Genetics of Familial and Sporadic Pancreatic Cancer

Genetics of Familial and Sporadic Pancreatic Cancer

Gastroenterology 2019;-:1–15 Q1 Q2 Q3 Q33 Genetics of Familial and Sporadic Pancreatic Cancer Laura D. Wood1,2 Matthew B. Yurgelun3,4 PANCREATIC...

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Gastroenterology 2019;-:1–15

Q1 Q2 Q3

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Genetics of Familial and Sporadic Pancreatic Cancer

Laura D. Wood1,2

Matthew B. Yurgelun3,4

PANCREATIC CANCER

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Michael G. Goggins1,2,5

1

Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; 3Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; 4Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and 5Department of Medicine, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland In the previous decade, comprehensive genomic analyses have yielded important insights about the genetic alterations that underlie pancreatic tumorigenesis. Wholeexome and whole-genome sequencing of pancreatic ductal adenocarcinomas have confirmed the critical driver genes altered in the majority of pancreatic cancers, as well as identified numerous less frequently altered driver genes, and have delineated cancer subgroups with unique biological and clinical features. It is now appreciated that pancreatic susceptibility gene alterations are often identified in patients with pancreatic cancer without family histories suggestive of a familial cancer syndrome, prompting recent efforts to expand gene testing to all patients with pancreatic cancer. Studies of pancreatic cancer precursor lesions have begun to elucidate the evolutionary history of pancreatic tumorigenesis and to help us understand the utility of biomarkers for early detection and targets to develop new therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic ductal adenocarcinoma and its precursor lesions, and we highlight translational applications in early detection and therapy.

Keywords: Pancreatic Cancer; Mutation; Gene Testing; Progression Model.

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ancreatic cancer is a deadly disease with a dismal prognosis that is predicted to be the second-leading cause of cancer death in the United States by 2030.1 The morbidity and mortality of pancreatic cancer are fueled by 2 clinical gaps—the lack of effective early detection approaches and the lack of efficacious therapies. Recent comprehensive genomic characterization of pancreatic cancers and their precursor lesions have provided critical insights that can help close these gaps. Identification of the somatic and germline genetic alterations that underlie pancreatic tumorigenesis can provide biomarkers for use in

early detection strategies and can form a rational foundation for the design of screening and surveillance programs. Moreover, knowledge of the genomic landscape of pancreatic cancer has informed clinical trials to develop new targeted therapeutic strategies. In this review, we discuss the results of comprehensive genomic characterization of pancreatic neoplasms, along with the translational application to early detection and therapy.

The Molecular Landscape of Sporadic Pancreatic Cancer The most frequently altered driver genes in pancreatic cancer were identified through traditional molecular genetic approaches before the broad application of genomesequencing technology (Table 1).2 Activating mutations in the oncogenic hotspots in exons 2 and 3 of KRAS occurs in the vast majority (>90%) of pancreatic ductal adenocarcinomas (PDACs), leading to activation of the downstream mitogen-activated protein kinase pathway.3–5 Mutations in 3 tumor suppressor genes also occur commonly in PDAC. Function of the p16 protein, a key regulator of the cell cycle encoded by the CDKN2A gene, is frequently lost in PDAC. The percentage of PDACs with mutational inactivation of CDKN2A underestimates its role as a tumor suppressor gene, because many PDACs inactivate CDKN2A by homozygous deletions that often goes undetected, and gene silencing by promoter methylation also occurs.6,7 Overall, approximately 90% of PDACs inactivate CDKN2A. Mutations Abbreviations used in this paper: ctCNA, circulating tumor DNA; ICGC, International Cancer Genome Consortium; IPMN, intraductal papillary mucinous neoplasm; PARP, poly(adenosine diphosphate) ribose polymerase; PanIN, pancreatic intraepithelial neoplasia; PDAC, pancreatic ductal adenocarcinoma; PDO, patient derived organoid; TGF, transforming growth factor. © 2019 by the AGA Institute 0016-5085/$36.00 https://doi.org/10.1053/j.gastro.2018.12.039

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in TP53, which encodes a protein critical for the DNA damage response, are also common (occurring in 70%–85% of PDACs), and most frequently involve missense mutation followed by loss of the second allele.8–10 Finally, loss of Smad4 function leading to altered transforming growth factor-b (TGFb) signaling, most commonly by inactivating somatic mutation or homozygous deletion of SMAD4, occurs in approximately 50% of PDACs.11 Overall, the cellular and molecular effects of these critical driver genes are complex and have been reviewed in detail elsewhere.12–15 The altered cellular signaling induced by these somatic mutations leads to phenotypes previously described as “hallmarks of cancer,” such as sustained proliferative signaling, resistance to cell death, and invasion.16 However, the precise mechanisms by which specific somatic mutations contribute to malignant cell phenotypes are still being elucidated. A decade ago, Jones et al17 published the first wholeexome sequencing analysis of pancreatic ductal adenocarcinoma, confirming these 4 mountains that comprise the frequently altered driver genes in the pancreatic cancer genome landscape: the oncogene KRAS and the tumor suppressor genes CDKN2A, TP53, and SMAD4.17 Since then, hundreds of PDACs have been comprehensively analyzed, including whole-exome and whole-genome sequencing approaches. These sequencing efforts, which include collaborative efforts by the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas, as well as individual research groups, have provided a wealth of information about the genetic alterations that underlie pancreatic tumorigenesis, allowing insights with clinical implications. These larger comprehensive PDAC sequencing studies have highlighted several important hills in the PDAC landscape, infrequently altered genes that are likely to be drivers of pancreatic tumorigenesis (Table 1). For example, in the first report of data from the ICGC effort, Biankin et al18 identified recurrent mutations in axon guidance pathway genes, including SLIT2 and ROBO2. Several studies have confirmed the importance of chromatin remodeling genes in pancreatic tumorigenesis, including MLL3, ARID1A, ARID2, and KDM6A18–20; importantly, an association has been reported between mutations in MLL genes and improved prognosis.20 Such comprehensive genetic analyses also highlight the importance of considering genes as components of integrated cellular pathways. For example, although KRAS is by far the most common method for activation of the mitogen-activated protein kinase pathway in PDAC, oncogenic hotspot mutations in BRAF have also been reported in KRAS wild-type tumors,21 and a small subset of PDACs harbor ERBB2 amplification.22 Other KRAS wild-type PDACs have been reported to have oncogenic mutations in CTNNB1, highlighting the importance of WNT signaling in at least a subset of PDACs.23 Similarly, although the TGFb pathway is commonly altered by inactivating SMAD4 mutation, mutations in TGFBR2, ACVRB1, and other related genes also occur.21,24 Other genes that are mutated in a small percentage of PDACs include FBXW7, which results in overexpression of cyclin E, and the spliceosome gene SF3B1,

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which contributes to aberrant splicing. More recent studies have integrated genomic, transcriptomic, proteomic, and methylomic analyses.23 Widespread epigenetic changes occur during pancreatic tumorigenesis,25,26 and in a minority of pancreatic cancers these events can lead to gene silencing of tumor suppressor genes such as CDKN2A and CDH1.27,28 In addition to identifying mutated genes that drive pancreatic tumorigenesis, patterns of somatic mutations Q11 identified by whole-exome or whole-genome sequencing can also be used to suggest underlying mutagenic processes.29 Application of these patterns (so-called mutational signatures) to pancreatic cancer showed 7 different signatures in sequenced PDAC samples.30 Four major subtypes of PDAC were identified based on mutational signature: an age-related group, a group with defects in DNA doublestrand break repair, a group with defects in DNA mismatch repair, and a group characterized by a signature of unknown etiology (controversially associated with smoking). The group with the signature suggestive of defects in double-strand break repair had many structural rearrangements, and the group with the signature suggestive of mismatch repair defects had germline or somatic mutations in mismatch repair with resultant loss of protein expression, showing the expected result of these mutational processes. Although point mutations are critical drivers of pancreatic tumorigenesis, copy number alteration and chromosomal rearrangements are also likely to play an important role. Focal amplification is a known mechanism for oncogene activation and occurs at the MYC locus on chromosome 8q24 in a subset of PDACs with a worse prognosis, and homozygous deletion is a frequent mechanism for inactivation of well-characterized tumor suppressor genes such as CDKN2A and SMAD4.21 The role of chromosomal rearrangements has also been increasingly appreciated. Waddell et al19 reported whole-genome sequencing of 100 PDACs as part of the ICGC effort, identifying many chromosomal rearrangements but without detecting any recurrent gene fusions. The pattern of chromosomal rearrangements can be used to classify PDACs into 4 subtypes: stable, locally rearranged, scattered, and unstable. The unstable subtype, with >200 structural variation events, was associated with deleterious mutations in BRCA1, BRCA2, and PALB2, as well as with a mutation signature indicative of loss of function in BRCA pathway genes. Importantly, only half of the tumors with an unstable genome had identified mutations in BRCA pathway genes, suggesting alternative mechanisms for genomic instability in these tumors. These findings have important clinical implications, because patients with genomic instability due to defective DNA repair are especially susceptible to specific types of chemotherapy (see the “Translational Oncology” section). The importance of chromosomal rearrangements in pancreatic tumorigenesis was also highlighted by Notta et al31 in their whole-genome analysis of more than 100 PDACs. This study identified polyploidization (with either tetraploidy or hexaploidy) in almost half of PDACs; computational analyses of tumor sequencing data suggested

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Table 1.Driver Genes With Frequent Somatic Mutations in Pancreatic Neoplasms Gene

Mutation prevalencea

Gene type

Mutated neoplasms

Alteration type

KRAS CDKN2A

Common Common

Oncogene TSG

PanIN, IPMN, PDAC PanIN, IPMN, PDAC

Missense mutation Inactivating mutation/LOH, homozygous deletion Missense mutation/LOH

TP53

Common

TSG

PanIN, IPMN, PDAC

SMAD4

Common

TSG

PDAC

GNAS RNF43 ARID1A

Common Common Uncommon

Oncogene TSG TSG

IPMN, PDAC IPMN, PDAC PDAC

Inactivating mutation/LOH, homozygous deletion Missense mutation Inactivating mutation/LOH Inactivating mutation/LOH

SLIT2 BRCA2 MYC

Uncommon Uncommon Uncommon

TSG TSG Oncogene

PDAC PDAC PDAC

Mutation/LOH Inactivating mutation/LOHb Amplification

ERBB2c

Uncommon

Oncogene

PDAC

Amplification

Affected pathways MAPK signaling Cell cycle control DNA damage response TGFb signaling G-protein signaling Ubiquitin signaling Chromatin remodeling Axon guidance DNA repair Transcriptional regulation EGF signaling

Related altered genes BRAF FBXW7, RB1 — TGFBR2, ACVRB1 — — MLL3, ARID2, KDM6A ROBO2 ATM, PALB2 — —

LOH, loss of heterozygosity; MAPK, mitogen-activated protein kinase; TSG, tumor suppressor gene. a Common: >20% prevalence; uncommon: <10% prevalence. b Germline mutations also frequently occur. c Amplifications or fusions involving RET, BRAF, ALK, ROS1, and NTRK are rare (<1%) in PDAC but are therapeutically targetable.

that point mutations typically precede polyploidization, whereas copy number alterations occur afterward. In addition, they found that >60% of PDACs harbored at least 1 chromothripsis event, some of which altered known driver genes such as SMAD4. These results suggest the rapid (termed catastrophic) accumulation of copy number and chromosomal alterations in PDAC, which lies in contrast to the gradual accumulation of point mutations in key driver genes documented by analysis of pancreatic cancer precursor lesions (see the “Genetic Alterations in Pancreatic Cancer Precursor Lesions” section). Still, several genetic events are required for malignant transformation in the pancreas, including oncogene mutation and loss of both alleles of multiple tumor suppressor genes. Thus, multistep tumorigenesis occurs even if a copy number or chromothripsis event decreases the number of steps by targeting more than 1 driver gene at the same time. For example, a theoretical pancreatic cancer with an activating KRAS mutation and inactivation of CDKN2A and TP53 would require 5 gene alterations (KRAS mutation and inactivation of both copies of the 2 tumor suppressor genes). A chromothripsis event that caused simultaneous loss of 2 tumor suppressor loci would reduce the number of genetic events from 5 to 4, but it would not eliminate the need for sequential accumulation of genetic events. Comprehensive genetic analysis of primary and metastatic tumors from the same patients provides a unique opportunity to study the genetic basis and timing of metastatic progression. Analysis of such tumors harvested at autopsy from PDAC patients has shown that the clonal populations that give rise to the distant metastasis are present in the primary tumor, suggesting that there is not a recurrent genetic alteration that drives metastasis.32

Mathematical modeling from these data suggest a latent time of more than 15 years between the initiating mutation and the acquisition of metastatic ability, pointing to a broad time window for detection of a pancreatic neoplasm before metastasis.32 Moreover, mutations in well-characterized driver genes are present homogeneously throughout the primary tumor and metastasis, whereas the majority of alterations that are discordant between different metastases are likely passengers.33 Similarly, polyploidy, copy number alterations, and chromothripsis have been reported to be shared among the primary tumor and all metastases, suggesting that these types of alterations also precede the development of metastasis.31 In addition to the use of comprehensive DNA sequencing to identify somatic mutations, the gene expression of many PDACs has also been analyzed, either with microarrays or, more recently, RNA sequencing. Several studies have reported subtyping of pancreatic cancers based on transcriptomic profiling.34–36 Although the specific groups differ in each study, a shared theme is the distinction between a group with a classical/progenitor signature and a group with mesenchymal/basal features. A recent comprehensive study by The Cancer Genome Atlas confirmed the equivalence of these 2 expression groups across studies, and other reported subtypes are likely to reflect contamination of nonneoplastic exocrine or immune cells.23 These gene expression subtypes have clinical implications, with the mesenchymal/basal subtype showing worse prognosis in multiple studies.34–36 Deconvolution of gene expression data has also identified stroma-specific signatures, with activated stroma conferring a decreased survival.34 However, these epithelial and stromal transcriptomic subtypes have yet to be broadly applied for prognostication in clinical practice.

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Genetic Underpinnings of Familial Pancreatic Cancer

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The major known familial pancreatic cancer susceptibility genes include the BRCA2, ATM, PALB2, CDKN2A, PRSS1, MLH1 and MSH2, STK11, and TP53 genes (Table 2).37–43 All of these genes (with the exception of PRSS1 mutations, which cause pancreatic cancer by predisposing patients to hereditary pancreatitis), are cancer susceptibility genes that predispose to other cancers. Two additional genes that have been recently implicated as pancreatic cancer susceptibility genes encode for pancreatic enzymes, CPA1 and CPB1, with rare deleterious variants identified in approximately 1% of patients with pancreatic cancer.44 Germline mutations in CPA1 are known to cause recurrent acute pancreatitis, but mutation carriers may develop pancreatic cancer without prior attacks of pancreatitis.44 Recent studies have investigated pancreatic cancer susceptibility by using gene panels of other cancer predisposition genes; these studies have also identified rare germline mutations in other genes in patients with pancreatic cancer, including RAD51C and others43,45–47; deleterious variants in these genes are so uncommon in the population that it is difficult even with large studies to establish whether these genes contribute to pancreatic cancer susceptibility.46 Mutations in other genes such as CHEK2 that are not rare in the population are associated with a moderately increased risk of breast cancer but have not been conclusively associated with pancreatic cancer, although they have been identified in some pancreatic cancer probands, possibly as incidental findings.46 The most commonly mutated germline susceptibility genes in patients with pancreatic cancer in most populations involve BRCA2 or ATM45,46; deleterious germline mutations involving other genes are much less common The mutation prevalence is higher in populations with common founder mutations, such as those with many individuals of Ashkenazi Jewish heritage because of the common BRCA2 founder mutation in that population48–53 or the Dutch founder mutation involving CDK2NA.54 The average lifetime risk of developing pancreatic cancer is highest among patients who carry germline mutations in PRSS1 (w30%),40 STK11 (w30%),55 and CDKN2A (w17%).56 Germline mutations in BRCA2 are thought to increase the risk of pancreatic cancer by approximately 6-fold, to a cumulative lifetime risk of approximately 7%.57–59 The penetrance of PALB2 mutations to cause pancreatic cancer is not yet known, but it is thought to be similar to those with BRCA2 mutations60; this is the case for breast cancer among PALB2 mutation carriers.61 Germline BRCA1 mutations increase the average overall risk of developing pancreatic cancer by approximately 2fold.41,43,62,63 The penetrance of ATM mutations to cause pancreatic and other cancers is not yet known. The cancer risk estimates for these susceptibility gene mutations are approximate and vary depending on the germline variant and other inherited and environmental factors. The role of other genes in pancreatic cancer susceptibility is still being evaluated. Inherited mutations in known pancreatic cancer susceptibility genes explain only a small

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portion (<20%) of the familial clustering of pancreatic cancer, suggesting that other pancreatic cancer susceptibility genes remain to be identified. Some of the familial clustering of pancreatic cancer may be due to the combined effects of numerous low-penetrance variants (such as ABO, TERT, PDX1, and others) that have been identified in genome-wide association studies.64–70 One of the implications of the incomplete penetrance of cancer susceptibility gene variants is that evaluation of a careful cancer family history, although a very important cancer risk assessment tool,71 is not a comprehensive tool for identifying families with cancer susceptibility gene mutations. Therefore, it is not surprising that many individuals with germline mutations in cancer susceptibility genes have apparently sporadic forms of cancer. Recent studies have found that approximately 5% (and higher in certain populations47) of patients with apparently sporadic forms of pancreatic cancer (ie, without a family history of pancreatic cancer) have germline mutations in a pancreatic cancer susceptibility gene45,46; the prevalence among those with a family history of pancreatic cancer is somewhat higher,41,53,72–74 but overall, most germline mutations are found in individuals who do not have a family history of pancreatic cancer or a family history suggestive of an inherited cancer syndrome.45 Because of the potential value of identifying a germline susceptibility gene for patients and their families (more options for personalized medicine75 and the cancer screening and cancer prevention strategies family members can undertake54,76–79), routine gene testing for inherited susceptibility is now being advocated for patients with newly diagnosed pancreatic cancer. Recent National Comprehensive Q12 Cancer Network guidelines now include the recommendation to consider offering germline gene testing after appropriate counseling to all patients with a personal history of pancreatic cancer, regardless of family history or age at diagnosis. The clinical value of such routine germline gene testing of newly diagnosed pancreatic cancer is still being determined. Gene testing can be readily performed with panel testing that includes dozens of cancer susceptibility genes. The advantage of testing large panels of genes for variants is counterbalanced by the drawback that not infrequently, panel gene testing identifies 1 or more so-called deleterious variants that are only weakly associated with cancer risk, equivalent to the approximately 1.4-fold elevated risk of having pancreatic cancer for carriers of A or B blood groups, relative to blood group O.65,80 Interpreting such results can be challenging for practitioners not well grounded in genetic medicine and can create anxiety for patients. For gene mutation carriers, knowledge of their cancer susceptibility does hold the potential benefit of managing their risk with cancer screening. The utility of pancreatic screening and surveillance is still being evaluated, although recent evidence points to improvements in pancreatic cancer outcome for individuals who meet criteria for surveillance and who undertake regular surveillance. Initial studies from the Johns Hopkins Cancer of the Pancreas (ie, CAPS) program and from a European cohort that included individuals with the Dutch founder CDKN2A mutation found that regular surveillance with pancreatic imaging (mainly

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Table 2.Pancreatic Cancer Susceptibility Genes

Elevated relative risk of developing PDACa

BRCA2

w2

w6

Homologous repair

Breast, ovarian, prostate

ATM

w2

w6

DNA repair

Breast, prostate

BRCA1

0.5

w2.5-

Homologous repair

Breast, ovarian, prostate, colorectal

CDKN2A PALB2

0.4 0.4

w12–20 w6

Cell cycle Homologous repair

Melanoma Breast

MLH1

0.2

w7

Mismatch repair

MSH2

<0.1

w7

Mismatch repair

MSH6

0.4

w?

Mismatch repair

TP53 STK11

0.1 <0.1

w7 w30

DNA repair AMPK signaling

PRSS1

<0.1

w10

CPA1

0.5

?

CPB1

0.5

?

Trypsin activation causing pancreatitis Acinar-cell ER stress causing pancreatitis Acinar-cell ER stress causing pancreatitis

Colorectal, gynecologic, urothelial, brain, stomach, intestinal, others Colorectal, gynecologic, urothelial, brain, stomach, intestinal, others Colorectal, gynecologic, urothelial, brain, stomach, intestinal, others Numerous Breast, GI tract, gynecologic, lung, others None

Gene

Predominant mechanism

Other cancers

Implications for PDAC patients

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Platinum/PARP inhibitor–based therapyb Possible radiosensitivityc Platinum/PARP inhibitor based therapyb ? Platinum/PARP inhibitor based therapyb Checkpoint inhibitor immunotherapy

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Common founder mutation in w1% of Jewish ethnicity Biallelic germline ATM mutations cause ataxiatelangiectasia syndrome Common founder mutation in w1% of Jewish ethnicity FAMMM syndrome —

Lynch syndrome

Checkpoint inhibitor immunotherapy

Lynch syndrome

Checkpoint inhibitor immunotherapy

Lynch syndrome

? —

Li-Fraumeni syndrome Peutz–Jeghers syndrome

?

Hereditary pancreatitis

None

?

None

?

Hereditary pancreatitis Subclinical pancreatitis Subclinical pancreatitis

AMPK, adenosine monophosphate–activated protein kinase; ER, endoplasmic reticulum; FAMMM, familial atypical multiple mole melanoma; GI, gastrointestinal. a From Hu et al.37 Chemosensitivity to PARP inhibitors/platinums if wild-type allele is inactivated in the cancer. b The prevalence of deleterious variants in other known cancer susceptibility genes is too low, making it difficult to determine their role in pancreatic cancer susceptibility. c Radiosensitivity shown in PDAC cells in vitro.

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Prevalence of deleterious germline mutations in patients with PDAC, %

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magnetic resonance imaging/magnetic resonance cholangiopancreatography and endoscopic ultrasonography) leads to down-staging of pancreatic cancer and better 5year survival after a pancreatic cancer diagnosis.54,81 Pancreatic surveillance is offered to individuals of the appropriate age who are either 1) carriers of a germline mutation in a pancreatic cancer susceptibility gene and 2) individuals with multiple blood relatives with pancreatic cancer (generally at least 1 first-degree and 1 second-degree relative with pancreatic cancer).82 Pancreatic imaging with endoscopic ultrasonography and magnetic resonance imaging/magnetic resonance cholangiopancreatography has been used as the method of surveillance because such imaging can identify worrisome precancerous changes as well as small cancers, but surveillance could be enhanced with accurate blood tests, and many patients are found to have small pancreatic cysts of low malignant potential78 that can contribute additional worry for patients already concerned about their pancreatic cancer family history.83 The role of pancreatic surveillance is still undergoing evaluation and is best undertaken at expert centers as part of long-term research studies.

Genetic Alterations in Pancreatic Cancer Precursor Lesions PDAC arises from noninvasive precursor lesions that are curable if detected early—knowledge of the molecular alterations in these precursor lesions can provide a rational foundation for early-detection approaches. The most common PDAC precursor lesion is pancreatic intraepithelial neoplasia (PanIN), a microscopic lesion graded based on the degree of architectural and cytologic atypia. Low-grade PanINs (PanIN-1, PanIN-2) are common and have a low risk of malignant progression, whereas high-grade PanINs (PanIN-3) are much less frequent (<1% in autopsy series) and are considered to be carcinoma in situ.84 Several studies have documented the sequential accumulation of somatic mutations in PDAC driver genes in PanINs. KRAS mutation is the earliest known genetic alteration, present in >90% of all PanINs regardless of grade.85–87 Mutant KRAS DNA concentrations have been reported to increase with increasing grade of dysplasia in PanINs, raising the intriguing possibility that low-grade PanINs contain a mixture of KRAS mutant and wild-type cells.85 In contrast, inactivation of CDKN2A is uncommon in low-grade PanINs but has been reported to occur in >70% of high-grade PanINs.88 Mutations in TP53 and SMAD4 occur even later in PanIN progression, found almost exclusively in high-grade PanIN and invasive PDAC. Early studies showed aberrant p53 expression and loss of Smad4 expression at the protein level (indicative of somatic mutation/inactivation) in >30% of high-grade PanINs, whereas almost all low-grade PanINs retained normal expression.89,90 However, these studies analyzed PanIN in the setting of co-occurring invasive PDAC, which can confound such studies through intraductal spread of invasive carcinoma, a lesion that is histologically indistinguishable from high-grade PanIN.91 When analyzing only

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high-grade PanINs in the absence of invasive PDAC, nextgeneration sequencing and immunohistochemistry showed that TP53 alterations were far less common (occurring in only 17% of high-grade PanINs) and that SMAD4 alterations were completely absent.92 In addition to somatic point mutations, other types of genetic alterations have been described in PanINs. These include telomere shortening, thought to be an early sign Q14 even in pancreatic tumorigenesis and frequently present in low-grade PanIN.93 Copy number alterations have been reported in PanIN; such alterations are uncommon in lowgrade PanIN but occur more frequently in high-grade PanIN, sometimes affecting known driver genes.94,95 Biallelic inactivation of SMAD4 was not identified in PanINs in these studies, supporting the concept that it is a driver of invasive PDAC. In addition, chromothripsis-like regions were identified in both low-grade and high-grade PanINs, showing that this phenomenon can precede the development of invasive PDAC.95 In addition to microscopic PanIN, pancreatic cancer can also arise from macroscopic cystic precursor lesions, most commonly intraductal papillary mucinous neoplasm (IPMN). IPMNs involve the pancreatic duct system and are by definition >1 cm in size, although many grow to be much larger. Like PanINs, IPMNs are graded (as low grade or high grade) based on the architectural and cytologic atypia of their lining epithelium, but they are also subtyped based on the direction of differentiation of this lining, including gastric, intestinal, and pancreatobiliary.84,96 IPMNs are driven by the 4 mountains of PanIN-based pancreatic tumorigenesis, including early alterations in KRAS and later mutations in CDKN2A, TP53, and SMAD4, with SMAD4 mutation typically limited to IPMN-associated invasive carcinoma.97–99 However, there are also 2 frequently altered driver genes that are specific to the IPMN pathway. Mutations in the oncogenic hotspot of GNAS occur early in IPMN tumorigenesis and are most common in IPMNs with intestinal differentiation.97,100,101 Inactivating mutations (often followed by loss of heterozygosity) in RNF43, which encodes a ubiquitin ligase involved in WNT signaling, are also common in IPMNs.102 Mutations in RNF43 have also been reported less commonly in PDACs not associated with IPMNs, as well as in other cystic precursor lesions (as will be discussed).19,102 The precise timing of RNF43 mutations in IPMN tumorigenesis has not yet been systematically investigated. Although IPMNs are the most common cystic precursor to PDAC, several other types of such precursor have also been studied with molecular techniques. Intraductal oncocytic papillary neoplasm, originally classified as a subtype of IPMN, has recently been shown to be driven by a distinct spectrum of genetic alterations, lacking mutations in KRAS and GNAS.103 Similarly, intraductal tubulopapillary neoplasms also lack KRAS mutations but do have uncommon mutations in the oncogene PIK3CA, which have also been reported in IPMNs.104,105 Mucinous cystic neoplasms (MCNs), which do not involve the pancreatic duct system and have a distinct pathognomonic ovarian-type stroma, have some genetic overlap with IPMNs; KRAS mutations are a common initiator,

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but GNAS mutations have not been reported in mucinous cystic neoplasms.102,106 Mutations in other tumor suppressor genes, including RNF43, occur later.102,106–108 Recent genetic analyses of pancreatic cancer precursor lesions have shown genetic heterogeneity with respect to driver gene mutations, suggesting a more complex evolutionary trajectory than was previously appreciated. One study in PanINs that used ultrasensitive mutation techniques showed multiple KRAS mutations in almost 25% of lesions.85 Similarly, analysis of cyst fluid showed that 13% of IPMN samples contained multiple KRAS mutations and that 4% contained multiple GNAS mutations.100 Dissection and subsequent next-generation sequencing of 2 different IPMN regions showed that 23% contained multiple KRAS or GNAS mutations, and up to 4 different KRAS mutations were detected within a single IPMN.109 Recent single-cell DNA sequencing analyses of IPMNs have shown that these heterogeneous KRAS mutations occur in different cells, raising the possibility of polyclonal origin of at least a subset of IPMNs.110 In addition to this heterogeneity within a single precursor lesion, multiple studies have provided evidence for multifocal neoplasia in the pancreas. Targeted nextgeneration sequencing showed that the vast majority of co-occurring low-grade and high-grade PanINs did not share any genetic alterations and, thus, likely arose independently.92 Similarly, a sizable proportion (18%) of cooccurring IPMNs and PDACs were genetically independent despite their close proximity.109 In addition, more than half of the pancreatic neoplasms that occurred in the remnant pancreas after IPMN resection were likely independent due to lack of shared genetic alterations.111 Taken together, these studies highlight the frequency at which multiple seemingly independent neoplasms occur in the same patient’s pancreas. It is currently not clear whether this risk of multifocal neoplasia represents the result of normal aging or varies based on as yet undefined molecular factors. Although some interpret these data as suggesting a field defect that puts the entire pancreas at risk for neoplasia, the mechanistic basis of such a field defect is unknown. If such a field defect does exist, its mechanism does not appear to be a somatic mutation in a well-characterized driver gene. In contrast to the occurrence of multiple independent neoplasms in close proximity, recent work also highlights the ability of a single neoplasm to move throughout the pancreatic ductal system. Whole-exome sequencing of cooccurring yet anatomically distant PanINs and invasive carcinomas suggests that neoplastic clones can spread throughout the pancreatic ductal system.112

Translational Application of Molecular Insights DNA harboring acquired mutations in KRAS and other genes is shed from pancreatic cancers into the blood, pancreatic fluids, and stool and has potential value in earlydetection tests. Circulating tumor DNA (ctDNA) has been extensively studied as a tool for the detection and surveillance of multiple cancer types.113,114 However, even with assays designed to detect mutations in low abundance, the

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amount of ctDNA detected in most patients with pancreatic cancer is very low (often in concentrations in the 0.1% range), and the percentage of patients with stage I/II disease who have any ctDNA detectable with existing technologies is low (w30%–40%).20,114,115 Patients with pancreatic cancer and a positive ctDNA test result have a poorer prognosis vs those without.115 Somatic mutations are also shed into the pancreatic ductal system, and the detection of these mutations in pancreatic cyst fluid and pancreatic juice has been studied to determine how the detection of these mutations can improve the evaluation of patients undergoing pancreatic surveillance. For example, the mutation profile of pancreatic cyst fluid can be used to reliably classify cysts into mucinous and nonmucinous cysts,116,117 and the neoplastic grade of pancreatic cysts can be determined with very good accuracy by using a test panel that combines the detection of mutations with chromosomal copy number alterations.117 Similarly, pancreatic juice collected from the duodenum after secretin infusion contains mutations that reflect neoplastic changes within the pancreas.118,119 Pancreatic juice is thought to contain DNA shed from the pancreatic ductal system and may be helpful in identifying occult neoplasia not visible by pancreatic imaging tests.120,121 The mutational profiles in pancreatic cyst fluid and pancreatic juice samples mirror the timing of mutations and other genetic alterations that arise during pancreatic neoplastic development, with KRAS and GNAS mutations detected with the presence of low-grade dysplasia in PanINs and IPMNs, as well as later stages of neoplastic progression and invasive cancer, whereas mutations that arise during later stages of neoplastic development (TP53 and SMAD4) are usually detected only in the presence of high-grade dysplasia or invasive cancer.118,119 Protein markers,122 aberrantly methylated DNA,123 telomerase activity,124 and other markers are also being evaluated to understand the most cost effective and accurate diagnostic marker panel for pancreatic cyst fluids.

Translational Oncologic Therapeutics in Pancreatic Cancer At first glance, the field of pancreatic adenocarcinoma therapeutics might seem like a failure with regard to targeted and/or immune-based therapeutics. More than 90% of pancreatic adenocarcinomas harbor activating mutations in KRAS,23 for which targeted therapies have been notoriously ineffective across all cancer types. Furthermore, aside from erlotinib125 (the use of which has largely become obsolete with the improvements from multiagent cytotoxic chemotherapy with folinic acid, fluorouracil, irinotecan, Q15 and oxaliplatin [FOLFIRINOX]126 and gemcitabine/nabpaclitaxel127), no molecularly targeted agents have been approved by the US Food and Drug Administration (FDA) for treating pancreatic adenocarcinoma, despite numerous randomized trials128 examining therapies directed at PI3K,129 IGF1R,130 EGFR,131 KIT,132 the VEGF pathway,133–135 and other theoretically druggable targets.136 Additionally, immune checkpoint inhibitors have failed to show any

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Figure 1. The PanIN progression model. More than 90% of low-grade PanIN-1 lesions have KRAS codon 12 mutations and have telomere shortening. The percentage of PanIN DNA with KRAS mutations increases with PanIN grade. Progression of low-grade PanIN-1 to low-grade PanIN-2 and high-grade PanINs (PanIN-3) is usually associated with inactivation of both copies of CDKN2A. TP53 mutation is rarely detected in low-grade PanIN but is often found in high-grade PanIN and invasive cancer. Inactivation of both copies of SMAD4 is found in invasive cancer. Loss of chromosomal arms contributes to biallelic inactivation and are increasingly found as PanINs progress to low-grade PanIN-2 to high-grade PanIN and invasive cancer. In addition to the loss of a chromosomal arm, shattering and rearrangement of one or more chromosomal regions (chromothripsis) may occur. Bi-allelic inactivation of BRCA2 inactivation of BRCA2 is thought to occur in the late stages of PanIN progression. The timing of mutation of other low-frequency driver genes during PanIN progression (eg, ATM and ARID1A) has not been extensively studied.

meaningful therapeutic benefit in treating pancreatic adenocarcinoma137–139 (with the notable exception140 of the 1% of tumors141–143 with high-level microsatellite instability/mismatch repair deficiency). Despite the current dearth of FDA-approved noncytotoxic treatment options for pancreatic cancer, recent years have brought about an abundance of novel genomic, molecular, and immunologic insights into the diverse and complex biology of this notoriously “undruggable” malignancy, providing hope that rational translational oncologic therapeutics can soon become critical, effective, feasible, and routine components of pancreatic cancer care. KRAS wild-type pancreatic cancers appear to be a particularly appealing subgroup for targeted therapies, with various investigators having found such cases to be enriched for targetable alterations, amplifications, or fusions in oncogenes including BRAF, ROS1, NRG1, RET, ALK, and ERBB2, with real-world cases of such patients showing substantial responses to matched targeted therapies.143–145 The unique Know Your Tumor initiative143 led by the Pancreatic Cancer Action Network (ie, PanCAN) advocacy group recently showed the potential feasibility and benefits of using multi-omic tumor profiling to guide targeted therapy use among 640 pancreatic cancer patients from 44 different states. This effort identified potentially actionable alterations in 165 (26%) of all individuals (nearly all of which were associated with therapies already FDA approved for other malignancies), and an overall 50% rate of potentially actionable findings. Although the most common such alterations were in DNA damage repair/homologous recombination (HR) genes (as will be discussed), other

tumors were noted to have potentially targetable variants, amplifications, or fusions in ERBB2, RET, BRAF, ALK, ROS1, and NTRK.143 Furthermore, individuals with pancreatic cancers found to have such alterations in this study had superior progression-free survival when their treatment was guided by these genomic data vs those receiving nontargeted therapies, although with a small magnitude of difference (4.1 months vs 1.9 months).143 A recent singleinstitution feasibility study145 incorporating real-time whole-exome and RNA sequencing into the clinical treatment workflows of individuals with pancreatic cancer similarly showed 48% of all individuals to have potentially actionable findings (again, with the most common such findings being sequence alterations and/or mutational signatures of HR deficiency), with 30% of individuals undergoing a therapeutic change in management based on their tumor profiling. Other investigators have similarly reported the feasibility of real-time whole-genome and RNA sequencing to guide the management of pancreatic cancer patients with median turnaround times of slightly more than a month.146 Despite such promising preliminary data, however, the oncologic literature is littered with numerous examples of theoretically “druggable” somatic alterations that have proven to be markedly more difficult to target in real-world treatment than initially assumed, especially when extrapolating across different tumor types (eg, the anti-ERBB2 agents lapatinib and pertuzumab, each of which has failed to show benefit in randomized phase III studies of ERBB2amplified gastroesophageal cancers, in spite of their significant activity in ERRB2-amplified breast cancers).147,148 The

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aforementioned studies145,146,149 illustrate the relative rarity of each individual potentially targetable alteration, amplification, and rearrangement in pancreatic cancer, strongly suggesting that pancreatic cancer-specific clinical trials to evaluate the efficacy of given drugs for each individual molecular target are highly likely to be unfeasible. Although they may not be able to account for the possibility of heterogeneous responses across different tumor types, basket trials have proven to be a promising approach for evaluating the efficacy of targeted therapies for rare and uncommon molecular targets, and they are likely to be a critical approach to advancing the therapeutic landscape for the fraction of pancreatic cancers with such molecular targets. Indeed, recent basket trials examining larotrectinib in tumors with NTRK fusions150 and pembrolizumab in tumors with mismatch repair deficiency140 both identified significant responses in the few enrolled pancreatic cancer patients, illustrating the potential for such study designs to help make inroads in learning how to therapeutically leverage such molecular targets. Further expanding on the notion of using tumor biopsy specimens to guide personalized therapy, emerging data on pancreatic adenocarcinoma patient-derived organoids (PDOs) hold additional promise in helping to expand and refine treatment options for individuals with pancreatic cancer. One recent study suggested that in vitro PDO sensitivity (or lack thereof) to cytotoxic agents appeared highly concordant with the corresponding patients’ realworld responses (or lack thereof) to systemic chemotherapy.151 Perhaps more important, however, this work also demonstrated the ability to use such PDOs for multiomic tumor profiling and also to assay for sensitivity to various molecularly targeted agents, particularly among specimens that appear to be inherently resistant to cytotoxic chemotherapy.151 The most common subtype of potentially therapeutically targetable alterations identified in pancreatic adenocarcinomas are those with somatic and/or germline defects in DNA damage repair pathways, particularly those involved in homologous recombination (HR).143,145 Recent data suggest that anywhere from 3.2-8.1% of all pancreatic adenocarcinoma cases arise in the setting of germline variants in HR genes, most commonly BRCA2, ATM, BRCA1, PALB2, and CHEK2.45,46,152,153 In parallel, an additional 2.5%–9.9% of pancreatic adenocarcinomas harbor somatic alterations in these same genes, and 7.0%–7.6% have mutational signatures of HR deficiency without identifiable germline or somatic HR gene alterations.30,154 A number of small studies have suggested that such germline HR gene variants and/or HR deficiency mutational signatures likely predict response to cisplatin- or oxaliplatin-based chemotherapy in pancreatic adenocarcinoma.152,155–158 Such findings have naturally led to the hypothesis that poly(adenosine diphosphate) ribose polymerase (PARP) inhibitors, known to have significant benefit in breast and ovarian cancers with HR deficiency, may have therapeutic benefit in this important subset of pancreatic adenocarcinomas. A phase I study159 of olaparib combined with cisplatin, irinotecan, and mitomycin-C in 18 patients with

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advanced pancreatic cancer showed a 23% objective response rate, though only 2 participants were known to carry germline BRCA2 variants (the others had unknown BRCA1/2 status), 1 of whom experienced more than 4 years of disease control. Unfortunately, 2 participants (including the BRCA2 carrier with prolonged disease control) developed therapy-related myelodysplastic syndrome, and thus the regimen was believed to be unacceptably toxic for further study.159 Another multiagent phase I study160 examined veliparib in combination with cisplatin and gemcitabine as first-line therapy in 17 patients with advanced pancreatic cancer (7 of whom were known to carry germline BRCA1 or BRCA2 variants). Overall, this combination showed a 41.2% overall objective response rate, although all of the responses occurred in the BRCA1/2 carriers (who overall had a 77.8% objective response rate).160 The BRCA1/2 carriers in this study also had significantly superior median overall survival compared with noncarriers (23.3 months vs 11 months).160 As single agents, on the other hand, PARP inhibitors have shown modest activity (0%–22% objective response rates) in small studies of pancreatic adenocarcinoma patients with germline BRCA1 or BRCA2 gene variants,161–164 although these rates appear to be lower than what has been observed in HR-deficient breast and ovarian cancers.165–167 One potential explanation for this lower response rate may stem from the observation152 that roughly half of pancreatic adenocarcinomas arising in the setting of germline HR gene variants lack an identifiable somatic “second hit” within the tumor, thereby suggesting that a substantial fraction of such tumors may not be truly HR deficient.151 Such data call into question the paradigm used in most PARP inhibitor trials for pancreatic cancer to date, in which the presence of a pathogenic germline HR gene variant alone (rather than paired germline and somatic HR gene defects) is used to determine eligibility. Ongoing randomized clinical trials are evaluating PARP inhibitors in combination with platinum-based chemotherapy (NCT10585805) and as maintenance therapy after an initial response to multiagent platinum-based chemotherapy (NCT02184195) in individuals with pathogenic germline HR gene variants, although studies examining PARP inhibitors in pancreatic adenocarcinoma patients with somatic HR gene alterations and/or with mutational signatures of HR deficiency would be of significant interest, so as to attempt to expand the therapeutic reach of these agents. The abundance of pancreatic cancers with defects in HR machinery is particularly intriguing with regard to expanding the use of immunotherapy in pancreatic cancer. Various in vitro and in vivo data have strongly suggested the potential for synergy between PARP inhibitors and immune checkpoint blockade in breast and ovarian cancers,168–170 possibly via PARP inhibitor-induced DNA damage leading to increased neoantigen production and immunogenicity. Furthermore, mutational signature data from pancreatic cancer specimens suggest a strong correlation between tumors with DNA damage repair gene alterations/signatures and markers of immunogenicity, including neoantigen load, PD-L1 expression, CTLA-4 expression, and CD8þ T-cell activation.30

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Conclusion Pancreatic cancer represents one of the best characterized cancer types at the genetic level, with comprehensive genetic analysis (whole-exome or whole-genome sequencing) to identify somatic alterations reported on more than 500 individual cancers. In addition, extensive investigation into germline alterations that underlie inherited pancreatic cancer predisposition has been performed, and premalignant lesions have been characterized at the molecular level. These comprehensive molecular analyses have led to several clinically important insights, informing both early detection approaches and targeted therapeutics. Future work will further refine these clinical translations so that the molecular basis of pancreatic cancer can be better leveraged to improve the lives of patients with this disease.

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31. Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538:378–382. 32. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114–1117. 33. Makohon-Moore AP, Zhang M, Reiter JG, et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat Genet 2017;49:358–366. 34. Moffitt RA, Marayati R, Flate EL, et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nature Genet 2015;47:1168–1178. 35. Collisson EA, Sadanandam A, Olson P, et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat Med 2011;17:500–503. 36. Bailey P, Chang DK, Nones K, et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531:47–52. 37. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009;302:1790–1795. 38. Roberts NJ, Jiao Y, Yu J, et al. ATM mutations in patients with hereditary pancreatic cancer. Cancer Discov 2012;2:41–46. 39. Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog 2012;51:14–24. 40. Lowenfels AB, Maisonneuve P, DiMagno EP, et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 1997;89:442–446. 41. Zhen DB, Rabe KG, Gallinger S, et al. BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 2015;17:569–577. 42. Jones S, Hruban RH, Kamiyama M, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324:217. 43. Roberts NJ, Norris AL, Petersen GM, et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov 2016; 6:166–175. 44. Tamura K, Yu J, Hata T, et al. Mutations in the pancreatic secretory enzymes CPA1 and CPB1 are associated with pancreatic cancer. Proc Natl Acad Sci U S A 2018; 115:201720588. 45. Shindo K, Yu J, Suenaga M, et al. Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma. J Clin Oncol 2017;35:3382–3390. 46. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018; 319:2401–2409. 47. Lowery MA, Wong W, Jordan EJ, et al. Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms. J Natl Cancer Inst 2018; 110:1067–1074. 48. Couch FJ, Farid LM, DeShano ML, et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 1996;13:123–125.

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49. Neuhausen S, Gilewski T, Norton L, et al. Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 1996;13:126–128. 50. Oddoux C, Struewing JP, Clayton CM, et al. The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 1996;14:188–190. 51. Figer A, Irmin L, Geva R, et al. The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with noncolonic gastrointestinal tract tumours in Israel. Br J Cancer 2001;84:478–481. 52. Ozcelik H, Schmocker B, Di Nicola N, et al. Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet 1997;16:17–18. 53. Salo-Mullen EE, O’Reilly EM, Kelsen DP, et al. Identification of germline genetic mutations in patients with pancreatic cancer. Cancer 2015;121:4382–4388. 54. Vasen H, Ibrahim I, Ponce CG, et al. Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers. J Clin Oncol 2016; 34:2010–2019. 55. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:1447–1453. 56. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000; 87:809–811. 57. 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;42:711–719. 58. Struewing JP, Abeliovich D, Peretz T, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 1995;11:198–200. 59. Ferrone CR, Levine DA, Tang LH, et al. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol 2009;27:433–438. 60. Hu C, LaDuca H, Shimelis H, et al. Multigene hereditary cancer panels reveal high-risk pancreatic cancer susceptibility genes. JCO Precis Oncol 2018. 61. Antoniou AC, Casadei S, Heikkinen T, et al. Breastcancer risk in families with mutations in PALB2. N Engl J Med 2014;371:497–506. 62. Thompson D, Easton DF. Cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst 2002;94:1358– 1365. 63. Mocci E, Milne RL, Mendez-Villamil EY, et al. Risk of pancreatic cancer in breast cancer families from the breast cancer family registry. Cancer Epidemiol Biomarkers Prev 2013;22:803–811. 64. Wolpin BM, Chan AT, Hartge P, et al. ABO blood group and the risk of pancreatic cancer. J Natl Cancer Inst 2009;101:424–431. 65. Wolpin BM, Kraft P, Gross M, et al. Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. Cancer Res 2010; 70:1015–1023.

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1741 1742 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 Received September 20, 2018. Accepted December 5, 2018. 1768 1769 Reprint requests 1770 Address requests for reprints to: Laura Wood, MD, PhD, Johns Hopkins Medical Institutions, CRB2 351, 1550 Orleans Street, Baltimore, Maryland 1771 Q4 Q5 21231. e-mail: [email protected]; fax: 410-614-0671; Matthew B. Yurgelun, 1772 MD, Johns Hopkins Medical Institutions, CRB2 351, 1550 Orleans Street, Baltimore, Maryland 21231. e-mail: [email protected]; fax: 1773 410-614-0671; Michael Goggins, MD, Johns Hopkins Medical Institutions, Q6 1774 CRB2 351, 1550 Orleans Street, Baltimore, Maryland 21231. e-mail: [email protected]; fax: 410-614-0671. 1775 1776 Q7 Conflicts of interest 1777 The authors disclose no conflicts. 1778 Funding 1779 Q8 This work was supported by National Institutes of Health grants U01210170, R01CA176828, K08 DK107781, and CA62924; Susan Wojcicki and Dennis 1780 Troper; the Pancreatic Cancer Action Network; the Lustgarten Foundation for Q32 1781 Pancreatic Cancer Research; Stand Up to Cancer; Buffone Family Gastrointestinal Cancer Research Fund; Kaya Tuncer Career Development 1782 Award in Gastrointestinal Cancer Prevention; American Gastroenterological Q9 1783 Association–Bernard Lee Schwartz Foundation Research Scholar Award in Pancreatic Cancer; Sidney Kimmel Foundation for Cancer Research Kimmel 1784 Scholar Award; American Association of Cancer Research–Incyte Q10 1785 Corporation Career Development Award for Pancreatic Cancer Research; 1786 Rolfe Pancreatic Cancer Foundation; Joseph C. Monastra Foundation; and The Gerald O. Mann Charitable Foundation. Michael G. Goggins is the Sol 1787 Goldman Professor of Pancreatic Cancer Research. 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800

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