMAD4 gene status may someday be useful for prognostic stratification and therapeutic decision-making.

DNA mismatch repair genes 

DNA mismatch repair genes such as hMLH1 and hMSH2 are well known for their important role in the pathogenesis of colorectal cancer, particularly in Lynch syndrome (Hereditary Non-polyposis Colorectal Cancer Syndrome [HNPCC]). Patients with Lynch syndrome have inherited (germline) mutations in one of several DNA mismatch repair genes and an elevated risk of several gastrointestinal cancers, including pancreatic cancer [36].

DNA mismatch repair genes are mutated in approximately 4% of pancreatic cancers [37,38]. Some of these cancers have a distinctive «medullary» histologic appearance, and pancreatic cancers with defects in DNA mismatch repair gene can, therefore, sometimes be recognized histologically at the diagnostic microscope [37,38].

These tumors are important to recognize for the following reasons:

  • As is true in the colorectum, the inactivation of a DNA repair gene in a patient with pancreatic cancer suggests the possibility of a germline mutation and HNPCC syndrome [36-39]. These patients (and their family members) are at risk for a variety of gastrointestinal neoplasms. There are published screening guidelines.
  • Pancreatic cancers with microsatellite instability (MSI), the hallmark of an inactivated DNA mismatch repair gene, appear to have a somewhat better prognosis than standard ductal adenocarcinomas [40].
  • Pancreatic cancers with MSI also may be less responsive to chemotherapeutic agents, such as fluorouracil (FU) [41], as are colon cancers, at least in the adjuvant setting.

Instead, an intriguing report suggests that some cancers with high levels of MSI are particularly sensitive to immune-based therapies, such as immune checkpoint inhibitors [42]. To date, however, there are no published clinical trials examining the efficacy of immune checkpoint inhibitors, such as pembrolizumab, in pancreatic cancer.

Issues related to screening of mutation carriers for pancreatic cancer are addressed in detail elsewhere.

Familial pancreatic cancer genes 

Pancreatic cancer aggregates in some families, and mutations in a number of genes have been identified that, when inherited, predispose to pancreatic cancer.


Germline mutations in BRCA2 (one of the causes of the hereditary breast and ovarian cancer syndrome) on chromosome 13q are associated with an increased risk of pancreatic cancer [10,43-47]. The inherited germline mutation is then coupled with somatic loss of the second allele in the cancer, completely inactivating gene function in the cancer [10]. This constitutes one of the most important causes of familial aggregation of pancreatic cancer. BRCA2 mutations are found in up to 17% of patients with multiple family members affected with pancreatic cancer. Issues related to screening for pancreatic cancer in mutation carriers are discussed in detail elsewhere.

The protein product of the BRCA2 gene functions in the Fanconi anemia pathway, and it plays an important role in the repair of DNA cross-linking damage [48,49].

It has been suggested that this function of BRCA2 can be exploited therapeutically. In vitro studies suggest that pancreatic cancers with genetically inactivated BRCA2 are significantly more susceptible to DNA cross-linking agents then are pancreatic cancers with a genetically intact BRCA2. Indeed, several reports have documented remarkable therapeutic responses to DNA cross-linking agents such as mitomycin, platinum derivatives such as cisplatin, or to poly ADP-ribose polymerase (PARP) inhibitors in patients whose cancers have inactivated BRCA2 [50,51]. The platinum-based drug, oxaliplatin, is part of the FOLFRINOX chemotherapy combination for the treatment of advanced pancreatic cancer.


The PALB2 gene on chromosome 16p encodes for a BRCA2 binding protein [52]. Germline mutations in PALB2 are known to increase the risk of breast cancer, and germline truncating mutations in the PALB2 gene have been identified in approximately 3% of individuals with familial pancreatic cancer [10,53,54]. Issues related to screening for pancreatic cancer in mutation carriers are discussed in detail elsewhere.

Since PALB2, like BRCA2, is a member of the Fanconi anemia pathway, pancreatic cancers in which PALB2 has been genetically inactivated should have some of the same specific therapeutic sensitivities that have been observed in BRCA2 mutant cancers.


The STK11 gene on chromosome 19p encodes for a serine/threonine kinase, which regulates cell polarity and functions as a tumor suppressor gene [55]. Germline mutations in the STK11 gene are associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder in which affected individuals develop hamartomatous polyps of the gastrointestinal tract, pigmented macules on the lips and buccal mucosa, and a variety of gastrointestinal malignancies [55-58]. Patients with the PJS have a dramatically increased risk of developing pancreatic cancer, with a lifetime risk of 36% [57].

In addition, somatic STK11 mutations have been observed in a small fraction (approximately 4%) of pancreatic cancers, particularly those that arise in association with an intraductal papillary mucinous neoplasm (IPMN) [18,56,58]. Loss of heterozygosity (LOH) for STK11 is reported in 25% of patients with IPMN from patients lacking features of PJS [58]. Thus, inactivation of the STK11 gene appears to play a role in both hereditary and sporadic pancreatic cancers.

Screening of individuals with PJS and other high-risk hereditary conditions using endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI)-based imaging methods can detect asymptomatic early pancreatic neoplasms, including IPMNs, at a time when they are potentially curable [59-61].


The ataxia-telangiectasia mutated (ATM) gene on chromosome 11q encodes for a member of the PI3/PI4-kinase family. The ATM kinase gene product plays an important role in the cell’s response to DNA damage [62]. Germline mutations in the ATM gene cause ataxia-telangiectasia, a neurodegenerative disease characterized by poor coordination (ataxia) and dilated vessels (telangiectasia). People with ataxia-telangiectasia have a 25% lifetime risk of developing cancer. Germline mutations in the ATM gene have also been reported in 3% of families with familial pancreatic cancer, and somatic (acquired) ATM mutations have been reported in ductal adenocarcinomas [2,11,63]. These mutations are of particular interest, as pancreatic cancers in which the ATM gene has been bi-allelically inactivated may be more sensitive to certain therapies [64].

Issues related to screening for pancreatic cancer in mutation carriers are addressed elsewhere.

Other lower prevalence genes 

A number of other genes have been identified that are only rarely mutated in pancreatic cancer [1], and they are of generally less importance than KRASp16/CDKN2ATP53, and SMAD4. Among the genes that are mutated at low frequency are EP300SMARCA4CDH1EPHA3, FBXW7, MLL3, ROBO2, DPP6, BAI3, GPR133, GUCY1A2, PRKCG, ARID1AGATA6, and TGF beta R2 [1-3,65]. In addition, inactivating mutations in the ring finger protein 43 (RNF43) gene, a component of ubiquitin-dependent pathways, and the guanine nucleotide binding protein alpha stimulating activity (GNAS) complex locus, which encodes the alpha subunit of guanine nucleotide binding protein, have also been identified in IPMNs of the pancreas as well as the invasive cancers that arise from IPMNs [17,18,66].

While this list is long, many of these genes are involved in common signaling pathways, and the complexity of the mutational spectrum in pancreatic cancer can be simplified by thinking of the cellular pathways targeted by these genetic alterations [1]. For example, in one study, cellular pathways regulating apoptosis, the G1/S phase transition, hedgehog signaling, KRAS signaling, TGFb signaling and Wnt/Notch-signaling were all found to be mutated in all of the 24 pancreatic cancers that were completely sequenced [1].


In addition to mutational inactivation, the expression of a number of genes in pancreatic cancer can be silenced by aberrant promoter methylation, an epigenetic method of gene silencing [67-69]. Among the genes that can be silenced in this manner in pancreatic cancer are UCHL1NPTX2, SARP2, CLDN5REPRIMO (RPRM), LHX1, WNT7A, FOXE1, TJP2, CDH3, ST14 and p16/CDKN2A [69].

Conversely, some of the genes that are overexpressed in pancreatic cancer are hypomethylated [68]. A number of investigators are working to exploit the differences in methylation patterns between pancreatic neoplasms and normal cells to develop early detection tests and novel approaches to therapy [67-71]. Additional work is needed before any of these approaches can be adopted for routine clinical use.

Mitochondrial mutations 

Mutations most often target nuclear DNA, but mitochondrial DNA can also be somatically mutated in pancreatic cancer [72,73]. It is unclear if any of these mutations play a role in tumorigenesis.

However, some have suggested that mitochondrial mutations could be exploited for the development of early detection tests. Mitochondrial mutations are a particularly attractive target for early detection, as cells contain thousands of mitochondria, and a clonal mutation in mitochondria should therefore be easier to detect than a clonal mutation in nuclear DNA [72].

MicroRNA expression 

MicroRNAs are short, non-coding segments of RNA that regulate the expression of other genes. A number of microRNAs appear to be differentially expressed in pancreatic cancer and in the precursor lesions that give rise to pancreatic cancer [74-78]. For example, miR-34a is often deleted in pancreatic cancer, and miR-34a appears to play a role in TP53-related gene expression [77].

Genetic progression model 

Careful genetic analyses of small intraductal lesions in the pancreas have helped to establish that PanIN can be a precursor to invasive ductal adenocarcinoma [6,79]. Whole exome sequencing of PanINs and adjacent ductal adenocarcinomas shows a large proportion of shared somatic mutations in most cases, supporting the idea that PanIN gives risk to ductal adenocarcinomas [79].

PanIN lesions harbor many of the same mutations as are found in invasive ductal adenocarcinomas, and increasing numbers of mutations are associated with increasing degrees of dysplasia in PanIN [6].KRAS gene mutations appear to occur first, in the lowest grade of PanIN, called PanIN-1. p16/CDKN2A gene mutations start to appear in PanIN-2 lesions, and SMAD4 and TP53 inactivation do not appear until the highest grade of PanIN, the PanIN-3 lesion, or perhaps even later in invasive carcinomas [6]. The exact molecular events that underlie the progression from intraductal to invasive neoplasia are not yet understood; it has recently been suggested that genomic loss of the dual-specificity phosphatase 4 (DUSP4) gene may be involved [80].

The development of a progression model of pancreatic tumorigenesis has important implications for the development of chemoprevention and early detection strategies. As an example, very early molecular events may be appropriate targets for chemoprevention, while later events may be useful for early detection strategies for pancreatic neoplasia. This model was also critical to the development of genetically engineered animal models of pancreatic cancer. The recognition that KRAS gene mutations are one of the earliest events in pancreatic tumorigenesis led investigators to introduce mutant KRAS into the pancreatic glands of mice, and these mice developed pancreatic tumors that appear to accurately mimic human disease [19,81].

Clinical implications

Molecular classification 

The patterns of genetic alterations identified in neoplasms of the pancreas are beginning to be integrated with tumor morphology and patient prognosis, and a new «molecular classification» of pancreatic neoplasia is slowly emerging [5]. As examples:

  • Almost all solid-pseudopapillary neoplasms of the pancreas harbor a beta-catenin (CTNNB1) gene mutation, and these mutations may explain the poor cohesion that is so characteristic of the neoplastic cells in this tumor type [17,82,83].
  • Serous cystadenomas of the pancreas are almost always benign and slow-growing neoplasms, and they are characterized by mutations in the von Hippel-Lindau (VHL) gene [17]. In the sporadic setting, these are acquired, while in patients with VHL syndrome, they are inherited (germline).
  • Intraductal papillary mucinous neoplasms (IPMNs) often harbor mutations in GNAS, RNF43, KRAS, TP53, and SMAD4, and mucinous cystic neoplasms have mutations in RNF43, KRAS, TP53, andSMAD4 [17].
  • Thus, each of the four major cystic neoplasms of the pancreas has a specific mutational profile [17]. It is anticipated that molecular profiling of cyst fluid obtained at the time of endoscopy will help in the clinical classification of cyst type [84].
  • The vast majority of undifferentiated carcinomas of the pancreas show a loss of e-cadherin (CDH-1) expression, and the loss of e-cadherin may correlate with the invasive phenotype and poor prognosis associated with these neoplasms [85].
  • Most pancreatoblastomas arise in childhood, and the majority of these distinctive neoplasms have lost the maternal copy of chromosome 11p [86]. This molecular finding unites this disease with other primitive tumors of childhood such as the nephroblastoma (Wilms’ tumor) and hepatoblastoma, which also have typically lost the maternal copy of chromosome 11p.
  • Pancreatic neoplasms with prominent osteoclast-like giant cells have been recognized for decades, but their fundamental direction of differentiation was not clear. However, it is now apparent that the undifferentiated pleomorphic cells that are between the osteoclast-like giant cells are the cells that harbor genetic alterations and that these genetic alterations are identical to the mutations found in adjacent epithelial precursors [87]. These observations helped to establish that these distinctive neoplasms are, in fact, carcinomas, and the name of these tumors was therefore changed to undifferentiated carcinomas with osteoclast-like giant cells [87].
  • Several more recent studies have used gene expression in an attempt to further classify pancreatic cancers [88,89]. Both a four-group classification (squamous, immunogenic, pancreatic progenitor, or aberrantly differentiated endocrine exocrine [ADEX]) and a two-group classification (basal-like or classical) have been suggested. Some of these, such as the squamous subtype, correspond to well-established histologic subtypes (the adenosquamous carcinoma), while the clinical meaning of the others is less clear.

Familial pancreatic cancer 

One of the most significant benefits from the improved understanding of the molecular genetics of pancreatic cancer has been the discovery of some of the genes that are responsible for the familial aggregation of pancreatic cancer [10,90]. Between 3 and 16% of pancreatic cancers are either syndromic or familial.

As discussed in detail in the sections above, the genes which, when mutated in the germline, increase the risk of pancreatic cancer are outlined in the table (table 1).

Improved understanding of the genetic basis for the development of pancreatic cancer has had a significant impact on individuals with an inherited predisposition. Selected individuals from these kindreds can now be tested for inherited germline mutations in genes that are known to predispose carriers to pancreatic cancer. Individuals found to carry a mutation associated with an increased risk of developing pancreatic cancer may be recommended for periodic screening or even prophylactic surgery. Screening of individuals with high-risk hereditary conditions using endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI)-based methods can detect predominantly asymptomatic early pancreatic neoplasms, including noninvasive IPMNs and pancreatic intraepithelial neoplasia (PanIN), at a time when they are potentially curable.

Individuals carrying one of these inherited mutations may also benefit from screening for extra-pancreatic neoplasms. For example, patients with Familial Atypical Multiple Mole Melanoma (FAMMM) should be screened for melanocytic lesions and individuals with inherited BRCA2 gene mutations for breast cancer.

In addition, the discovery of familial syndromes with an increased risk of pancreatic cancer forms the basis for the design and implementation of early detection tests for this disease.

Molecular screening and early detection 

The vast majority of patients with pancreatic cancer are not diagnosed until after their cancer has metastasized. However, even when diagnosed at a time when it is potentially resectable, the prognosis of invasive pancreatic cancer is poor.

Given these facts, an accurate and sensitive test for the diagnosis of early, potentially curable noninvasive pancreatic neoplasia is urgently needed. Several techniques can detect rare mutant genes even when they are admixed with thousands of normal copies of the gene. Acquired genetic mutations that are associated with particular cancers can provide new targets for the development of sensitive screening tests for that disease. Genetic alterations are attractive targets for such early detection tests because, as has been discussed above, many of these alterations are specific for the cancer (they do not occur in normal cells and thus are highly specific), and many occur in the vast majority of the cancers (they have the potential of being very sensitive).

As examples:

  • KRASgene mutations can be detected in duodenal juice and even in the stool of patients with pancreatic cancer [91-93]. However, questions remain as to the ability of KRAS mutations to differentiate between pancreatic neoplasms and chronic pancreatitis.
  • A novel five-gene classifier has been reported to be sensitive and specific for discriminating pancreatic ductal adenocarcinoma from non-tumor samples, including chronic pancreatitis [94].

However, much further work is needed before any molecular diagnostic test can be used in routine clinical practice.

Personalized medicine 

Although in its infancy, a growing body of evidence suggests that individualized therapies that are based upon the specific genetic alterations in an individual patient’s pancreatic cancer will soon be a reality. Already, examples were given of the increased sensitivities of BRCA1BRCA2, and PALB2 mutant cancers to DNA cross-linking agents, and of microsatellite instability (MSI) high cancers to immunotherapies [42,50,51].


  • Carcinoma of the exocrine pancreas is a genetic disease that is caused by inherited and acquired mutations in specific cancer-associated genes.
  • The patterns of genetic alterations identified in neoplasms of the pancreas are beginning to be integrated with tumor morphology and patient prognosis, and a new «molecular classification» of pancreatic neoplasia is slowly emerging [17].
  • Progress in our understanding of the genes involved in pancreatic carcinogenesis has also provided insight into the familial aggregation of the disease and the progression of normal pancreatic ductal cells to noninvasive precursor lesions and to invasive carcinoma.
  • Acquired genetic mutations may represent new targets for the development of sensitive screening tests for early diagnosis of pancreatic cancer, particularly before it becomes invasive. However, this work is in its infancy, and additional study is needed before any molecular screening test can be recommended for routine clinical practice.

Table 1. Pancreatic cancer predisposition syndromes and risk of pancreatic cancer

Group (mutated gene) Other characteristics Relative risk for pancreatic cancer Lifetime risk for pancreatic cancer by age 70 years (incidence)
No history   1 0.5%
HBOC (BRCA1) Predisposition to breast, ovarian, prostate cancer 3 1.2%
HBOC (BRCA2) Predisposition to breast, ovarian, prostate cancer, Jewish ancestry in some (refer for gene testing) 3.5 to 10 2 to 5%
Familial PC + 1 FDR affected Pancreatic ductal adenocarcinoma in an individual with one affected FDR (sibling, parent, or child) 4.6  
Familial PC+ 2 FDR affected (unknown) Pancreatic ductal adenocarcinoma in an individual with two affected FDRs 6.4  
Lynch II syndrome (mismatch repair genes MLH1, MSH2, MSH6) Predisposition to colorectal, endometrial cancer 8.6 3.7%
FAMMM (CKDN2A) Predisposition to melanoma, multiple nevi, atypical moles (autosomal dominant) 13 to 36 10 to 19%
Familial PC + 3 FDR affected (unknown) Pancreatic ductal adenocarcinoma in an individual with three affected FDRs 32  
Hereditary pancreatitis (PRSS1, SPINK1) Young-onset pancreatitis (autosomal dominant) 50 to 82 25 to 44%
Peutz-Jeghers syndrome (STK11)   132 11 to 66%
HBOC (PALB2)   unknown unknown
Ataxia-telangiectasia (ATM)   unknown unknown
Li-Fraumeni (TP53)   unknown unknown

HBOC: hereditary breast ovarian cancer syndrome; BRCA: breast-related cancer; familial PC: familial pancreatic cancer (pancreatic ductal adenocarcinoma) in the absence of a definable high-risk inherited mutation; FDR: first-degree relative; FAMMM: familial atypical multiple mole melanoma syndrome; CDKN: cyclin-dependent kinase inhibitor.


  1. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 2008; 321:1801.
  2. Biankin AV, Waddell N, Kassahn KS, et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012; 491:399.
  3. Waddell N, Pajic M, Patch AM, et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015; 518:495.
  4. Hruban RH, Canto MI, Griffin C, et al. Treatment of familial pancreatic cancer and its precursors. Curr Treat Options Gastroenterol 2005; 8:365.
  5. Shi C, Daniels JA, Hruban RH. Molecular characterization of pancreatic neoplasms. Adv Anat Pathol 2008; 15:185.
  6. Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res 2000; 6:2969.
  7. Wilentz RE, Iacobuzio-Donahue CA, Argani P, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 2000; 60:2002.
  8. Basturk O, Hong SM, Wood LD, et al. A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas. Am J Surg Pathol 2015; 39:1730.
  9. Hruban RH, Yeo CJ, and Kern SE. Pancreatic Cancer. In: The Genetic Basis of Human Cancer, Vogelstein B, Kinzler KW (Eds), McGraw-Hill, New York 1998. p.659.
  10. Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 2015; 17:569.
  11. Roberts NJ, Norris AL, Petersen GM, et al. Whole Genome Sequencing Defines the Genetic Heterogeneity of Familial Pancreatic Cancer. Cancer Discov 2016; 6:166.
  12. Hruban RH, van Mansfeld AD, Offerhaus GJ, et al. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 1993; 143:545.
  13. Almoguera C, Shibata D, Forrester K, et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 1988; 53:549.
  14. Moskaluk CA, Hruban RH, Kern SE. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 1997; 57:2140.
  15. Jimenez RE, Warshaw AL, Z’graggen K, et al. Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 1999; 230:501.
  16. Z’graggen K, Rivera JA, Compton CC, et al. Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 1997; 226:491.
  17. Wu J, Jiao Y, Dal Molin M, et al. Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways. Proc Natl Acad Sci U S A 2011; 108:21188.
  18. Amato E, Molin MD, Mafficini A, et al. Targeted next-generation sequencing of cancer genes dissects the molecular profiles of intraductal papillary neoplasms of the pancreas. J Pathol 2014; 233:217.
  19. Hingorani SR, Petricoin EF, Maitra A, et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003; 4:437.
  20. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest 2012; 122:639.
  21. Aguirre AJ, Bardeesy N, Sinha M, et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 2003; 17:3112.
  22. Rozenblum E, Schutte M, Goggins M, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res 1997; 57:1731.
  23. Caldas C, Hahn SA, da Costa LT, et al. Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 1994; 8:27.
  24. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 1997; 57:3126.
  25. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 2016; 351:1208.
  26. Subhi AL, Tang B, Balsara BR, et al. Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer. Clin Cancer Res 2004; 10:7290.
  27. Kryukov GV, Wilson FH, Ruth JR, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 2016; 351:1214.
  28. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 1994; 54:3025.
  29. Hahn SA, Schutte M, Hoque AT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996; 271:350.
  30. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003; 425:577.
  31. Goggins M, Shekher M, Turnacioglu K, et al. Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 1998; 58:5329.
  32. Wilentz RE, Su GH, Dai JL, et al. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas : a new marker of DPC4 inactivation. Am J Pathol 2000; 156:37.
  33. Hruban RH, Pitman MB, Klimstra DS. Tumors of the pancreas. In: Atlas of tumor pathology, American Registry of Pathology and Armed Forces Institute of Pathology, Washington, DC 2007.
  34. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009; 27:1806.
  35. Blackford A, Serrano OK, Wolfgang CL, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15:4674.
  36. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009; 302:1790.
  37. Goggins M, Offerhaus GJ, Hilgers W, et al. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 1998; 152:1501.
  38. Wilentz RE, Goggins M, Redston M, et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol 2000; 156:1641.
  39. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol 2012; 30:958.
  40. Nakata B, Wang YQ, Yashiro M, et al. Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res 2002; 8:2536.
  41. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 2003; 349:247.
  42. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015; 372:2509.
  43. Goggins M, Schutte M, Lu J, et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 1996; 56:5360.
  44. van Asperen CJ, Brohet RM, Meijers-Heijboer EJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 2005; 42:711.
  45. Hahn SA, Greenhalf B, Ellis I, et al. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003; 95:214.
  46. Phelan CM, Lancaster JM, Tonin P, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996; 13:120.
  47. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002; 62:3789.
  48. van der Heijden MS, Brody JR, Dezentje DA, et al. In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor. Clin Cancer Res 2005; 11:7508.
  49. Yuan SS, Lee SY, Chen G, et al. BRCA2 is required for ionizing radiation-induced assembly of Rad51 complex in vivo. Cancer Res 1999; 59:3547.
  50. Lowery MA, Kelsen DP, Stadler ZK, et al. An emerging entity: pancreatic adenocarcinoma associated with a known BRCA mutation: clinical descriptors, treatment implications, and future directions. Oncologist 2011; 16:1397.
  51. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015; 33:244.
  52. Xia B, Sheng Q, Nakanishi K, et al. Control of BRCA2 cellular and clinical functions by a nuclear partner, PALB2. Mol Cell 2006; 22:719.
  53. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009; 324:217.
  54. Slater EP, Langer P, Niemczyk E, et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010; 78:490.
  55. Jenne DE, Reimann H, Nezu J, et al. Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 1998; 18:38.
  56. Su GH, Hruban RH, Bansal RK, et al. Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 1999; 154:1835.
  57. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000; 119:1447.
  58. Sato N, Rosty C, Jansen M, et al. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001; 159:2017.
  59. Canto MI, Goggins M, Hruban RH, et al. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006; 4:766.
  60. Canto MI, Goggins M, Yeo CJ, et al. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2004; 2:606.
  61. Larghi A, Verna EC, Lecca PG, Costamagna G. Screening for pancreatic cancer in high-risk individuals: a call for endoscopic ultrasound. Clin Cancer Res 2009; 15:1907.
  62. Stracker TH, Roig I, Knobel PA, Marjanović M. The ATM signaling network in development and disease. Front Genet 2013; 4:37.
  63. Roberts NJ, Jiao Y, Yu, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery 2012; 2:41.
  64. Williamson CT, Kubota E, Hamill JD, et al. Enhanced cytotoxicity of PARP inhibition in mantle cell lymphoma harbouring mutations in both ATM and p53. EMBO Mol Med 2012; 4:515.
  65. Jones S, Li M, Parsons DW, et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 2012; 33:100.
  66. Wu J, Matthaei H, Maitra A, et al. Recurrent GNAS mutations define an unexpected pathway for pancreatic cyst development. Sci Transl Med 2011; 3:92ra66.
  67. Omura N, Li CP, Li A, et al. Genome-wide profiling of methylated promoters in pancreatic adenocarcinoma. Cancer Biol Ther 2008; 7:1146.
  68. Sato N, Maitra A, Fukushima N, et al. Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res 2003; 63:4158.
  69. Sato N, Fukushima N, Maitra A, et al. Discovery of novel targets for aberrant methylation in pancreatic carcinoma using high-throughput microarrays. Cancer Res 2003; 63:3735.
  70. Parsi MA, Li A, Li CP, Goggins M. DNA methylation alterations in endoscopic retrograde cholangiopancreatography brush samples of patients with suspected pancreaticobiliary disease. Clin Gastroenterol Hepatol 2008; 6:1270.
  71. Hong SM, Kelly D, Griffith M, et al. Multiple genes are hypermethylated in intraductal papillary mucinous neoplasms of the pancreas. Mod Pathol 2008; 21:1499.
  72. Jones JB, Song JJ, Hempen PM, et al. Detection of mitochondrial DNA mutations in pancreatic cancer offers a «mass»-ive advantage over detection of nuclear DNA mutations. Cancer Res 2001; 61:1299.
  73. Maitra A, Cohen Y, Gillespie SE, et al. The Human MitoChip: a high-throughput sequencing microarray for mitochondrial mutation detection. Genome Res 2004; 14:812.
  74. Habbe N, Koorstra JB, Mendell JT, et al. MicroRNA miR-155 is a biomarker of early pancreatic neoplasia. Cancer Biol Ther 2009; 8:340.
  75. Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene 2007; 26:4442.
  76. Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 2007; 297:1901.
  77. Chang TC, Wentzel EA, Kent OA, et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol Cell 2007; 26:745.
  78. Ryu JK, Hong SM, Karikari CA, et al. Aberrant MicroRNA-155 expression is an early event in the multistep progression of pancreatic adenocarcinoma. Pancreatology 2010; 10:66.
  79. Murphy SJ, Hart SN, Lima JF, et al. Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor. Gastroenterology 2013; 145:1098.
  80. Hijiya N, Tsukamoto Y, Nakada C, et al. Genomic Loss of DUSP4 Contributes to the Progression of Intraepithelial Neoplasm of Pancreas to Invasive Carcinoma. Cancer Res 2016; 76:2612.
  81. Hingorani SR, Wang L, Multani AS, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 2005; 7:469.
  82. Tanaka Y, Kato K, Notohara K, et al. Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res 2001; 61:8401.
  83. Abraham SC, Klimstra DS, Wilentz RE, 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; 160:1361.
  84. Springer S, Wang Y, Dal Molin M, et al. A combination of molecular markers and clinical features improve the classification of pancreatic cysts. Gastroenterology 2015; 149:1501.
  85. Winter JM, Ting AH, Vilardell F, et al. Absence of E-cadherin expression distinguishes noncohesive from cohesive pancreatic cancer. Clin Cancer Res 2008; 14:412.
  86. Abraham SC, Wu TT, Klimstra DS, 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; 159:1619.
  87. Westra WH, Sturm P, Drillenburg P, et al. K-ras oncogene mutations in osteoclast-like giant cell tumors of the pancreas and liver: genetic evidence to support origin from the duct epithelium. Am J Surg Pathol 1998; 22:1247.
  88. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016; 531:47.
  89. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat Genet 2015; 47:1168.
  90. Klein AP, Hruban RH, Brune KA, et al. Familial pancreatic cancer. Cancer J 2001; 7:266.
  91. Shi C, Fukushima N, Abe T, 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 Ther 2008; 7:353.
  92. Kondo H, Sugano K, Fukayama N, et al. Detection of K-ras gene mutations at codon 12 in the pancreatic juice of patients with intraductal papillary mucinous tumors of the pancreas. Cancer 1997; 79:900.
  93. Caldas C, Hahn SA, Hruban RH, et al. Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 1994; 54:3568.
  94. Bhasin MK, Ndebele K, Bucur O, et al. Meta-analysis of transcriptome data identifies a novel 5-gene pancreatic adenocarcinoma classifier. Oncotarget 2016; 7:23263.



Добавить комментарий

Войти с помощью: 

Ваш e-mail не будет опубликован. Обязательные поля помечены *