Germline Alterations

Approximately 10% of pancreatic ductal adenocarcinomas (PDAs) have a familial basis, and several genetic syndromes lead to an increased risk of PDA ( Table 34.1 ). However, the genetic basis for most cases of familial PDA remains unknown. Still, the influence of inherited genetics is clear: a family history of PDA significantly increases an individual’s risk for the disease.

Germline mutations in genes in the Fanconi anemia pathway, which encode proteins involved in repair of DNA cross-linking damage, have been strongly associated with familial PDA. Germline mutations in BRCA2 , a crucial component of this pathway, result in increased risk of breast, ovarian, pancreatic, and other cancers. Importantly, some patients with BRCA2 -related familial PDA have no personal or family history of breast or ovarian cancer, and the low penetrance of some germline BRCA2 mutations necessitates a high index of suspicion for this genetic alteration in patients with familial PDA. In addition to germline BRCA2 mutations, germline alterations in other genes in the Fanconi pathway also play important roles in familial pancreatic cancer. The gene PALB2 (also known as FANCN ) encodes a protein that interacts with the BRCA2 protein. Germline mutations in PALB2 account for a subset (~3%) of patients with familial PDA. Germline mutations in other Fanconi pathway genes, such as FANCC and FANCG , have been reported in young patients with PDA, but their specific role in familial PDA remains to be firmly established. In addition, although the importance of FANCA in familial PDA has been investigated, germline mutations in this gene do not significantly contribute to familial PDA. Finally, germline mutations in BRCA1 may slightly increase the risk of PDA in breast cancer kindreds, but mutations in this gene only minimally contribute to familial PDA in the absence of breast or ovarian cancer.

In addition to syndromes associated with germline mutations in Fanconi pathway genes, increased risk of PDA is also a key feature in several other inherited syndromes (see Table 34.1 ). Germline mutations in p16/CDKN2A cause familial atypical mole melanoma syndrome (FAMMM); patients with this syndrome have an increased risk of melanoma (with multiple nevi and atypical nevi) and PDA. Germline mutations in STK11/LKB1 are associated with Peutz-Jeghers syndrome (PJS), a syndrome associated with gastrointestinal hamartomas and pigmented macules on the lips and buccal mucosa, as well as cancer predisposition, including an increased risk of PDA. PDAs in these patients show somatic loss of the wild-type STK11/LKB1 allele, indicating the importance of biallelic inactivation of the gene for carcinoma development in these patients. Patients with hereditary pancreatitis are also at markedly increased risk for PDA. Hereditary pancreatitis, caused by germline mutations in PRSS1 and SPINK1 , is characterized by young age at onset and continuous or relapsing chronic pancreatic inflammatory disease. In contrast to patients with germline mutations in tumor suppressor genes, the increased risk of cancer in these patients appears to be the result of repeated bouts of inflammation and repair, and the increased cancer risk is limited to the pancreas.

In other inherited syndromes, the increased risk of PDA is less well established. Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) is caused by germline mutations in hMSH2 , hMLH1 , hPMS1 , hPMS2 or hMSH6 (formerly GTBP ) , which lead to defects in DNA mismatch repair (and thus microsatellite instability), as well as markedly increased risk of carcinomas of the colon and other sites. There appears to be a slight, but real, increased risk of PDA in patients with HNPCC. In addition, microsatellite instability caused by somatic mutations in one of these mismatch repair genes occurs in sporadic PDA and has been associated with a characteristic “medullary” morphology.

Germline mutations in the ATM gene, which encodes a protein with roles in DNA damage response as well as cell cycle regulation, also rarely occur in familial PDA kindreds. Whereas biallelic germline mutations in ATM cause ataxia-telangiectasia, a syndrome characterized by cerebellar ataxia, sensitivity to ionizing radiation, and increased frequency of multiple malignancies, germline heterozygous ATM mutations have been reported in approximately 2% of patients with familial PDA. Germline mutations in APC are the cause of familial adenomatous polyposis (FAP), a syndrome with a marked increase in adenomatous colorectal polyps as well as colorectal adenocarcinoma. Although an increased risk of PDA has been reported in patients with FAP, some of this risk probably reflects the increased risk of duodenal carcinomas, which can invade the pancreas and mimic primary PDA.

Somatic Alterations

In sporadic PDA, somatic alterations clearly play a crucial role in tumorigenesis ( Table 34.2 ). Whole exome sequencing of PDA revealed that each carcinoma contains an average of 48 nonsynonymous somatic mutations. Aside from known driver genes (discussed later), the individual genes altered in each carcinoma are markedly heterogeneous, but there are 12 core cellular pathways that are altered in the vast majority of carcinomas. These pathways, including KRAS signaling, transforming growth factor-β (TGF-β) signaling, DNA damage control, and cell adhesion, represent key cellular processes that are dysregulated in the development of PDA.

Numerous studies have shown that KRAS is the most frequently altered oncogene in PDA (somatic KRAS mutations are present in >90% of cancers), clearly indicating that this gene is a driver of tumorigenesis in the pancreas. KRAS is a small guanosine triphosphatase (GTPase) that mediates downstream signaling from growth factor receptors. Somatic mutations in KRAS cluster in a few specific hotspots (most commonly in codon 12), confirming the role of KRAS as an oncogene. Mutations have been reported in other oncogenes in the same cell-signaling pathway (including BRAF ) in rare KRAS wild-type carcinomas.

Several frequently altered tumor suppressor genes have also been identified in PDA, including p16/CDKN2A , TP53 , and SMAD4/DPC4 , and these genes also represent drivers in pancreatic tumorigenesis. p16/CDKN2A is the most frequently altered tumor suppressor gene in ductal adenocarcinoma, with loss of p16 protein function identified in more than 90% of carcinomas. Multiple genetic and epigenetic mechanisms underlie the loss of p16 protein expression, including intragenic mutation coupled with loss of the second allele, homozygous deletion of both copies of the gene, and promoter methylation. Loss of p16 results in cell cycle dysregulation, because this protein normally blocks cell cycle progression by preventing inactivation of the retinoblastoma tumor suppressor protein Rb, another important cell cycle regulator.

TP53 , which encodes a protein with a pivotal role in the cellular stress response, is another key tumor suppressor gene in PDA. Somatic mutations have been reported in approximately 75% of cases. These somatic mutations almost always occur through intragenic mutation followed by loss of the wild-type allele.

Somatic inactivation of SMAD4/DPC4 also occurs frequently in PDA. Homozygous deletion or intragenic mutation followed by loss of the wild-type allele occurs in approximately 55% of carcinomas. The Smad4 (Dpc4) protein mediates cellular signaling downstream of the TGF-β receptor. Less frequently, somatic mutations occur in other components of the same signaling pathway, including the TGF-β receptors, TGFBR2 and TGFBR1 ( ALK-5 ) .

In addition to these known driver genes, somatic mutations are present at a low prevalence in numerous other genes in PDA. However, the role of these genes as drivers or passengers is more difficult to establish when only a few mutations are identified. Infrequent mutations in genes known to be altered in other tumor types are likely to play a functional role in pancreatic neoplasia. For example, ARID1A , which encodes a chromatin remodeling protein, is rarely mutated in PDA (with somatic mutations in approximately 8% of carcinomas) but is frequently mutated in ovarian clear cell carcinomas (somatic mutations in >50% of carcinomas). Although the mutations in the pancreas are infrequent, the gene’s importance in ovarian cancer supports a role for mutations in ARID1A in pancreatic neoplasia. Similarly, the histone methyltransferase KMT2C (MLL3) is mutated in only a small percentage of PDA, but somatic mutations in this gene have been reported in several other tumor types, supporting a role for this gene in tumorigenesis in multiple organs.

In addition to small somatic mutations, large chromosomal gains and losses and complex karyotypic abnormalities also occur frequently in ductal adenocarcinoma. Some alterations target known driver genes, whereas many others (such as the frequently altered chromosome 6p) identify regions that may contain specific loci with important roles in pancreatic tumorigenesis. Further characterization and validation of specific target genes is necessary. Additionally, PDAs also contain alterations in microRNAs, small, noncoding RNAs that regulate gene expression. Differential expression of multiple microRNAs has been reported in PDA compared with nonneoplastic pancreatic tissue.

Although pancreatic intraepithelial neoplasia (PanIN) have been recognized histologically for years, data on the genetic alterations in PanIN lesions firmly established them as noninvasive precursors to PDA in 2001. As PanINs acquire increasing cytologic and architectural abnormality with increasing grade, they also sequentially acquire genetic alterations—the same alterations that occur in invasive PDA. Some molecular changes occur early and are present in low-grade PanINs, whereas others are limited to severely dysplastic and invasive lesions. KRAS mutation and loss of p16 expression are early events that are present in low-grade PanINs. When extremely sensitive techniques are used, KRAS mutations are identified in more than 90% of low-grade PanINs, suggesting that KRAS mutations may represent a key initiating step in pancreatic neoplasia. In contrast, loss of Smad4 and TP53 mutation are late events, occurring only in high-grade PanIN and invasive PDA. For both SMAD4/DPC4 and TP53 , allelic loss may occur earlier than somatic mutation, with a subset of intermediate-grade PanINs showing loss of one allele.

Alterations other than those in known driver genes also occur in PanINs. Telomere shortening is one of the most common early events in pancreatic tumorigenesis, with shortening detected in approximately 90% of low-grade PanINs. Early telomere shortening may make the cells susceptible to chromosomal fusion and anaphase bridges, which may produce some of the chromosomal abnormalities observed in invasive PDA.

In addition to expanding knowledge of precursors to PDA, detailed study of somatic mutations in primary tumors and metastases has deepened understanding of the process of clonal evolution within tumors, enabling estimation of evolutionary time in tumors. These studies suggest a time window of approximately 15 years between tumor initiation and the acquisition of metastatic ability, providing a broad time window for early detection and subsequent clinical intervention.

Implications for Pathology

Knowledge of the genetic underpinnings of familial PDA has direct clinical implications for pathologists in several ways. First, the pathologist is the first to have the opportunity to recognize subtypes of pancreatic cancer (e.g., “medullary” carcinoma) that are associated with specific familial syndromes. Second, some familial syndromes have specific treatment implications, which highlights the importance of recognizing them clinically at the time of diagnosis. For example, PDAs in patients with germline alterations in the Fanconi anemia pathway ( BRCA2 , PALB2 ) are exquisitely sensitive to drugs that target their specific DNA repair defect, such as mitomycin C and inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP). Carcinomas in patients with HNPCC also possess specific recommendations for treatment: tumors with microsatellite instability are resistant to fluorouracil-based chemotherapy. Finally, clinical recognition of familial PDA syndromes lead to increased screening of at-risk patients. Knowledge of these syndromes is crucial in the interpretation of specimens from these patients.

Somatic alterations in sporadic PDA also affect pathology practice. Immunohistochemistry can be used to demonstrate alterations of protein expression that are indicative of characteristic gene mutations. For example, TP53 mutations result in strong diffuse TP53 nuclear labeling by immunohistochemistry, providing a histologic surrogate for the genetic alteration and a potential technique for identifying neoplastic pancreatic cells ( Fig. 34.1 ). In addition, loss of Smad4 protein expression by immunohistochemistry correlates with genetic alterations in the SMAD4/DPC4 gene ( Fig. 34.2 ). This technique can be used to distinguish PDA (loss of Smad4) from nonneoplastic pancreatic diseases (retention of Smad4) and may suggest that a metastatic adenocarcinoma is of pancreatobiliary origin. Importantly, this technique can also be used to evaluate prognosis in ductal adenocarcinomas, because mutations in SMAD4/DPC4 have been associated with a worse prognosis.

TP53 immunohistochemistry in pancreatic ductal adenocarcinoma. Immunohistochemical labeling for the TP53 protein shows aberrant strong nuclear labeling in this neoplastic gland of a pancreatic ductal adenocarcinoma, whereas the associated nonneoplastic stroma is negative.

Smad4 (Dpc4) immunohistochemistry in pancreatic ductal adenocarcinoma. Immunohistochemical labeling for the Smad4 protein shows loss of expression in the neoplastic glands of a pancreatic ductal adenocarcinoma, whereas the associated non-neoplastic stromal cells retain normal nuclear labeling.

Molecular studies interrogating genetic alterations also demonstrate clinical utility. For example, molecular analyses of KRAS , TP53 , and SMAD4/DPC4 can supplement morphologic diagnosis in cytology specimens to increase the sensitivity of fine-needle aspiration. In addition, microRNA levels in fine-needle aspiration specimens show diagnostic promise as indicators of ductal adenocarcinoma or mucinous pancreatic cysts. It has been suggested that microRNA profiles can be used to prognosticate in some cases. Finally, with the continuous development of targeted therapies, molecular studies will likely serve a critical role in determining eligibility for therapy.

Germline Alterations

IPMNs are large, noninvasive, mucin-producing precursor lesions that arise in the larger pancreatic ducts. IPMNs occur rarely in inherited cancer predisposition syndromes (see Table 34.1 ). For example, they have been reported in patients with PJS, caused by germline mutations in the STK11/LKB1 gene on chromosome 19p. IPMNs in patients with PJS frequently undergo loss of heterozygosity (LOH) at the STK11/LKB1 gene locus, suggesting a second somatic hit to the remaining wild-type allele. In addition, IPMNs have been reported in patients with HNPCC (Lynch syndrome) and FAP, suggesting that IPMNs may be uncommon extracolonic manifestations of these syndromes. Germline alterations in BRCA2 have also been reported in patients with IPMN and a family history of PDA.

Somatic Alterations

Recent whole exome sequencing of noninvasive sporadic IPMNs identified an average of 26 nonsynonymous mutations per IPMN (approximately half as many as in invasive ductal adenocarcinoma). Many of the genes mutated in IPMNs are the same ones commonly mutated in PDAs (see Table 34.2 ). Somatic point mutations in KRAS occur frequently in IPMNs (30% to 70% of cases), with increasing mutation prevalence in neoplasms with higher grades of dysplasia or invasive adenocarcinoma. When extremely sensitive techniques are used, KRAS mutations are identified in 80% of IPMNs. Somatic mutations in TP53 have also been reported in IPMNs with high-grade dysplasia or invasive carcinoma, and TP53 overexpression similarly occurs in the most dysplastic areas. Smad4 expression is retained in most noninvasive IPMNs but is lost in approximately one third of IPMN-associated invasive carcinomas. Therefore, the frequency of Smad4 loss is lower in IPMN-associated invasive carcinomas than in invasive ductal adenocarcinomas not arising in association with an IPMN. Loss of p16 protein expression occurs in IPMNs both with and without associated invasive carcinomas, but the frequency of p16 loss is much higher in IPMNs with associated carcinoma (as much as 100% of IPMN-associated invasive carcinomas, compared with 10% of noninvasive IPMNs). Promoter hypermethylation of the p16/CDKN2A gene is a frequent mechanism of expression loss; it occurs in more than 50% of all IPMNs, including those with and without associated carcinoma.

In addition to alterations in genes frequently altered in PDA, IPMNs also contain mutations in genes that are unique among pancreatic neoplasms (see Table 34.2 ). Somatic mutations in GNAS have been reported in approximately 60% of IPMNs. The protein encoded by GNAS plays a crucial role in numerous signaling pathways by coupling transmembrane receptors to their downstream signaling proteins. The GNAS mutations in IPMNs all occur in a previously described oncogenic hotspot (codon 201), providing strong evidence for their functional importance in IPMNs. Mutations in GNAS are most prevalent in intestinal-type IPMNs but occur in most histologic subtypes, with the possible exception of oncocytic IPMNs. In IPMNs with associated invasive carcinoma, GNAS mutations are identified in both noninvasive and invasive components, providing further genetic evidence that IPMNs give rise to invasive carcinoma.

The gene RNF43 is also frequently altered in IPMNs; approximately 75% of IPMNs contain somatic mutations in RNF43 , which encodes an E3 ubiquitin ligase. The majority of these alterations are nonsense substitution mutations that lead to the insertion of stop codons and thus to loss of function of the encoded protein. This mutation pattern, along with frequent LOH at the RNF43 locus on chromosome 17q, provides strong evidence that RNF43 is a tumor suppressor gene in IPMNs. Approximately 10% of intestinal-type IPMNs contain somatic mutations in PIK3CA , the catalytic component of a crucial cell signaling pathway known to be an oncogene in several other tumor types, and some somatic mutations in IPMNs occur at previously described oncogenic hotspots in PIK3CA. Approximately 5% of sporadic IPMNs contain mutations in STK11/LKB1 (the locus of PJS), and rare mutations in EGFR (epidermal growth factor receptor) and ERBB2 (also called Her2/Neu ) have been reported in IPMNs, although the functional significance of these latter mutations is not yet established.

Genetic mechanisms other than somatic mutation also likely play a role in the development of IPMNs. Large chromosomal alterations have been identified in IPMNs with all grades of dysplasia, but these alterations are more frequent in neoplasms with intermediate- or high-grade dysplasia compared with those with low-grade dysplasia. Promoter hypermethylation occurs in several genes in IPMNs, and hypermethylation is more prevalent and more extensive in IPMNs with associated invasive adenocarcinoma than in those without adenocarcinoma. MicroRNAs may also play a role in IPMN pathogenesis, because significantly higher expression of miR-21, miR-221, and miR-17-3p has been reported in IPMN cyst fluid compared with fluid from nonmucinous cysts.

Implications for Pathology

These genetic data provide strong evidence for the role of IPMNs as a precursor to PDA, a role strongly supported by clinical data as well. The knowledge of frequent somatic mutations in IPMNs can also be used in the development of diagnostic assays. As in PDAs, neoplastic cells with mutations in TP53 can be identified with immunohistochemical stains. In addition, mutations from neoplastic cells can be detected in aspirated cyst fluid, indicating that molecular analyses of cyst fluid may be useful as a preoperative diagnostic tool in pancreatic cysts. Importantly, more than 95% of IPMNs contain a somatic mutation in either KRAS or GNAS , suggesting that a molecular assay involving these two genes may be highly sensitive for the identification of IPMNs. In addition, the specificity of RNF43 mutations for mucin-producing cystic lesions suggests that assays for these mutations may hold future diagnostic promise. Finally, identification of microRNAs shows promise in preoperative diagnosis of pancreatic cysts, because several microRNAs are differentially expressed in mucin-producing versus non–mucin-producing cysts.

Germline Alterations

There is no known genetic predisposition or association with particular genetic syndromes for mucinous cystic neoplasm (MCN).

Somatic Alterations

Frequent somatic mutations occur in MCNs. Recent whole exome sequencing of noninvasive MCNs revealed an average of 16 nonsynonymous mutations per MCN, fewer than in IPMN or invasive ductal adenocarcinoma. Similar to IPMNs, MCNs contain frequent somatic alterations in genes that are commonly mutated in PDA (see Table 34.2 ). Somatic mutations in KRAS oncogenic hotspots occur frequently in MCNs. Mutation prevalence correlates with degree of dysplasia (30% KRAS mutation prevalence in MCNs with low-grade dysplasia versus 80% KRAS mutation prevalence in MCNs with high-grade dysplasia or associated invasive carcinoma). Somatic mutation of TP53, as well as TP53 protein overexpression, are limited to MCNs with high-grade dysplasia. Loss of Smad4 protein expression, indicating somatic mutation in the SMAD4/DPC4 gene, has been reported primarily in invasive carcinomas associated with MCNs. Loss of Smad4 expression occurs in only 14% of MCN-associated carcinomas, a far lower prevalence rate than in invasive carcinomas not associated with MCNs. The p16/CKDN2A gene is also infrequently altered in MCNs; Somatic mutation has been reported in a neoplasm with high-grade dysplasia, and promoter hypermethylation occurs in approximately 15% of MCNs. In addition, aneuploidy has been reported in MCNs and is associated with poor prognosis.

These findings suggest a stepwise genetic progression in MCNs, from low-grade dysplasia to invasive carcinoma, in which KRAS mutation is an early event and loss of Smad4 is a late event. This concept is supported by the finding in a mouse model of pancreatic neoplasia that oncogenic KRAS mutation and haploinsufficiency of SMAD4/DPC4 led to the development of MCNs, associated with the occurrence of additional somatic alterations in TP53 , p16/CDKN2A , and SMAD4/DPC4 .

In addition to mutations in genes frequently altered in PDA, MCNs also share alterations in genes unique to mucin-producing cyst-forming neoplasms of the pancreas (see Table 34.2 ). Similar to IPMNs, MCNs contain frequent alterations in RNF43 ; approximately 40% of MCNs harbor somatic mutations in RNF43 , and these mutations are enriched for nonsense substitutions.

Molecular studies have also provided insight into the biphasic nature of MCNs. Gene expression studies suggest different expression profiles in the epithelial and stromal components. Activation of the Notch pathway ( JAG1 and HES1 ) occurs in the epithelial component and activation of estrogen metabolism ( STAR and ESR ) occurs in the stromal component. The genetic or epigenetic bases for these differences remain unclear. In exceedingly rare mixed malignant neoplasms with both epithelial and high-grade “sarcomatous” components, LOH studies suggest a monoclonal origin for the two components with subsequent genetic and morphologic divergence.

Implications for Pathology

Immunohistochemical staining for TP53 and Smad4 facilitates identification of high-grade neoplastic cells in MCNs, although the prevalence rate of alterations in these genes is far lower in MCNs than in PDAs. As in IPMNs, identification of mutations in DNA from cyst fluid (including mutations KRAS and RNF43 ) represents a promising preoperative diagnostic test to determine the likelihood of a premalignant mucin-producing cyst.

Germline Alterations

Serous cystadenomas (SCAs) occur in approximately 90% of patients with von Hippel-Lindau (VHL) syndrome, an autosomal dominant disorder that is characterized by the development of clear cell neoplasms in multiple organs (see Table 34.1 ). VHL is caused by germline mutations in the VHL gene on chromosome 3p, which encodes a regulator of the hypoxia-inducible factor 1 (HIF1α) pathway. SCAs that occur in this syndrome are often combined serous-neuroendocrine neoplasms.

Somatic Alterations

A recent whole exome sequencing study of sporadic SCAs identified approximately 10 nonsynonymous somatic alterations per tumor, approximately half the number of alterations in IPMN and far fewer than in invasive PDA. Importantly, SCAs lack somatic alterations in genes frequently mutated in invasive PDA, such as KRAS and TP53 (see Table 34.2 ). Sporadic SCAs frequently contain somatic mutations of the VHL gene, which has been reported in as many as 50% of SCAs. LOH at the VHL locus on chromosome 3p also occurs in a large proportion of sporadic SCAs. In addition to frequent loss of chromosome 3p, allelic loss of chromosome 10q has been reported in 50% of SCAs, and loss of several other chromosomal regions occurs less frequently. No target genes for these latter losses have been identified. Aberrant methylation at a few loci has been reported in only a small proportion of SCAs.

Implications for Pathology

The frequency of SCAs in patients with VHL syndrome requires a high index of suspicion when examining pancreata from these patients. Conversely, the finding of multiple SCAs or a combined serous-neuroendocrine neoplasm should raise the suspicion that the patient has VHL. In addition, VHL mutations have been identified in DNA from pancreatic cyst fluid. The specificity of these mutations for SCAs suggest that molecular assays to identify VHL mutations in cyst fluid may provide a useful preoperative diagnostic test, separating cysts with a risk of malignant progression (IPMNs and MCNs) from benign cysts (SCAs).

Germline Alterations

Pancreatic neuroendocrine tumors (PanNETs) occur as a key feature of many inherited syndromes (see Table 34.1 ). PanNETs occur in 60% to 70% of patients with multiple endocrine neoplasia syndrome type 1 (MEN1), an autosomal dominant syndrome characterized by neuroendocrine lesions of the parathyroid, pituitary, pancreas, duodenum, and adrenal. MEN1 is caused by germline mutations in the MEN1 gene on chromosome 11q. PanNETs also occur in 5% to 10% of patients with VHL syndrome, which is caused by germline mutations in the VHL gene on chromosome 3p. Patients with VHL are predisposed to neoplasms in various organs, including the adrenal glands, kidneys, and pancreas, many of which are composed of optically clear neoplastic cells.

In addition, PanNETs occur rarely in other genetic syndromes. Tuberous sclerosis complex is caused by germline mutations in TSC1 on chromosome 9q or TSC2 on chromosome 16p. This autosomal dominant clinical syndrome is characterized by the development of hamartomas and rare malignant neoplasms, and PanNETs are a rare feature. Neurofibromatosis type 1 (NF1) is an autosomal dominant clinical syndrome characterized most prominently by nervous system abnormalities. PanNETs expressing somatostatin (somatostatinomas) are a rare finding in this syndrome, which is caused by germline mutations in the tumor suppressor gene NF1 on chromosome 17q. Although pancreatic neoplasms have been reported, somatostatinomas occur more frequently in the duodenum of patients with NF1.

Somatic Alterations

In sporadic PanNETs, frequent somatic mutations occur in multiple genes (see Table 34.2 ). Sequencing of all protein coding genes in 10 PanNETs revealed an average of 16 nonsynonymous somatic mutations per PanNET, far fewer than in invasive PDA. Somatic mutations in MEN1 occur in 45% of sporadic PanNETs. LOH at the MEN1 locus also frequently occurs in PanNETs. Loss occurs in 30% to 70% of sporadic PanNETs, including some without somatic MEN1 mutations. Somatic mutations in MEN1 cause defects in MEN1 protein function, with loss of expression or aberrant localization. Additional mechanisms also likely cause MEN1 protein dysfunction, because some neoplasms without MEN1 mutation show aberrant MEN1 protein localization.

Somatic mutations in the ATRX and DAXX genes are also common in sporadic PanNETs. These somatic mutations, which occur in approximately 45% of sporadic PanNETs, inactivate the encoded proteins that function in a chromatic remodeling complex. The proteins encoded by ATRX and DAXX are components of a complex involved in telomere maintenance. Inactivating mutations in PanNETs are associated with the telomerase-independent telomere maintenance mechanism termed “alternative lengthening of telomeres (ALT).” Inactivating mutations in ATRX and DAXX are associated with acquisition of the ALT phenotype, indicating that the telomeres of PanNETs are fundamentally different from the telomeres of PDA, which exhibit telomere shortening and reactivation of telomerase. Moreover, mutations in ATRX and DAXX (as well as the ALT phenotype) occur late in the development of PanNETs: they occur only in large tumors (>3 cm) and are absent from microadenomas.

The cell signaling pathway of mammalian target of rapamycin (mTOR) is also altered in some PanNETs. Mutations in components of this pathway (including PIK3CA , PTEN , and TSC2 ) occur in approximately 15% of sporadic PanNETs. In addition to somatic mutations, LOH at the TSC2 locus on chromosome 16p occurs in approximately 30% of sporadic PanNETs.

Although rare alterations in some genes have been reported, PanNETs lack frequent alterations in genes commonly mutated in PDA, including KRAS , TP53 , SMAD4/DPC4 , and p16/CDKN2A. Somatic mutations in KRAS and BRAF have not been identified in PanNETs. Mutations in TP53 are rare in PanNETs, occurring in approximately 3% of neoplasms, a far lower prevalence rate than in PDA. However, dysregulation of the TP53 signaling pathway may still be important in PanNETs, because copy number alterations of TP53 regulators (e.g., MDM2 ) have also been reported in PanNETs. No mutations were identified in SMAD4 / DPC4 in a recent whole exome sequencing study of PanNETs. Neither homozygous deletion nor somatic mutation of p16/CDKN2A has been identified in PanNETs, but promoter hypermethylation of that locus occurs in approximately 50% of gastrinomas.

Several large chromosomal gains and losses (including some recurrent alterations) have been reported in PanNETs, but the target genes for most alterations remain to be identified. Promoter hypermethylation and deletion of the VHL locus on chromosome 3p occurs in approximately 35% of sporadic PanNETs, but no other target genes for aberrant methylation in PanNETs have been identified.

Implications for Pathology

Knowledge of the genetic syndromes predisposing to PanNETs (including MEN1 and VHL) allows recognition of these neoplasms in syndromic patients. In particular, pathologists need to carefully examine the duodenum in patients with MEN1, because small duodenal neuroendocrine tumors (gastrinomas) in these patients can metastasize to a peripancreatic lymph node and mimic a primary pancreatic neoplasm. In addition, some somatic alterations have prognostic implications—mutations in MEN1, ATRX , and DAXX have been associated with improved prognosis. Immunohistochemistry can be used to show loss of ATRX or DAXX protein expression in mutant cases ( Fig. 34.4 ). In contrast, the presence of multiple chromosomal abnormalities confers a worse prognosis in sporadic PanNETs regardless of the specific loci altered, and patients with these neoplasms are more likely to be seen with metastatic disease.

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