Molecular pathogenesis of exocrine pancreatic cancer

Author:: Ralph H Hruban, MD
Section Editor:: Richard M Goldberg, MD
Deputy Editor:: Sonali M Shah, MD

Literature review current through: Jan 2024.

This topic last updated: Apr 20, 2022.

INTRODUCTION — Carcinoma of the exocrine pancreas is a genetic disease that is caused by inherited and acquired mutations in specific cancer-associated genes. 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]. Additional whole-genome and whole-exome sequencing studies from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) have built on this foundation, and the genetics of pancreatic cancer are now well understood [2-4]. 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 and the progression of normal pancreatic cells to noninvasive precursor lesions and to invasive carcinoma, and has led to a new classification system of pancreatic neoplasms that encompasses both morphology and genetics [5-9].

As a general rule, multiple combinations of genetic mutations are commonly found in pancreatic adenocarcinomas [1-4]. These can be divided into three broad categories [10]:

●Mutational activation of oncogenes such as KRAS

●Inactivation of tumor suppressor genes such as TP53, p16/cyclin-dependent kinase inhibitor 2A (CDKN2A), and SMAD4

●Inactivation of genome maintenance genes such as mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), and mutS homolog 6 (MSH6), which control the repair of deoxyribonucleic acid (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 [11,12]. (See 'Familial pancreatic cancer' below.)

SPECIFIC GENE ABNORMALITIES INVOLVED IN MOLECULAR PATHOGENESIS — The following sections will provide a brief overview of the current understanding of the molecular events that underlie pancreatic carcinogenesis.

Overall, there are four major driver genes in pancreatic ductal adenocarcinoma (one oncogene [KRAS] and three tumor suppressor genes [cyclin-dependent kinase inhibitor 2A (CDKN2A), TP53, 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 abnormal activation of the protein product of the gene [13].

Over 90 percent of pancreatic cancers harbor a KRAS gene mutation [1,4,13,14]. 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 [15-19]. 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 [20-22]. (See "Pathology of exocrine pancreatic neoplasms" and "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations".)

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. Although once thought to be "undruggable," more recent advances have made therapeutically targeting pancreatic cancers with certain KRAS gene mutations a reality [23,24]. (See 'Molecular screening and early detection' below.)

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) [1-4,25].

p16/CDKN2A — The p16/cyclin-dependent kinase inhibitor 2A (CDKN2A) gene on chromosome 9p is somatically inactivated in almost all pancreatic cancers (approximately 95 percent) [1-4,25-27]. Most of these inactivating mutations lead to loss of function of p16, the protein product of the CDKN2A gene. In 40 percent of the cancers, the gene is inactivated by homozygous deletion; in 40 percent, there is an intragenic mutation coupled with deletion of the second allele; and in 15 percent, 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 familial atypical multiple mole melanoma (FAMMM) syndrome [11]. Patients with 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. (See "Inherited susceptibility to melanoma" and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Familial atypical multiple mole and melanoma syndrome'.)

●The homozygous deletions that inactivate the p16/CDKN2A gene frequently also inactivate an adjacent gene, the MTAP gene [28,29]. Data from cell lines suggest that inactivation of the MTAP gene in some pancreatic cancers could theoretically be exploited therapeutically [28,30,31].

TP53 — 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 percent of pancreatic cancers, almost always by an intragenic mutation (which is most often somatically acquired) coupled with loss of the second allele [1-4,25,32]. Genetic inactivation of TP53 abrogates two important cell functions: regulation of cellular proliferation and cell death (apoptosis) in response to DNA damage.

SMAD4 — The SMAD4 gene (formerly known as DPC4), located on chromosome 18q, is inactivated in approximately 50 percent of pancreatic cancers [1-4,25,33]. In 30 percent of tumors, the gene is inactivated by homozygous deletion, and in another 20 percent 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 [34]. 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 [1-4,25,35], underscoring the importance of this signaling pathway to the development of pancreatic cancer [1,35].

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

●Immunolabeling for the SMAD4 protein has been developed, and the results of immunohistochemical labeling of tissue sections using this antibody strongly correlate with SMAD4 gene status [36]. This means that immunohistochemistry for the presence or 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 [36,37].

As an example, if a patient had a pancreatic cancer in which SMAD4 is genetically inactivated and later developed an adenocarcinoma in the lung that showed intact SMAD4 expression, it could be deduced that the tumor in the lung was a separate primary. (See "Adenocarcinoma of unknown primary site".)

●Pancreatic cancers with loss of SMAD4 expression have higher rates of distant metastases and a poorer prognosis [38,39]. 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 are mutated in approximately 2 to 3 percent of pancreatic cancers [2-4,25,40-42]. Some of these cancers have a distinctive "medullary" histologic appearance, and pancreatic cancers with defects in a DNA mismatch repair gene can therefore sometimes be recognized histologically at the diagnostic microscope [40,41]. (See "Pathology of exocrine pancreatic neoplasms".)

Since DNA mismatch repair gene inactivation in pancreatic cancer is most commonly seen in the familial setting, these cancers are discussed in greater detail below in the section on familial pancreatic cancer. (See 'Lynch syndrome' below.)

Issues related to screening mutation carriers for pancreatic cancer are addressed in detail elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Lynch syndrome' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

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. As many as 20 percent of patients with pancreatic cancer have germline mutations in known cancer predisposition genes. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Inherited cancer susceptibility syndromes'.)

BRCA2 and BRCA1

●BRCA2 – Germline mutations in breast cancer susceptibility (BRCA) 2 (one of the causes of hereditary breast and ovarian cancer syndrome [HBOC]) on chromosome 13q are associated with an increased risk of pancreatic cancer [11,43-49]. The inherited germline mutation is then coupled with somatic loss of the second allele in the cancer, completely inactivating gene function in the cancer [11]. Germline BRCA2 mutations increase the risk of pancreatic cancer 3.5- to 10-fold [49,50]. This constitutes one of the most important causes of familial aggregation of pancreatic cancer. BRCA2 mutations are found in up to 17 percent 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. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

●BRCA1 – Germline BRCA1 gene mutations also predispose to pancreatic cancer, but the penetrance is thought to be less than with germline BRCA2 gene mutations [48,49].

PALB2 — The partner and localizer of BRCA2 (PALB2) gene on chromosome 16p encodes for a BRCA2 binding protein [51]. 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 percent of individuals with familial pancreatic cancer [11,52-54]. Indeed, it is estimated that germline mutations in PALB2 increase the risk of pancreatic cancer 15-fold [48]. Issues related to screening for pancreatic cancer in mutation carriers are discussed in detail elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary breast cancer: BRCA and PALB2' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

Since PALB2, similar to BRCA2 and BRCA1, 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 [55]. (See "ER/PR negative, HER2-negative (triple-negative) breast cancer", section on 'Patients with previous exposure to chemotherapy' and "Overview of hereditary breast and ovarian cancer syndromes", section on 'PALB2'.)

STK11 — The serine/threonine kinase 11 (STK11) gene on chromosome 19p encodes for a serine/threonine kinase that regulates cell polarity and functions as a tumor suppressor gene [56]. 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 [56-59]. Patients with the PJS have a dramatically increased risk of developing pancreatic cancer, with a lifetime risk of 36 percent [58]. (See "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management".)

In addition, somatic STK11 mutations have been observed in a small fraction (approximately 4 percent) of pancreatic cancers, particularly those that arise in association with IPMN [18,57,59]. Loss of heterozygosity for STK11 is reported in 25 percent of IPMN from patients lacking features of PJS [59]. Thus, inactivation of the STK11 gene appears to play a role in both hereditary and sporadic pancreatic cancers. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations", section on 'Pathogenesis'.)

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 [60-63]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Peutz-Jeghers syndrome' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening' and "Peutz-Jeghers syndrome: Clinical manifestations, diagnosis, and management", section on 'Pancreatic cancer'.)

ATM — 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 [64]. 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 percent lifetime risk of developing cancer. Germline mutations in the ATM gene have also been reported in 3 percent of families with familial pancreatic cancer, and somatic (acquired) ATM mutations have been reported in ductal adenocarcinomas [2,12,65-67]. Germline mutations in ATM increase the risk of pancreatic cancer eight- to ninefold [50]. These mutations are of particular interest as pancreatic cancers in which the ATM gene has been biallelically inactivated may be more sensitive to certain therapies [68,69]. (See "Ataxia-telangiectasia".)

Issues related to screening for pancreatic cancer in ATM mutation carriers are addressed elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Ataxia-telangiectasia' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

Lynch syndrome — DNA mismatch repair genes, such as mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), and mutS homolog 6 (MSH6), are well known for their important role in the pathogenesis of colorectal cancer, particularly in Lynch syndrome (hereditary nonpolyposis colorectal cancer [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 [48,70]. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Clinical features' and "Molecular genetics of colorectal cancer".)

Carcinomas of the pancreas with an inactivated DNA mismatch repair gene are important to recognize for the following reasons:

●As is true in the colorectum, the somatic inactivation of a DNA repair gene in a patient with pancreatic cancer suggests the possibility of a germline mutation and Lynch syndrome [40,41,70,71]. All patients with a pancreatic cancer that has high levels of microsatellite instability (MSI-H) or deficient mismatch repair (dMMR) should undergo germline genetic assessment for Lynch syndrome, regardless of age or family history [72]. These patients (and their family members) are at risk for a variety of gastrointestinal neoplasms, for which there are published screening guidelines. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis" and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening'.)

●Pancreatic cancers with MSI-H, the hallmark of an inactivated DNA mismatch repair gene, appear to have a somewhat better prognosis than standard ductal adenocarcinomas [73].

●Pancreatic cancers with MSI-H also may be less responsive to chemotherapeutic agents such as fluorouracil [74], as are colon cancers, at least in the adjuvant setting.

Instead, and perhaps most importantly, some cancers with MSI-H are particularly sensitive to immune-based therapies, such as immune checkpoint inhibitors. Objective, in some instances complete, and durable responses to immune checkpoint inhibitors, such as pembrolizumab, have been reported in a variety of patients with MSI-H cancers [75]. (See "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)

Hereditary pancreatitis — Inherited variants in genes that predispose to pancreatitis, including PRSS1 and SPINK1, also increase the risk of pancreatic cancer [76]. This risk is sufficiently high that several groups have recommended the screening of asymptomatic individuals with hereditary pancreatitis [77]. This subject is discussed in detail elsewhere. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Hereditary pancreatitis' and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Candidates for screening'.)

Other lower prevalence somatically altered genes — A number of other genes have been identified that are only rarely somatically mutated in pancreatic cancer [1], and they are generally of less importance than KRAS, p16/CDKN2A, TP53, and SMAD4. Among the genes that are mutated or otherwise genetically altered at low prevalence are AKT2, AIB1, ALK4, ARID1A, AXIN1, BRAF, CDH1, CDK4, CTNNB1, EP300, EPHA3, ERBB2, FBXW7, FGFR1, GATA6, GNAS, MAP2K4, MKK4, MLL3, MYB, MYC, NOTCH1, PBRM1, PIK3CA, ROBO2, SMARCA2, SMARCA4, and TGFbR2 [1-4,78]. In addition, inactivating mutations in the RNF43 gene, a component of ubiquitin-dependent pathways, and the GNAS complex locus, which encodes the alpha subunit of guanine nucleotide binding protein, have also been identified in IPMN of the pancreas as well as the invasive cancers that arise from IPMN [17,18,79]. Similarly, specific translocations involving the PRKACA and PRKACB genes have been identified more recently that drive intraductal oncocytic papillary neoplasms and their associated invasive carcinomas [80]. (See "Intraductal papillary mucinous neoplasm of the pancreas (IPMN): Pathophysiology and clinical manifestations", section on 'Pathogenesis'.)

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].

Methylation — 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 [81-83]. Among the genes that can be silenced in this manner in pancreatic cancer are UCHL1, NPTX2, SARP2, CLDN5, REPRIMO (RPRM), LHX1, WNT7A, FOXE1, TJP2, CDH3, ST14, and p16/CDKN2A [83].

Conversely, some of the genes that are overexpressed in pancreatic cancer are hypomethylated [82]. 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 [81-85]. 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 [86,87]. 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 [86].

MicroRNA expression — MicroRNAs (miRNAs) are short, noncoding segments of RNA that regulate the expression of other genes. A number of miRNAs appear to be differentially expressed in pancreatic cancer and the precursor lesions that give rise to pancreatic cancer [88-92]. For example, miR-34a is often deleted in pancreatic cancer, and miR-34a appears to play a role in TP53-related gene expression [91].

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 [7,19,93]. Whole-exome sequencing of PanIN 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 [93]. (See "Pathology of exocrine pancreatic neoplasms", section on 'Pancreatic intraepithelial neoplasia'.)

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 [7,19]. KRAS gene mutations appear to occur first in the lowest grade of PanIN (PanIN-1). Alterations in the p16/CDKN2A gene start to appear in intermediate lesions (PanIN-2), and SMAD4 and TP53 inactivation does not appear until high-grade PanIN (PanIN-3), or perhaps even later, in invasive carcinomas [7,19].

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 [20,94].

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 [6]. 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 [17,95,96]. (See "Pathology of exocrine pancreatic neoplasms", section on 'Solid pseudopapillary neoplasms'.)

●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). (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease" and "Molecular biology and pathogenesis of von Hippel-Lindau disease".)

●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, and SMAD4 [17].

●As noted above, intraductal oncocytic papillary neoplasms of the pancreas are characterized by distinct translocations involving either the PRKACA or the PRKACB gene [80].

●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 [97,98].

●The vast majority of undifferentiated carcinomas of the pancreas show a loss of CDH1 expression, and the loss of epithelial cadherin may correlate with the invasive phenotype and poor prognosis associated with these neoplasms [99]. An undifferentiated carcinoma with "rhabdoid" features with loss of SMARCB1 (INI1) has been described [100].

●Most pancreatoblastomas arise in childhood, and the majority of these distinctive neoplasms have lost the maternal copy of chromosome 11p [101]. This molecular finding unites this disease with other primitive tumors of childhood, such as nephroblastoma (Wilms tumor) and hepatoblastoma, which also have typically lost the maternal copy of chromosome 11p. (See "Pathology of exocrine pancreatic neoplasms", section on 'Pancreatoblastoma'.)

●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 [102,103]. 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 [102].

●Several more recent studies have used gene expression in an attempt to further classify pancreatic cancers [25,104]. 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 immunogenic and ADEX subtypes may be artifacts of stromal contamination in the original studies [4,105].

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 [11,106]. Up to 20 percent of patients with pancreatic cancer have germline mutations in known cancer predisposition syndromes. As discussed in detail in the sections above, the genes that when mutated in the germline increase the risk of pancreatic cancer are outlined in the table (table 1). (See 'Familial pancreatic cancer genes' above and "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Inherited cancer susceptibility syndromes'.)

All patients diagnosed with pancreatic cancer should undergo assessment of their risk of a familial predisposition to cancer with a detailed personal and family cancer history [107]. Germline genetic testing is now recommended for all patients, even those without a family history of pancreatic cancer [108]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Referral for genetic evaluation'.)

Individuals found to carry a pathogenic or likely pathogenic variant associated with an increased risk of developing pancreatic cancer may be recommended for periodic screening. Screening of individuals with high-risk hereditary conditions using endoscopic ultrasound (EUS) and/or 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 [63,109,110]. (See "Familial risk factors for pancreatic cancer and screening of high-risk patients", section on 'Pancreatic cancer screening'.)

Individuals carrying one of these inherited mutations may also benefit from screening for extrapancreatic neoplasms. For example, patients with familial atypical multiple mole melanoma (FAMMM) should be screened for melanocytic lesions, and individuals with inherited breast cancer susceptibility (BRCA) 2 gene mutations should be screened for breast cancer. (See "Inherited susceptibility to melanoma".)

In addition, a growing body of evidence makes it clear that some of the germline variants that predispose to pancreatic cancers make the cancers particularly sensitive to targeted therapies [3,111-113].

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. (See "Overview of surgery in the treatment of exocrine pancreatic cancer and prognosis", section on 'Prognosis and prognostic factors'.)

Given these facts, an accurate and sensitive test for the diagnosis of potentially curable early 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 [114]. 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 an example, KRAS gene mutations can be detected in the blood of patients with pancreatic cancer [115]. Even greater sensitivity can be obtained when these tests for circulating tumor DNA are combined with tests for proteins and cancer antigens expressed by the neoplastic cells [116].

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

Molecularly targeted therapy — For patients with metastatic pancreatic cancer, genomic (ie, germline) testing and gene profiling of tumor tissue (ie, with next-generation sequencing) should be undertaken as quickly as possible after diagnosis because of the significant treatment implications. Targeted therapies that are based on the specific germline or somatic pathogenic or likely pathogenic alterations are routinely used to select treatment, both in the setting of locally advanced nonmetastatic but unresectable tumors and in those with metastatic disease. These issues are addressed separately. (See "Initial chemotherapy and radiation for nonmetastatic, locally advanced, unresectable and borderline resectable, exocrine pancreatic cancer", section on 'Influence on choice of chemotherapy agents' and "Second-line systemic therapy for advanced exocrine pancreatic cancer", section on 'Molecularly-targeted therapy' and "Initial systemic chemotherapy for metastatic exocrine pancreatic cancer".)

SUMMARY

●Carcinoma of the exocrine pancreas is a genetic disease that is caused by inherited and acquired mutations in specific cancer-associated genes. (See 'Specific gene abnormalities involved in molecular pathogenesis' above.)

●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]. (See 'Molecular classification' above.)

●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 cells to noninvasive precursor lesions and to invasive carcinoma. (See 'Familial pancreatic cancer' above and 'Genetic progression model' above.)

●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. (See 'Molecular screening and early detection' above.)

●For patients with pancreatic cancer, genomic (ie, germline) testing and gene profiling of tumor tissue (ie, with next-generation sequencing) should be undertaken as quickly as possible after diagnosis because of the significant treatment implications. (See 'Molecularly targeted therapy' above.)

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Topic 2492 Version 25.0

خرید پکیج

Molecular pathogenesis of exocrine pancreatic cancer

References