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Familial pancreatic cancer
Annals of Oncology 10 Suppl. 4: S69-S73, 1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.
Review Familial pancreatic cancer R. H. Hruban,1-2 G. M. Petersen,3 M. Goggins,1 A. C. Tersmette,4 G. J. A. Offerhaus,4 F. Falatko,1 C. J. Yeo,2-5 & S.E. Kern1'2
Summary Background: For many years anecdotal case reports have suggested that pancreatic cancer aggregates in some families. Methods: Two recent advances have established that this is in fact the case. First, large registries, such as the National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, have identified a number of families in which multiple family members have been diagnosed with pancreatic cancer. As a result, the patterns of inheritance of pancreatic cancer can now be studied on a scale not possible before. Second, advances in molecular genetic techniques make it possible to test members of these families for germline mutations in known candidate cancer causing genes. As a result, some of the genetic alterations responsible for the familial aggregation of pancreatic cancer have been identified in some families. Results: The NFPTR has enrolled 362 families in which at least one family member has been diagnosed with pancreatic cancer. These include 151 families in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Analysis of
Introduction Over the last quarter of a century there have been a number of case reports of families in which multiple family members developed pancreatic cancer [1-16]. For example, in 1973 MacDermott and Kramer reported a kindred in which four siblings developed pancreatic cancer [13] and in 1977 Reimer et al. reported a kindred in which a father and son were affected [14]. While reports such as these suggest that an increased risk of developing pancreatic cancer can be inherited, it is also possible that chance and shared environmental exposure cause the rare aggregation of pancreatic cancer in a family. In fact, Reimer et al. note that the son and father who developed pancreatic cancer worked together, and both were exposed to vinyl chloride and possibly to mycotoxins [14]. Clearly, anecdotal case reports are not enough to establish the genetic transmission of an increased risk of developing pancreatic cancer.
Familial pancreatic cancer registries In order to overcome the problems associated with small numbers, several large familial pancreatic cancer registries have been established [2,16-19]. Probably the first of these was established by Henry Lynch [2,16]. In 1990, Lynch
these families has revealed that even second-degree relatives of patients from these families are at increased risk of developing pancreatic cancer. In addition, a number of kindreds which exhibit aggregation of cancer have been tested for germline mutations in known cancer causing genes. Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in pi 6 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS). Conclusions: Pancreatic cancer aggregates in some families, and relatives of patients with pancreatic cancer have an increased risk of developing pancreatic cancer themselves. The genetic basis for the familial aggregation of pancreatic cancer has been shown to be germline mutations in known cancer causing genes in some of these families. Key words: familial, families, inheritance, pancreas, pancreatic cancer, tumor suppressor genes.
reported 18 kindred with a familial clustering of pancreatic cancer [2]. These families were identified from a review of medical records of all kindred on file at the Hereditary Cancer Institute at Creighton University. There appeared to be an autosomal dominant mode of transmission in several of the families, but the mean age of onset, the histologic types, and the survival times of the patients with a familial clustering of pancreatic cancer were similar to those reported for unselected patients with pancreatic cancer. Although primarily descriptive, these data indicate the need to learn more about the role of inheritance in the etiology of pancreatic cancer [2]. We therefore established The National Familial Pancreas Tumor Registry at Johns Hopkins in 1994 [17]. Patients with pancreas cancer are identified and recruited into the registry, and patients and families may enroll by self referral through learning of the registry from their physicians or the internet. This registry is probably the largest registry of familial pancreatic cancer and is truly an international registry with kindreds enrolled from the United States, Europe, and Australia. As of 10/3/98, 362 kindreds have enrolled in this registry. These include 151 kindreds in which two or more first degree relatives have been diagnosed with pancreatic cancer (referred to here as "familial kindreds") and 211 kindreds in which only one family member has been diagnosed with pancreatic cancer (referred to here as "non-
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Departments of 'Pathology,''Oncology, and 'Surgery, The Johns Hopkins Medical Institutions; 'Department of Epidemiology, The Johns Hopkins School of Public Health, Baltimore, MD. USA; and the 'Department of Pathology, the Academic Medicine Center, Amsterdam, The Netherlands
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The NFPTR c/o Dr. Ralph Hruban Meyer 7-181 The Johns Hopkins Hospital 600 N. Wolfe St. Baltimore, MD 21287 USA E-mail: ffalatko @ welchlink.welch.jhu.edu Web: http://pathology.jhu.edu/pancreas
Case control studies One way to overcome the potential selection biases inherent in self referred registries is to perform case control studies. In 1991, Ghadirian et al. reported a population-based casecontrol study of familial aggregation of pancreatic cancer in the Francophone community of Montreal, Canada [20]. They interviewed 179 patients with pancreatic cancer and 179 controls matched for age, gender, and language and selected by a modified random digit dialing method [20]. Remarkably, 7.8% of the pancreatic cancer patients reported a positive family history of pancreatic cancer, as compared to only 0.6% of the controls. This 13 fold difference between the cases in controls was statistically significant, and there were no apparent differences in environmental risk exposures in the two groups. In 1994, Fernandez et al. reported a study from Northern Italy in which they examined the relationship between family history and pancreatic cancer [21]. In a case-control study of 362 histologic confirmed incident cases of pancreatic cancer and 1,408 controls admitted to the hospital for acute, non-neoplastic, non-digestive tract disorders, they found a significant association between a family history of pancreatic cancer and risk of pancreatic cancer (odds ratio (OR)=3.0; 95% confidence limits (CL)=1.4 to 6.6) [21]. The risk for pancreatic cancer did not change appreciatively after allowance for tobacco, alcohol, dietary factors, and medical history of diabetes and pancreatitis (OR 2.8; 95% CL 1.3 to 6.3). These case-control studies help establish that shared environmental risk factors do not account for the familial aggregation of pancreatic cancer. Instead, they suggest that there is a genetic component to pancreas cancer.
Table 1. Familial kindred enrolled in the NFPl'R
Description of Kindred One Generation 2 siblings 3 siblings 4 siblings S siblings 2 siblings and one third-degree relative 2 siblings and two third-degree relatives
31 10 2 1
Two Generations Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent,
69 6 3 8 1 1 1 1 2
1 offspring 2 offspring 3 offspring 1 offspring, one sibling 1 offspring, three siblings 2 offspring, one sibling offspring, sibling, one second-degree relative offspring, sibling, one third-degree relative offspring, one second-degree relative 1 offspring, one third-degree relative
Three Generations Grandparent, Grandparent, Grandparent, Grandparent, rplativp
TOTAL
parent, parent, parent, parent,
grandchild grandchild, one first-degree relative grandchild, two first-degree relatives grandchild, one third-degree
No. of Kindreds
5 1
2
3
2 1 1
151
Total No. of Pancreas Cancer Cases 62 30 8 5 15 3
138 18 12 24 5 4 4 4 6 6
9 8 5 4
370
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familial kindreds"). The 151 familials kindreds (table 1) include 50 in which one generation is affected (figure 1), 94 in which two generations are affected, and 7 in which three generations are affected (figure 2). An initial analysis of the first 212 kindreds enrolled in this registry revealed that second-degree relatives of patients from the familial kindreds had a greater risk of pancreatic cancer than did second-degree relative patients from the non-familial kindreds (3.7% vs. 0.6%, p<0.0001)[17]. Furthermore, nonpancreatic cancers were also increased in second-degree relatives of patients with pancreatic cancer from the familial kindreds (27.2% vs. 12.1%, p<0.0001)[17]. The other types of cancer which developed in these families included breast, colon, and lung cancer. Similarly, Crowley et al. analyzed the 65 kindreds in the Familial Pancreatic Registry at the University of Pittsburgh and they found an increased risk of breast, colon, male genital, and stomach cancers [19]. These data clearly suggest that there is a genetic basis for the aggregation of pancreatic cancer in some families and that the risk of cancer in these families also includes nonpancreatic cancer such as breast and colon cancer. Registries such as the NFPTR will play a critical role in establishing a basis for these increased risks. Persons wishing to enroll in the NFPTR may do so by contacting us at:
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1:1 Gastric CA@
i k -to * ll:2 Pancreas CA@68
Pancreas CA@64
Breast CA@47
116 Pancreas CA@42
11:7 Pancreas CA@69
1:1 Pancreas CA@73
k
11:1 Pancreas CA@34
'11:2 Pancreas CA@63
l:2 Pancreas CA@47
11:3 Pancreas CA@68
h to
11:4 Esophageal CA@56
11:5 Lung CA@65
•O 11:6
*\tl.A 1 Pancreas CA@39
Figure 2: Pedigree of NFPTR family 994 showing pancreatic cancer in three generations
Genetic alterations A number of genetic alterations have been identified in families in which there is an aggregation of pancreatic cancer. The identification of these alterations establishes a genetic basis for some of the kindreds in which there is familial aggregation of pancreatic cancer, and it also helps explain the increased risk of non-pancreatic cancer reported in these families. Furthermore, the identification of these genetic alterations has helped confirm the operation of Knudson's hypothesis for pancreas cancer, that the same genes are inactivated in familial and sporadic forms of the cancer [22,23].
P16 and the FAMMM syndrome The pl6 tumor suppressor gene is inactivated in >95% of sporadic pancreatic cancers [24-26]. In 40% of the cancers pl6 is inactivated by mutation of one allele coupled with loss of the second allele (loss of heterozygosity, LOH), in 40% by loss of both alleles (homozygous deletion) and in approximately 15% by hypermethylation of the pl6 promoter. P16 is also frequently inactivated in melanomas
[27]. One would therefore predict, based on Knudson's hypothesis, that pl6 alterations will play a role in the development of familial forms of pancreatic cancer and melanoma. This has recently been shown to be the case [28]. The Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome is a rare syndrome associated with germline pl6 mutations which predisposes affected family members to develop multiple nevi, atypical nevi, melanomas, and pancreatic cancer [3,15,16]. For example, Goldstein et al. analyzed 19 melanoma-prone families for germline pi6 mutations and they found that kindreds with germline mutations in pl6 that impaired pl6 function had a 22-fold increased risk of pancreatic cancer [29]. Moskaluk et al. have recently extended this to a family having two firstdegree relatives with pancreatic cancer [28]. This family was not originally recognized to have the FAMMM Syndrome [28]. Clinically, this means that members of families in which there is a strong aggregation of pancreatic cancer and melanoma now can be tested for germline mutations in the pi6 gene. Family members found to carry pl6 mutations can be more carefully screened for melanomas and perhaps pancreatic cancer and some lives may be saved.
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Figure 1: Pedigree of National Familial Pancreas Tumor Registry (NFPTR) kindred 1437 showing 4 siblings with pancreatic cancer and a fifth with breast cancer
72 LKB1 and the Peutz-Jeghers Syndrome
BRCA2 and breast cancer As discussed earlier, the risk of breast cancer is increased in families in which there is an aggregation of pancreatic cancer [17]. Conversely, the risk of pancreatic cancer is also increased in families of patients with breast cancer. For example, Tulinius et al. studied the families of 947 female breast cancer patients from the Icelandic Tumor Registry and showed that the male first-degree relatives of these patients had an increased risk of pancreatic cancer (OR = 1.66)[35]. More recently, a number of investigators have shown that the risk of pancreatic cancer is increased in carriers of mutations in BRCA2, the second breast cancer gene [36-40]. Goggins et al. therefore screened a series of patients with pancreatic cancers and found that 5 (-7%) of these patients had germline mutations in BRCA2 and that the pancreatic cancers from these patients had lost the wild-type BRCA2 allele [41]. The function of the BRCA2 gene product was therefore lost in these cancers. Remarkably, only one of the five patients with germline BRCA2 mutations and pancreatic cancer had a family history of breast cancer and none had a family history of pancreatic cancer. The lack of a strong family history of the cancer in these patients may be explained by a low penetrance of this trait. Therefore, although Ozcelik et al. have estimated that carriers of the 6174 del T BRCA2 mutation have a ten-fold increased risk of developing pancreatic cancer, most carriers do not develop the disease because other factors must influence penetrance or lifetime disease risk [40]. Germline mutations in BRCA2 are therefore the most
Trypsinogen and hereditary pancreatitis While the syndromes discussed thus far have been cancer syndromes caused by genetic mutations in tumor suppressor genes, pancreatic cancer can also aggregate in families with an inflammatory condition, i.e, hereditary pancreatitis [4245]. Hereditary pancreatitis is characterized by the dominant inheritance of a tendency to recurrent episodes of severe pancreatitis. These patients develop pancreatitis at a young age and most eventually develop chronic pancreatitis. Whitcomb et al. have recently demonstrated that familial pancreatitis can be caused by germline mutations in the cationic trypsinogen gene on 7q35 [45,46]. These germline mutations block the inactivation of trypsin, resulting in autodigestion of the pancreas. It is believed that the increased risk of the pancreatic cancer seen in these patients is secondary to chronic injury and repair caused by the pancreatitis [15,47,48].
HNPCC Although pancreatic carcinoma is a rare cancer in patients with the Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), HNPCC may predispose affected individuals to pancreatic cancer [1,16]. HNPCC is caused by germline mutations in one of the DNA mismatch repair genes, including hMSH2 and hMLHl, [49-54]. These genes code for proteins which correct small errors that normally occur during DNA replication. As a result, tumors which arise in patients with HNPCC often accumulate mutations which change the length of repeated DNA sequences resulting in phenotype called "microsatellite instability." While germline mutations in DNA mismatch repair genes have not been demonstrated to date in patients with pancreatic carcinoma, Goggins et al. have reported microsatellite instability in ~4% of pancreatic cancers [50], and as noted previously, we and others have shown that colon cancer is increased in familial pancreatic cancer kindreds [17,19]. Therefore, some cases of pancreatic cancer, especially those which develop in patients with a strong family history of colorectal cancer, may be associated with HNPCC.
Discussion Pancreatic cancer aggregates in some families. Some of this aggregation may be caused by shared environmental influences; however, inheritance also clearly plays a role. Germline mutations in BRCA2, STK11/LKB1, pl6, the cationic trypsinogen genes, and possibly even in DNA mismatch repair genes may all predispose carriers to an increased risk of pancreatic cancer. The identification of the
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The Peutz-Jeghers Syndrome is characterized by hamartomatous polyps of the gastrointestinal tract and by pigmented macules on the lips, buccal mucosa, and digits [30,31]- Patients with the Peutz-Jeghers Syndrome have also been shown to have an increased risk of developing pancreatic cancer [32]. Germline mutations in the STK11/LKB1 gene have recently been shown to cause the Peutz-Jeghers Syndrome [33,34]. Su etal. examined the role of STK11/LKB1 mutations in the development of pancreatic cancer [30]. They analyzed biopsies from two PJS patients who died of pancreatic cancer, a panel of 135 sporadic pancreatic and biliary cancers, and 11 cell lines for mutations in the exonic sequences and splice junctions of STK11/LKB1 [30]. A germline splice site mutation was identified in STK11/LKB1 in one of the two patients with PJS, and this patient's pancreatic cancer showed loss of the wild-type STK11/LKB1 gene. The function of the STK11/LKB1 gene product was therefore lost in this carcinoma. In addition, Su et al. found that 5-6% of the sporadic pancreatic and biliary carcinomas they examined harbored homozygous deletions or intragenic sequence mutations of STK11/LKB1 coupled with loss of the second allele [30]. These results not only demonstrate that genetic alterations in STK11/LKB1 play a role in the development of sporadic pancreatic cancer and in the development of pancreatic cancers in patients with PJS, but they also confirm the operation of Knudson's hypothesis in the pancreas - mat the same genes are frequently inactivated in familial and sporadic forms of pancreatic cancer [22,23].
common inherited predisposition to pancreatic cancer identified to date, and, because of the low penetrance of this trait, some cases of pancreatic cancer which appear sporadic, may in fact be caused by inherited mutations in BRCA2. Certainly, members of families in which there is an aggregation of breast and pancreatic cancer may benefit from screening for germline BRCA2 mutations.
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Acknowledgments The authors would like to thank Jennifer Galford for her hard work in preparing this manuscript. This work was supported by NIH grant P50-CA62924. To learn more about pancreatic cancer visit our Web site (http://pathology.jhu.edu/pancreas).
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Correspondence to: Ralph H. Hruban Meyer 7-181 Department of Pathology The Johns Hopkins Hospital 600 N. Wolfe St. Baltimore, MD 21287 USA
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genetic basis for the aggregation of pancreatic cancer has immediate clinical applications. Families in which there is an aggregation of pancreatic cancer and/or melanoma can be tested for pl6 mutations; families in which there is an aggregation of breast cancer and pancreatic cancer, for BRCA2 mutations; families in which there is an aggregation of pancreas cancer and pancreatitis, for mutations in the cationic trypsinogen gene; families in which there is the Peutz-Jeghers Syndrome, for mutations in LKB1/STK11; and families in which there is an aggregation of pancreatic cancer and colon cancer, for evidence of defects in a mismatch repair gene.
Review Familial pancreatic cancer R. H. Hruban,1-2 G. M. Petersen,3 M. Goggins,1 A. C. Tersmette,4 G. J. A. Offerhaus,4 F. Falatko,1 C. J. Yeo,2-5 & S.E. Kern1'2
Summary Background: For many years anecdotal case reports have suggested that pancreatic cancer aggregates in some families. Methods: Two recent advances have established that this is in fact the case. First, large registries, such as the National Familial Pancreas Tumor Registry (NFPTR) at Johns Hopkins, have identified a number of families in which multiple family members have been diagnosed with pancreatic cancer. As a result, the patterns of inheritance of pancreatic cancer can now be studied on a scale not possible before. Second, advances in molecular genetic techniques make it possible to test members of these families for germline mutations in known candidate cancer causing genes. As a result, some of the genetic alterations responsible for the familial aggregation of pancreatic cancer have been identified in some families. Results: The NFPTR has enrolled 362 families in which at least one family member has been diagnosed with pancreatic cancer. These include 151 families in which at least two first-degree relatives have been diagnosed with pancreatic cancer. Analysis of
Introduction Over the last quarter of a century there have been a number of case reports of families in which multiple family members developed pancreatic cancer [1-16]. For example, in 1973 MacDermott and Kramer reported a kindred in which four siblings developed pancreatic cancer [13] and in 1977 Reimer et al. reported a kindred in which a father and son were affected [14]. While reports such as these suggest that an increased risk of developing pancreatic cancer can be inherited, it is also possible that chance and shared environmental exposure cause the rare aggregation of pancreatic cancer in a family. In fact, Reimer et al. note that the son and father who developed pancreatic cancer worked together, and both were exposed to vinyl chloride and possibly to mycotoxins [14]. Clearly, anecdotal case reports are not enough to establish the genetic transmission of an increased risk of developing pancreatic cancer.
Familial pancreatic cancer registries In order to overcome the problems associated with small numbers, several large familial pancreatic cancer registries have been established [2,16-19]. Probably the first of these was established by Henry Lynch [2,16]. In 1990, Lynch
these families has revealed that even second-degree relatives of patients from these families are at increased risk of developing pancreatic cancer. In addition, a number of kindreds which exhibit aggregation of cancer have been tested for germline mutations in known cancer causing genes. Germline mutations in BRCA2 have been shown to predispose to both breast and pancreatic cancer, germline mutations in pi 6 to melanoma and pancreatic cancer (the FAMMM syndrome), and genetic mutations in STK11/LKB1 to pancreatic cancer in patients with the Peutz-Jeghers Syndrome (PJS). Conclusions: Pancreatic cancer aggregates in some families, and relatives of patients with pancreatic cancer have an increased risk of developing pancreatic cancer themselves. The genetic basis for the familial aggregation of pancreatic cancer has been shown to be germline mutations in known cancer causing genes in some of these families. Key words: familial, families, inheritance, pancreas, pancreatic cancer, tumor suppressor genes.
reported 18 kindred with a familial clustering of pancreatic cancer [2]. These families were identified from a review of medical records of all kindred on file at the Hereditary Cancer Institute at Creighton University. There appeared to be an autosomal dominant mode of transmission in several of the families, but the mean age of onset, the histologic types, and the survival times of the patients with a familial clustering of pancreatic cancer were similar to those reported for unselected patients with pancreatic cancer. Although primarily descriptive, these data indicate the need to learn more about the role of inheritance in the etiology of pancreatic cancer [2]. We therefore established The National Familial Pancreas Tumor Registry at Johns Hopkins in 1994 [17]. Patients with pancreas cancer are identified and recruited into the registry, and patients and families may enroll by self referral through learning of the registry from their physicians or the internet. This registry is probably the largest registry of familial pancreatic cancer and is truly an international registry with kindreds enrolled from the United States, Europe, and Australia. As of 10/3/98, 362 kindreds have enrolled in this registry. These include 151 kindreds in which two or more first degree relatives have been diagnosed with pancreatic cancer (referred to here as "familial kindreds") and 211 kindreds in which only one family member has been diagnosed with pancreatic cancer (referred to here as "non-
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Departments of 'Pathology,''Oncology, and 'Surgery, The Johns Hopkins Medical Institutions; 'Department of Epidemiology, The Johns Hopkins School of Public Health, Baltimore, MD. USA; and the 'Department of Pathology, the Academic Medicine Center, Amsterdam, The Netherlands
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The NFPTR c/o Dr. Ralph Hruban Meyer 7-181 The Johns Hopkins Hospital 600 N. Wolfe St. Baltimore, MD 21287 USA E-mail: ffalatko @ welchlink.welch.jhu.edu Web: http://pathology.jhu.edu/pancreas
Case control studies One way to overcome the potential selection biases inherent in self referred registries is to perform case control studies. In 1991, Ghadirian et al. reported a population-based casecontrol study of familial aggregation of pancreatic cancer in the Francophone community of Montreal, Canada [20]. They interviewed 179 patients with pancreatic cancer and 179 controls matched for age, gender, and language and selected by a modified random digit dialing method [20]. Remarkably, 7.8% of the pancreatic cancer patients reported a positive family history of pancreatic cancer, as compared to only 0.6% of the controls. This 13 fold difference between the cases in controls was statistically significant, and there were no apparent differences in environmental risk exposures in the two groups. In 1994, Fernandez et al. reported a study from Northern Italy in which they examined the relationship between family history and pancreatic cancer [21]. In a case-control study of 362 histologic confirmed incident cases of pancreatic cancer and 1,408 controls admitted to the hospital for acute, non-neoplastic, non-digestive tract disorders, they found a significant association between a family history of pancreatic cancer and risk of pancreatic cancer (odds ratio (OR)=3.0; 95% confidence limits (CL)=1.4 to 6.6) [21]. The risk for pancreatic cancer did not change appreciatively after allowance for tobacco, alcohol, dietary factors, and medical history of diabetes and pancreatitis (OR 2.8; 95% CL 1.3 to 6.3). These case-control studies help establish that shared environmental risk factors do not account for the familial aggregation of pancreatic cancer. Instead, they suggest that there is a genetic component to pancreas cancer.
Table 1. Familial kindred enrolled in the NFPl'R
Description of Kindred One Generation 2 siblings 3 siblings 4 siblings S siblings 2 siblings and one third-degree relative 2 siblings and two third-degree relatives
31 10 2 1
Two Generations Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent, Parent,
69 6 3 8 1 1 1 1 2
1 offspring 2 offspring 3 offspring 1 offspring, one sibling 1 offspring, three siblings 2 offspring, one sibling offspring, sibling, one second-degree relative offspring, sibling, one third-degree relative offspring, one second-degree relative 1 offspring, one third-degree relative
Three Generations Grandparent, Grandparent, Grandparent, Grandparent, rplativp
TOTAL
parent, parent, parent, parent,
grandchild grandchild, one first-degree relative grandchild, two first-degree relatives grandchild, one third-degree
No. of Kindreds
5 1
2
3
2 1 1
151
Total No. of Pancreas Cancer Cases 62 30 8 5 15 3
138 18 12 24 5 4 4 4 6 6
9 8 5 4
370
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familial kindreds"). The 151 familials kindreds (table 1) include 50 in which one generation is affected (figure 1), 94 in which two generations are affected, and 7 in which three generations are affected (figure 2). An initial analysis of the first 212 kindreds enrolled in this registry revealed that second-degree relatives of patients from the familial kindreds had a greater risk of pancreatic cancer than did second-degree relative patients from the non-familial kindreds (3.7% vs. 0.6%, p<0.0001)[17]. Furthermore, nonpancreatic cancers were also increased in second-degree relatives of patients with pancreatic cancer from the familial kindreds (27.2% vs. 12.1%, p<0.0001)[17]. The other types of cancer which developed in these families included breast, colon, and lung cancer. Similarly, Crowley et al. analyzed the 65 kindreds in the Familial Pancreatic Registry at the University of Pittsburgh and they found an increased risk of breast, colon, male genital, and stomach cancers [19]. These data clearly suggest that there is a genetic basis for the aggregation of pancreatic cancer in some families and that the risk of cancer in these families also includes nonpancreatic cancer such as breast and colon cancer. Registries such as the NFPTR will play a critical role in establishing a basis for these increased risks. Persons wishing to enroll in the NFPTR may do so by contacting us at:
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1:1 Gastric CA@
i k -to * ll:2 Pancreas CA@68
Pancreas CA@64
Breast CA@47
116 Pancreas CA@42
11:7 Pancreas CA@69
1:1 Pancreas CA@73
k
11:1 Pancreas CA@34
'11:2 Pancreas CA@63
l:2 Pancreas CA@47
11:3 Pancreas CA@68
h to
11:4 Esophageal CA@56
11:5 Lung CA@65
•O 11:6
*\tl.A 1 Pancreas CA@39
Figure 2: Pedigree of NFPTR family 994 showing pancreatic cancer in three generations
Genetic alterations A number of genetic alterations have been identified in families in which there is an aggregation of pancreatic cancer. The identification of these alterations establishes a genetic basis for some of the kindreds in which there is familial aggregation of pancreatic cancer, and it also helps explain the increased risk of non-pancreatic cancer reported in these families. Furthermore, the identification of these genetic alterations has helped confirm the operation of Knudson's hypothesis for pancreas cancer, that the same genes are inactivated in familial and sporadic forms of the cancer [22,23].
P16 and the FAMMM syndrome The pl6 tumor suppressor gene is inactivated in >95% of sporadic pancreatic cancers [24-26]. In 40% of the cancers pl6 is inactivated by mutation of one allele coupled with loss of the second allele (loss of heterozygosity, LOH), in 40% by loss of both alleles (homozygous deletion) and in approximately 15% by hypermethylation of the pl6 promoter. P16 is also frequently inactivated in melanomas
[27]. One would therefore predict, based on Knudson's hypothesis, that pl6 alterations will play a role in the development of familial forms of pancreatic cancer and melanoma. This has recently been shown to be the case [28]. The Familial Atypical Multiple Mole Melanoma (FAMMM) Syndrome is a rare syndrome associated with germline pl6 mutations which predisposes affected family members to develop multiple nevi, atypical nevi, melanomas, and pancreatic cancer [3,15,16]. For example, Goldstein et al. analyzed 19 melanoma-prone families for germline pi6 mutations and they found that kindreds with germline mutations in pl6 that impaired pl6 function had a 22-fold increased risk of pancreatic cancer [29]. Moskaluk et al. have recently extended this to a family having two firstdegree relatives with pancreatic cancer [28]. This family was not originally recognized to have the FAMMM Syndrome [28]. Clinically, this means that members of families in which there is a strong aggregation of pancreatic cancer and melanoma now can be tested for germline mutations in the pi6 gene. Family members found to carry pl6 mutations can be more carefully screened for melanomas and perhaps pancreatic cancer and some lives may be saved.
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Figure 1: Pedigree of National Familial Pancreas Tumor Registry (NFPTR) kindred 1437 showing 4 siblings with pancreatic cancer and a fifth with breast cancer
72 LKB1 and the Peutz-Jeghers Syndrome
BRCA2 and breast cancer As discussed earlier, the risk of breast cancer is increased in families in which there is an aggregation of pancreatic cancer [17]. Conversely, the risk of pancreatic cancer is also increased in families of patients with breast cancer. For example, Tulinius et al. studied the families of 947 female breast cancer patients from the Icelandic Tumor Registry and showed that the male first-degree relatives of these patients had an increased risk of pancreatic cancer (OR = 1.66)[35]. More recently, a number of investigators have shown that the risk of pancreatic cancer is increased in carriers of mutations in BRCA2, the second breast cancer gene [36-40]. Goggins et al. therefore screened a series of patients with pancreatic cancers and found that 5 (-7%) of these patients had germline mutations in BRCA2 and that the pancreatic cancers from these patients had lost the wild-type BRCA2 allele [41]. The function of the BRCA2 gene product was therefore lost in these cancers. Remarkably, only one of the five patients with germline BRCA2 mutations and pancreatic cancer had a family history of breast cancer and none had a family history of pancreatic cancer. The lack of a strong family history of the cancer in these patients may be explained by a low penetrance of this trait. Therefore, although Ozcelik et al. have estimated that carriers of the 6174 del T BRCA2 mutation have a ten-fold increased risk of developing pancreatic cancer, most carriers do not develop the disease because other factors must influence penetrance or lifetime disease risk [40]. Germline mutations in BRCA2 are therefore the most
Trypsinogen and hereditary pancreatitis While the syndromes discussed thus far have been cancer syndromes caused by genetic mutations in tumor suppressor genes, pancreatic cancer can also aggregate in families with an inflammatory condition, i.e, hereditary pancreatitis [4245]. Hereditary pancreatitis is characterized by the dominant inheritance of a tendency to recurrent episodes of severe pancreatitis. These patients develop pancreatitis at a young age and most eventually develop chronic pancreatitis. Whitcomb et al. have recently demonstrated that familial pancreatitis can be caused by germline mutations in the cationic trypsinogen gene on 7q35 [45,46]. These germline mutations block the inactivation of trypsin, resulting in autodigestion of the pancreas. It is believed that the increased risk of the pancreatic cancer seen in these patients is secondary to chronic injury and repair caused by the pancreatitis [15,47,48].
HNPCC Although pancreatic carcinoma is a rare cancer in patients with the Hereditary Non-Polyposis Colorectal Cancer Syndrome (HNPCC), HNPCC may predispose affected individuals to pancreatic cancer [1,16]. HNPCC is caused by germline mutations in one of the DNA mismatch repair genes, including hMSH2 and hMLHl, [49-54]. These genes code for proteins which correct small errors that normally occur during DNA replication. As a result, tumors which arise in patients with HNPCC often accumulate mutations which change the length of repeated DNA sequences resulting in phenotype called "microsatellite instability." While germline mutations in DNA mismatch repair genes have not been demonstrated to date in patients with pancreatic carcinoma, Goggins et al. have reported microsatellite instability in ~4% of pancreatic cancers [50], and as noted previously, we and others have shown that colon cancer is increased in familial pancreatic cancer kindreds [17,19]. Therefore, some cases of pancreatic cancer, especially those which develop in patients with a strong family history of colorectal cancer, may be associated with HNPCC.
Discussion Pancreatic cancer aggregates in some families. Some of this aggregation may be caused by shared environmental influences; however, inheritance also clearly plays a role. Germline mutations in BRCA2, STK11/LKB1, pl6, the cationic trypsinogen genes, and possibly even in DNA mismatch repair genes may all predispose carriers to an increased risk of pancreatic cancer. The identification of the
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The Peutz-Jeghers Syndrome is characterized by hamartomatous polyps of the gastrointestinal tract and by pigmented macules on the lips, buccal mucosa, and digits [30,31]- Patients with the Peutz-Jeghers Syndrome have also been shown to have an increased risk of developing pancreatic cancer [32]. Germline mutations in the STK11/LKB1 gene have recently been shown to cause the Peutz-Jeghers Syndrome [33,34]. Su etal. examined the role of STK11/LKB1 mutations in the development of pancreatic cancer [30]. They analyzed biopsies from two PJS patients who died of pancreatic cancer, a panel of 135 sporadic pancreatic and biliary cancers, and 11 cell lines for mutations in the exonic sequences and splice junctions of STK11/LKB1 [30]. A germline splice site mutation was identified in STK11/LKB1 in one of the two patients with PJS, and this patient's pancreatic cancer showed loss of the wild-type STK11/LKB1 gene. The function of the STK11/LKB1 gene product was therefore lost in this carcinoma. In addition, Su et al. found that 5-6% of the sporadic pancreatic and biliary carcinomas they examined harbored homozygous deletions or intragenic sequence mutations of STK11/LKB1 coupled with loss of the second allele [30]. These results not only demonstrate that genetic alterations in STK11/LKB1 play a role in the development of sporadic pancreatic cancer and in the development of pancreatic cancers in patients with PJS, but they also confirm the operation of Knudson's hypothesis in the pancreas - mat the same genes are frequently inactivated in familial and sporadic forms of pancreatic cancer [22,23].
common inherited predisposition to pancreatic cancer identified to date, and, because of the low penetrance of this trait, some cases of pancreatic cancer which appear sporadic, may in fact be caused by inherited mutations in BRCA2. Certainly, members of families in which there is an aggregation of breast and pancreatic cancer may benefit from screening for germline BRCA2 mutations.
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Acknowledgments The authors would like to thank Jennifer Galford for her hard work in preparing this manuscript. This work was supported by NIH grant P50-CA62924. To learn more about pancreatic cancer visit our Web site (http://pathology.jhu.edu/pancreas).
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Correspondence to: Ralph H. Hruban Meyer 7-181 Department of Pathology The Johns Hopkins Hospital 600 N. Wolfe St. Baltimore, MD 21287 USA
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genetic basis for the aggregation of pancreatic cancer has immediate clinical applications. Families in which there is an aggregation of pancreatic cancer and/or melanoma can be tested for pl6 mutations; families in which there is an aggregation of breast cancer and pancreatic cancer, for BRCA2 mutations; families in which there is an aggregation of pancreas cancer and pancreatitis, for mutations in the cationic trypsinogen gene; families in which there is the Peutz-Jeghers Syndrome, for mutations in LKB1/STK11; and families in which there is an aggregation of pancreatic cancer and colon cancer, for evidence of defects in a mismatch repair gene.