Hereditary pancreatic cancer: A clinical perspective

Best Practice & Research Clinical Gastroenterology 23 (2009) 159–170

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Best Practice & Research Clinical Gastroenterology

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Hereditary pancreatic cancer: A clinical perspective Julia B. Greer, MD, MPH a, *, Henry T. Lynch, MD b,1, Randall E. Brand, MD c, 2 a

University of Pittsburgh School of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Medical Arts Building, 4th floor, Room 400.5, 3708 5th Ave. Pittsburgh, Pa 15213, USA b Creighton University School of Medicine, Department of Preventive Medicine, 2500 California Plaza, Hixson-Lied Science Building, Room 202, Omaha NE, 68178, USA c University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Division of Gastroenterology, Hepatology and Nutrition, UPMC Hillman Cancer Center, Lab 2.32 5115 Centre Avenue, Pittsburgh, PA 15232, USA

Keywords: pancreatic cancer familial hereditary cancer syndrome mutation gene risk surveillance genetic counselling

Pancreatic cancer is an extraordinarily deadly disease and is responsible for over 220,000 deaths worldwide each year. One of the greatest risk factors for developing pancreatic cancer is a positive family history. Hereditary pancreatitis patients have a greatly elevated pancreatic cancer risk and individuals with cystic fibrosis may rarely develop this cancer, but often at very young ages. Various genetically linked cancer syndromes have been associated with pancreatic cancer in mutation-positive family members. Finally, familial pancreatic cancerddefined as families with two or more first-degree relatives who have pancreatic cancer but do not have a known cancer syndromedis a known entity whose diseasecausing mutation remains unidentified. This article describes research to date on hereditary pancreatic cancer, addresses how best clinicians should recognise hereditary forms of pancreatic cancer and explains the emotional burden of discovering a potentially lethal mutation. Many controversies and unanswered questions in hereditary pancreatic cancer remain. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction The American Cancer Society estimates that there will be 37,680 new pancreatic cancer (PC) cases and 34,290 deaths due to PC in 2008 [1]. Despite advancements in diagnostic modalities and clinical care, the majority of patients with pancreatic adenocarcinoma will not be living one year beyond their cancer diagnosis [2]. PC has the highest case-fatality rate of any major cancer and an overall five year * Corresponding author. Tel.: þ1 412 977 1778; Fax: þ1 412 578 9537. E-mail addresses: [email protected] (J.B. Greer), [email protected] (H.T. Lynch), [email protected] (R.E. Brand). 1 Tel.: þ402 280 2942; Fax: þ402 280 1734. 2 Tel.: þ412 623 0021; Fax: þ412 623 7828. 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.02.001

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survival rate of less than 5% [3]. This cancer’s poor prognosis is due mainly to its late stage at presentation, when curative intent surgery is not an option. There is a growing effort to identify individuals at high risk of developing PC. One of the greatest risk factors for pancreatic adenocarcinoma is a family history of the disease. PC was noted to occur in some adenocarcinoma-prone families as early as 1967 [4]. The following decade, a family was described in which four of six siblings had PC [5]. In 1987, Ehrenthal et al published a paper describing three consecutive generations of women who were diagnosed with PC in the span of just 11 years; the grandmother was diagnosed at age 76, the mother at age 42 and the daughter at age 29 [6]. Shortly thereafter, case-control studies demonstrated an increased risk of PC in pedigrees with a family history of any type of cancer, most significantly in families with many cases of PC [7–9]. Current estimates are that approximately 5–10% of PC cases display familial clustering and that a hereditary component may be responsible for as many as 10–20% of all PC cases [10]. While the most instrumental, pathogenic germline mutations that segregate with PC-affected families have not yet been identified, recent growth in molecular genetics has provided a greater understanding of the heritable nature of this highly lethal disease. Diseases associated with an increased risk of pancreatic cancer Hereditary pancreatitis Hereditary pancreatitis is a rare, inflammatory pancreatic disorder characterised by recurrent attacks of acute pancreatitis, typically presenting in elementary or middle-school aged children [11]. Chronic pancreatitis is the end-stage, fibrotic complication of long-standing intrapancreatic inflammation that results in both exocrine and endocrine pancreatic failures. Non-heritable chronic pancreatitis cases typically occur late in life; individuals who develop chronic pancreatitis before the age of 25 years should be regarded with high clinical suspicion of having hereditary pancreatitis [12]. Other than its earlier age of onset, the chronic pancreatitis of hereditary pancreatitis is clinically indistinguishable from other etiologies [13]; morbid complications such as maldigestion, weight loss, diabetes mellitus and intractable pain are common to both [14]. The greatest proportion of hereditary pancreatitis cases are caused by gain-of-function mutations in the cationic trypsinogen gene (PRSSI) [15]. Trypsinogen is the pro-enzyme form of the powerful digestive enzyme trypsin. Trypsin has both autoactivation and autolysis functions that vary by the ambient calcium concentration. Mutations in PRSS1 result in premature activation or ineffective deactivation of trypsin, resulting in parenchymal pancreatic injury [16]. Although greater than 25 PRSS1 mutations have been identified, the two most frequently observed are R122H and N29I [17]. Over half of hereditary pancreatitis patients will develop chronic pancreatitis and these patients have a 40% lifetime risk of developing PC, usually 30 or more years after the onset of chronic pancreatitis [18]. One large, international study showed that hereditary pancreatitis patients have a 54-fold higher risk of PC than the general population; those patients who smoke cigarettes increase this cancer risk to 154-fold [18]. Therefore, hereditary pancreatitis patients must be strongly discouraged from smoking cigarettes and smoking cessation programs should be instituted for current smokers.

Cystic fibrosis Cystic fibrosis (CF) is the most common lethal, inherited disease among Caucasians [19]. Inherited in an autosomal recessive fashion, CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, whose protein product codes for a chloride ion channel critical in creating sweat, mucus and digestive juices [20]. Approximately two to four percent of all Caucasians carry the CF gene [21] and CF affects about 30,000 US children and adults [22]. Around 70% of people with CF carry the mutation, DF508 [22]. Profound clinical manifestations of CF include chronic obstructive lung disease and pancreatic insufficiency [23]. In previous decades, CF patients rarely survived beyond childhood; due to improvements in treatment and care, however, the median age of death for CF patients in the United States is currently 37 years of age. [22].

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CF patients may have an increased PC risk. A retrospective analysis of over 28,000 North American CF patients found that CF patients had an odds ratio of 31.5 of developing PC [21]. In contrast, the Cystic Fibrosis Foundation patient registry of 28,858 CF patients analysed data from 1990 to 1999 and noted significantly increased risks of small bowel, colorectal and biliary cancers among CF patients, but only a non-significantly 2.6-fold increased risk of PC [24]. One group recently evaluated Surveillance Epidemiology and End Results (SEER) data and applied it to US and European populations to determine the risk ratio for PC among individuals with CF to be 5.3 (95% CI 2.4-10.1) [25]. They noted that only nine cases of PC were documented among CF patients in the US and Europe between 1990 and 2005, but two of them were in teen-agers (ages 18 and 19) and two were among individuals in their twenties. Limitations in establishing cancer risk estimates for individuals with CF are due to the rarity of the disease and competing causes of mortality. Syndromes with a significantly increased pancreatic cancer risk A number of cancer syndromes are associated with an increased risk of developing pancreatic cancer in mutation-positive family members. Each cancer syndrome develops due to a germline mutation in a proto-oncogene, inactivation of both copies of a tumour suppressor gene, or a genetic defect in DNA mismatch repair genes [26]. In addition to hereditary pancreatitis and CF, the major genetic syndromes associated with PC are described in Table 1.

Peutz–Jeghers syndrome (PJS) PJS is an autosomal dominant condition with variable phenotype and penetrance characterised by hamartomatous gastrointestinal polyps and mucocutaneous pigmented lesions caused by a mutation in the serine/threonine protein kinase 11 STK11/LKB1 gene [27]. Characteristic PJS pigmentation may occur in any mucosal site and usually develops in infancy but frequently fades following adolescence. Individuals with PJS display a multi-cancer phenotype and are at increased risk of developing various gastrointestinal cancers as well as extraintestinal malignancies, including breast, lung, ovarian, testicular and endometrial cancer [28]. A meta-analysis of PJS studies demonstrated that patients had a relative risk of PC of 132 and a lifetime risk of 36% [29]. Table 1 Selected conditions and cancer syndromes associated with increased pancreatic cancer risk. Syndrome (abbreviation)

Location

Gene

Gene type

Inheritance

Estimated relative risk

Frequency in sporadic cases

Hereditary pancreatitis (HP)

7q35

PRSS1

Cationic trysinogen

20-75

Unknown

Cystic fibrosis (CF)

7q31.2

CFTR

Chloride ion channel

w5

Unknown

Peutz–Jeghers syndrome (PJS) Familial atypical multiple mole melanoma (FAMMM) Hereditary breast Ovarian Cancer (HBOC) Familial adenomatous polyposis (FAP) Hereditary nonpolyposis colorectal cancer (HNPCC) Family X: site specific pancreatic cancer

19p13.3

STK11/LKB1

132

4%

9p21

p16 INK4a/ MTS1

Tumour suppressor, serine threonine kinase Tumour suppressor

Autosomoal dominant, 80% penetrance Autosomal recessive Autosomoal dominant Autosomoal dominant

13–22

98%

17q21-24 and 13q12-13 5q21

BRCA1 and BRCA2

Tumour suppressor, linked to RAD51

Autosomoal dominant

APC

Tumour suppressor

7% for BRCA2 N/A for BRCA1 40%

MSH2 and MLH1*

Mismatch repair

Autosomoal dominant Autosomoal dominant

2.3–3.6 for BRCA1 3–10 for BRCA2 w5 Unknown

4–11%

Palladin

Cytoskeleton structure

Unknown

Unknown

2p22-21 and 3p21.3 4q32-34

Autosomal dominant

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Familial atypical multiple mole melanoma (FAMMM) Lynch et al recently recounted that FAMMM may have been documented as early as 1820, when three generations in a single family were observed to have multiple benign moles and/or malignant melanoma [30]. In addition to atypical moles and melanoma, individuals with FAMMM have been shown to develop cancers of the breast, lung, endometrium and pancreas [31]. FAMMM is inherited in an autosomal dominant pattern, displays variable penetrance and has been associated with dozens of different germline mutations. FAMMM patients who are predisposed to PC carry a mutation in the CDKN2A gene that encodes for p16, a cyclin-dependent kinase inhibitor [32]. A study by Vasen et al of 27 families suspected of having FAMMM identified the p16 mutation in 19 families, and estimated the cumulative risk of developing PC in putative mutation carriers to be 17% by age 75 years, with an average age of onset of 58 [33]. This finding was confirmed by the same group in a more extended series of patients [34]. BRCA1 and BRCA2 mutations in hereditary breast and ovarian cancers Mutations in the tumour suppressor BRCA1 and BRCA2 genes are associated with hereditary breast and ovarian cancers (HBOC). Mutations of BRCA1 carry a 2.3 to 3.6-fold increased risk of PC and those of BRCA2 may carry as much as a 3 to 10-fold PC risk [35–39]. Of clinical significance, the frequency of BRCA1 and BRCA2 mutations may vary by ethnicity. For instance, while about one in 40 individuals with PC of Ashkenazi Jewish descent may carry a BRCA mutation [40], a recent Asian study failed to find any common, truncating BRCA2 mutations in a sample of 60 Korean PC patients [41]. The significance of BRCA2 mutations in PC cases was demonstrated in two studies of PC-prone families lacking family history of breast and/or ovarian cancer. Hahn et al documented a BRCA2 mutation rate of 19% in European kindreds who had at least two first-degree relatives with histologically proven pancreatic adenocarcinoma [36]; Murphy et al reported a BRCA2 mutation rate of 17% in families with three or more relatives, of any degree, who had been diagnosed with PC [42]. In a recent multi-institutional study of familial PC kindreds, affected probands from 151 high-risk families identified from high-risk clinics were screened for BRCA2 mutations and these results were combined with those from a BRCA2 study of 29 additional families [43]. Researchers identified 10 carriers from the total of 180 families, which suggested that BRCA2 mutations may account for approximately 6% of moderate and high-risk PC families. Hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) HNPCC or Lynch syndrome is the most common form of hereditary colon cancer. HNPCC is responsible for a sizeable proportion of the colon cancer burden and is caused predominately by mutations in mismatch repair genes MSH2 or MLH1, and less frequently by mutations in MSH6, PMS1 and PMS2 [44]. Lynch syndrome has been divided into two forms, Lynch I and Lynch II, based on whether extracolonic tumours are part of the phenotype of these colon-cancer prone families [45]. Lynch II is characterised by an increased risk of cancers of the small bowel, stomach, hepatobiliary system, breast, ureter, pancreas, and transitional carcinoma of the renal pelvis [46]. The risk of PC among Lynch II families may be elevated but it is not well-defined. Familial adenomatous polyposis Familial adenomatous polyposis (FAP) is caused in approximately 80% of affected families by a mutation of the adenomatous polyposis coli (APC) gene, which is involved in cell signalling [47]. FAP is characterised by multiple (at least 100) colorectal adenomas as well as cancers in other organ sites. The adenomas of FAP tend to be benign, but over time they may become malignant. There may be a moderately increased risk of PC precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) in FAP kindreds [48,49]. One study noted that although the lifetime risk of PC in FAP kindreds was low, the relative risk of PC in polyposis patients and at-risk relatives was 4.46 [50].

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Practice points  Hereditary pancreatitis patients have a greatly increased risk of PC, especially if they smoke.  PC in hereditary pancreatitis patients does not occur unless they have had chronic pancreatitis for many years.  Cystic fibrosis patients may develop PC at very young ages.  Individuals with PJS, FAMMM, HBOC, HNPCC and FAP are at increased risk for PC. In general, however, they are more likely to develop other types of cancer prior to PC.

Familial pancreatic cancer ‘Familial pancreatic cancer’ is a term once used loosely to describe extended families with multiple cases of pancreatic cancer. Currently, this term is more stringently applied to families with two or more first-degree relatives who have been diagnosed with PC that is not associated with a known cancer syndrome. The genetic mutations for familial PC in large part are unknown, although there is mounting evidence that mutations common to cancer syndromes, such as BRCA2, may play a role [38,51]. Perhaps the most valuable study of PC risk in familial PC kindreds to date was published in 2004 and involved patients who were members of the Johns Hopkins National Familial Pancreas Tumor Registry [52]. This prospective study compared standardised incidence rates of PC among familial PC kindreds (kindreds having at least one pair of first-degree relatives with pancreatic cancer) with sporadic PC kindreds (families without a pair of first-degree relatives who had been diagnosed with PC). Of the 5179 studied participants, 3957 had at least one first-degree relative with PC and contributed 10,538 person-years of follow-up. Results demonstrated that any member of a kindred with a first-degree relative diagnosed with PC had a nine-fold increased risk of developing PC. Risk estimates varied by the number of PC-affected first-degree relatives: having one affected first-degree relative increased the risk to 4.6 (95% CI 0.5-16.4), two affected first-degree relatives gave a risk of 6.4 (95% CI 1.8-16.4) and three affected first-degree relatives increased the risk 32-fold (95% CI 10.2-74.7). Relative and lifetime risks of PC, stratified by number and degree of affected relatives, have been described by Michael Levy of the Mayo clinic and are shown in Table 2. A singular family, initially referred to as ‘Family X,’ was recently studied at the University of Washington in Seattle, due to their early onset and very high penetrance of a seemingly hereditary form of PC [53]. Five generations of family members had a characteristic phenotypic prodrome of diabetes mellitus and pancreatic exocrine failure and often recognised the onset of diabetes as a sign of their impending PC diagnosis. At-risk family members underwent pancreatic resection and a total of 18 cases of either PC or PanIN were identified in four generations of Family X. Collaborative studies between researchers at the Universities of Pittsburgh and Washington ensued and the family’s susceptibility gene for PC was mapped to chromosome 4q32-34 [54]. Gene sequencing demonstrated

Table 2 Relative and lifetime pancreatic cancer risk in familial pancreatic cancer kindreds. Number and type of affected relatives

Relative risk

Lifetime risk

3 First-degree relatives 2 First-degree relatives 1 First-degree relative 1 Second-degree relatives 1 Third-degree relative 1 Fourth-degree relative General population

32 6.4–9.0a 4.6 1.28 1.09 1.06 1

40% 8–12%a 6% 1.70% 1.40% 1.40% 1.30%

Table was adapted, with permission, from Levy MJ, should patients with a strong family history of pancreatic cancer be screened on a periodic basis for cancer of the pancreas? Controversies in Clinical Pancreatology; 2008, in press. a These values vary by the number of affected second and/or third degree relatives.

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that the mutation carried by Family X was in the palladin gene (PALLD), which encodes for a cytoskeleton element responsible for cell shape and motility [55]. Subsequent studies, however, have not shown any association of palladin mutations with PC [56]. One point of clinical relevance that was observed in Family X is the greater likelihood that successive generations of affected familial PC families may develop PC significantly earlier than previous generations. The phenomenon, called ‘genetic anticipation,’ was first documented over twenty years ago [6]. More recently, a European study of 1223 PC at-risk individuals from 106 families (264 affected individuals) was performed. Investigators defined the latest documented generation that included any individual aged over 39 years as G3; preceding generations were defined as G2 and G1. In all, they had 80 affected child–parent pairs, and the children died at a median (interquartile range) of 10 (7, 14) years earlier. The median (interquartile range) age of death from PC was 70 (59, 77), 64 (57, 69), and 49 (44, 56) years for G1, G2, and G3, respectively [57]. Additionally, a recent nested case-control study of 251 individuals from 28 families with a family history of PC showed that smokers developed PC one decade earlier than non-smokers [58]. These studies substantiate the need for clinicians’ heightened awareness of anticipation in familial PC kindreds and for them to begin counselling at-risk individuals on behavioural variables (such as cigarette smoking) and available cancer surveillance studies years prior to the average age of PC onset in the general population.

Practice points  Familial PC refers to families with two or more first-degree relatives (parent–child or siblings) with a diagnosis of PC.  Individuals from families with singular extended generation (3rd or 4th) relatives who have had PC are not at significantly increased risk of developing PC.  The greater the number of affected first-degree relatives, the greater the PC risk is to unaffected relatives.  PC may occur at younger ages in subsequent generations of familial PC kindreds, especially in smokers.

Clinical implications of hereditary pancreatic cancer: screening of high risk cohorts All forms of cancer are caused by genetic mutationsdwhether acquired or inherited. Recent work has shown that PC undergoes a stepwise progression from dysplasia to invasive adenocarcinoma, not unlike that of colorectal cancer [59]. New screening methods and protocols for cancers such as cervical, colorectal and breast have resulted in earlier identification of precancerous or pre-invasive lesions, resulting in more timely diagnoses and an overall decrease in mortality rates [60]. In an ideal world, a screening tool would be highly sensitive and specific, possess strong positive and negative predictive values, and be inexpensive as well as relatively noninvasive. For PC, there is no such tool. Due to the relative rarity of PC, population-based screening is not a realistic option. Nonetheless, screening of high-risk cohorts may establish a role in PC prevention. Because there is no single perfect screening method for PC in asymptomatic individuals, multimodality screening offers the greatest potential diagnostic accuracy. Advantages and disadvantages of some of the most common current screening methods for PC are presented in Table 3. To date, two groups have reported on the utility of screening individuals at high risk of PC. Dr. Teresa Brentnall and colleagues at the University of Washington in Seattle screened 75 high-risk individuals using endoscopic ultrasound (EUS) followed by endoscopic retrograde cholangiopancreatography (ERCP) if the EUS was abnormal [61]. Individuals who had an abnormal ERCP were provided the choice of histologic pancreatic tail examination or continued surveillance. High-risk individuals who showed PanIN III lesions on histological examination of the tailectomy specimen were offered surveillance versus total pancreatectomy. In all,15 high risk individuals underwent either partial or total pancreatectomy. Although none of

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Table 3 Utility of diagnostic methods in screening for pancreatic cancer in asymtomatic individuals. Method

Advantage(s)

Disadvantage(s)

Endoscopic Ultrasound (EUS)

Best method of demonstrating PanIN lesions, pre-malignant cystic lesions Good way to see chronic pancreatitis like changes, parenchymal heterogeneity Good method of detecting dysplasia, measuring CEA* levels in cystic lesions Can visualise large lesions and cystic lesions; best method of showing vascular invasion and metastases Best method of visualising irregularities and ectactic areas of small and medium-sized ducts, where PanIN typically arises

Familial pancreatic cancer kindreds often have pancreatitis like changes Effectiveness is operator dependent

EUS with fine needle aspiration (EUS-FNA) Computed Tomography (CT)

Endoscopic Retrograde Cholangiopancreatogram (ERCP)

Invasive procedure: complications, including pancreatitis, can occur Is not sensitive or specific enough to detect minute lesions with any accuracy or reliability Invasive procedure with the chance of complications, especially post-ERCP pancreatitis

these patients had a histologically normal pancreas and none had evidence of invasive adenocarcinoma, five surgical specimens demonstrated evidence of PanIN II changes and 10 had PanIN III lesions. Johns Hopkins University recently published the largest study of high-risk PC screening [62,63]. In all, 116 individuals at increased risk were evaluated, including seven individuals from PJS kindreds and 109 familial PC kindreds. Screening was performed using a combination of computed tomography (CT) and EUS. If the EUS was abnormal, EUS-fine needle aspiration (EUS-FNA), multidetector CT and ERCP were performed. In all, 29 participants displayed neoplastic-type lesions and 15 underwent surgery. Six high-grade or invasive lesions (PanIN III, IPMN with carcinoma in situ and one true adenocarcinoma), 11 low-grade lesions (PanIN II or IPMN) and six non-neoplastic lesions were documented by final pathological examination. An additional six extrapancreatic lesions were detected via screening, including one ovarian malignancy. The results of these screening studies indicate that screening for PC might prove beneficial in detecting dysplastic or pre-malignant lesions in select high-risk groups. However, pancreatic resection carries significant risks of mortality and incurs lifelong diabetes requiring insulin therapy. One-third or more of the participants in both screening studies who underwent pancreatectomy were found only to have benign disease and about half of the pre-malignant or malignant lesions that were noted in the Johns Hopkins screening study were actually found at surgery and not during the screening process. Additionally, because just a fraction of participants in both studies underwent pancreatic resection, it is impossible to accurately estimate the sensitivity or specificity of the diagnostic methods comprising each institution’s screening protocol. Nonetheless, these studies were valuable in demonstrating that EUS may be appropriate for detecting very small intrapancreatic changes and lesions. Additionally, the studies showed that over half of high risk individuals had notable pancreatic pathology, including chronic pancreatitis like changes, such as hypoechoic or hyperechoic foci, duct narrowing or irregularities, calcifications and cysts. Since these two screening studies were published, two additional analyses regarding the utility of EUS in familial PC kindreds have been performed. One study examined interobserver agreement of experienced endosonographers on EUS findings in individuals from familial PC families and controls [64]. The hypothesis was that strong agreement between endosonographers would be noted; in fact, this study found the opposite to be true. Seventeen endosonographers evaluated both a training set and a test set of EUS video clips and there was very little diagnostic agreement for either set; agreement for clips of familial PC kindreds was worse than for controls. A separate study conducted by investigators at the University of Michigan involved a systematic review and Markov modelling of 45-year old first-degree relatives of familial PC kindreds to compare four separate management strategies for preventing PC in high risk individuals, namely, (1) prophylactic total pancreatectomy, (2) annual surveillance by EUS, (3) annual surveillance by EUS-FNA, (4) doing nothing [65]. The authors asserted that the effectiveness of any screening program for familial PC kindreds would depend greatly on the subsequent management of the 50% or more of individuals demonstrating findings of chronic pancreatitis by EUS. Based on a 20% lifetime risk of PC, the investigators determined that the ‘doing nothing’ strategy actually provided the greatest quantity of remaining years of life, the greatest remaining quality-adjusted life years, and the lowest cost.

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Research agenda  EUS is a promising screening method for individuals from high-risk, PC-prone families.  At present, it is not clear if there is a role for screening of patients from familial PC kindreds.  Prospective, collaborative, multi-institutional studies of EUS in combination with other screening methods are warranted to define the utility of screening individuals for PC.

Genetic counselling of high risk individuals The most critical part of the genetic counselling process is taking a thorough family cancer history and building an extended family pedigree. Pedigree/family history information should be compiled in sufficient enough detail to arrive at the most likely hereditary cancer syndrome diagnosis so that

Fig. 1. This is a pedigree of a cancer-prone family with FAMMM syndrome in association with cutaneous malignant melanoma and PC. Two siblings in generation II both manifested PC: individual II-1 at age 71 years and individual II-2 at 65 years. In addition, individual III-2 had PC as well as two malignant melanoma primary cancers. The CDKN2A (p16) mutation was identified in this family.

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molecular genetics can be used to search for the mutation [66]. The history should include as many generations of family members as can be documented, the cancers that they had and age of cancer onset, especially of the youngest generation. It is important to bear in mind that there is a profound emotional component for individuals at high risk of developing PC, because mortality from PC closely approximates incidence. Individuals found to carry a potentially lethal mutation have worries not only about their own long-term survival but also about the health of their offspring. A recent study of 84 HBOC families with known deleterious BRCA mutations, for instance, found that regardless of their cancer status, compared with mutation non-carriers, a significantly higher percentage of carriers felt guilt about passing a mutation to their children, worried about developing additional cancer or their children developing cancer, and were concerned about health insurance discrimination [67]. FAMMM, described previously as one of several hereditary PC syndromes, has the striking phenotype of multiple atypical moles which highly predispose patients to malignant melanoma [2]; if individuals undergo genetic analysis and are found to harbour a CDKN2A (p16) mutation, they are significantly likely to develop both malignant melanoma and PC. High-risk FAMMM patients readily recognise these moles among themselves and their relatives and often have observed both melanoma and PC to occur in family members. Their anxiety is only compounded if they discover they carry the CDKN2A germline mutation. The pedigree in Fig. 1 shows an extended FAMMM family with the CDKN2A mutation and multiple cases of PC. A more common PC-predisposing syndrome is HBOC, due to a germline BRCA1 or BRCA2 mutation. Of keen interest is the BRCA2 mutation, since initially it was considered to be the only breast cancer gene that predisposed to PC. For example, we have a family in which three consecutive generations have displayed PC in association with a BRCA2 mutation (unpublished). The pedigree in Fig. 2 is an example of an extended family that segregates a BRCA1 mutation. Screening recommendations Participants of the Fourth International Symposium of Inherited Diseases of the Pancreas recently convened to discuss approaches for PC screening and established counselling and surveillance guidelines for individuals at high risk of developing PC [68]. A summary of this group’s screening recommendations is provided in Table 4. They recommended that PC screening studies be done in conjunction

Fig. 2. This is an HBOC family that manifested early onset breast cancer through 5 generations. Note individual IV-2 with breast cancer at age 33 years and PC at age 50. This family segregated the Ashkenazi BRCA1 founder mutation 5382insC.

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Table 4 Recommendations for pancreatic cancer screening. Any member of a Peutz–Jeghers family (a verified germline STK11/LKB1 mutation carrier, whenever possible) Any individual who has been diagnosed with hereditary pancreatitis A known BRCA1, BRCA2, or p16 mutation carrier with at least one 1st or 2nd degree relative who has been diagnosed with pancreatic cancer Families with two relatives in the same lineage with pancreatic cancer, one of whom is a 1st degree relative of the screening candidate Individuals from a pedigree that have had numerous 1st, 2nd, or 3rd degree relatives with pancreatic cancer

with a peer-reviewed protocol involving informed consent and human subjects’ protection and strongly encouraged that all screening be performed at centres that have a comprehensive genetics counselling program as well as documented expertise in the diagnosis and treatment of pancreatic diseases. The future of screening The greatest hope for pancreatic cancer screening would be the discovery of a biomarker of early disease. A variety of serum and pancreatic juice biomarkers have been evaluated in association with PC, with the hopes of being able to reliably predict a precursor lesion [69,70]. As one example of a biomarker study, researchers at Johns Hopkins built on the observation that methylation abnormalities occur during pancreatic carcinogenesis and evaluated CpG island methylation in eight genes in various degrees of PanIN lesions [71]; they noted aberrant methylation in 68% of all PanIN lesions examined and in more than 70% of the earliest lesions (PanIN-1A). In a second recent study, Tarafa et al investigated using mutational load distribution analysis as a tool for the early detection of PC and found that it was an effective means of longitudinally assessing risk and early detection of PC among individuals carrying a high risk, p16 germline mutation [72]. Summary Great progress has been made in elucidating the genetic alterations characteristic of hereditary PC. To the practising clinician, hereditary pancreatitis, CF, and cancer syndromes are more overt and phenotypically distinct conditions associated with increased PC risk, although they comprise a small percentage of all pancreatic cancer cases. Familial PC might be more common than some cancer syndromes, but in most cases, it is clinically indistinguishable from sporadic cases other than its positive family history. Although newly diagnosed cases of PC may occur at younger ages in successive compared with preceding generations, identifying PC-prone families often proves difficult because PC is less common than many other cancers and generally occurs at older ages. Additionally, some individuals are unable to provide a complete family history of cancer in earlier generations of their extended family. The variable phenotypic expressivity and reduced penetrance of some PC-predisposing conditions may complicate identifying many higher risk families. Nonetheless, it is critical to try to obtain a thorough family cancer history from each at-risk individual and construct a pedigree, including as many generations as can be identified and the age of cancer onset in each case. There is no perfect method of screening for PC among asymptomatic individuals; further research regarding the utility of EUS and other screening methods is warranted among high-risk cohorts. At present, increased clinical awareness of the heretible nature of pancreatic adenocarcinoma and the search for a biomarker indicative of early stage pancreatic neoplasia continue to be the focus of PC research. Conflict of interest Drs. Greer, Lynch and Brand have no conflicts of interest to disclose. References [1] American Cancer Society. Cancer Facts Figures 2008. *[2] Lynch HT, Fusaro RM, Lynch JF, et al. Pancreatic cancer and the FAMMM syndrome. Fam Cancer 2008;7(1):103–12. [3] Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol 2006;20(2):197–209.

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