Hereditary Pancreatic Cancer: Part II. Candidate Genes

July 1, 1997

This special series on cancer and genetics is compiled and edited by Henry T. Lynch, MD, director of the Hereditary Cancer Institute, professor of medicine, and chairman of the Department of Preventive Medicine and Public Health, Creighton University School of Medicine, and director of the Creighton Cancer Center, Omaha, Nebraska. Part I of this three-part series on pancreatic cancer appeared in June 1997. Part II (below) reviews the gene mutations thought to contribute to the development of hereditary pancreatic cancer, and Part III will explores the clinical recognition of a hereditary predisposition to pancreatic cancer.

This special series on cancer and genetics is compiledand edited by Henry T. Lynch, MD, director of the Hereditary Cancer Institute,professor of medicine, and chairman of the Department of Preventive Medicineand Public Health, Creighton University School of Medicine, and directorof the Creighton Cancer Center, Omaha, Nebraska. Part I of this three-part series on pancreatic cancer appeared in June 1997. Part II (below) reviews the gene mutations thought to contribute to the development of hereditary pancreatic cancer, and Part III will exploresthe clinical recognition of a hereditary predisposition to pancreatic cancer.

Before the genetic basis for a familial predisposition to a cancer canbe examined, it must first be established that such a predisposition exists.This has been done for pancreatic cancer.

It has been estimated that 5% to 10% of patients with pancreatic carcinomahave a hereditary susceptibility for the disease,[1-7] and a Canadian population-basedepidemiologic study found that approximately 8% of pancreatic cancer patientshave a first-degree relative with pancreatic cancer.[3]

In addition, patients suffering from a number of inherited syndromesare thought to be at increased risk of pancreatic cancer. These syndromesinclude von Hippel- Lindau disease, HNPCC (hereditary nonpolyposis colorectalcancer) due to germline defects in mismatch repair genes[4], the Peutz-Jegherssyndrome,[7] hereditary relapsing acute pancreatitis,[8] and the Li-Fraumenisyndrome.[9] These well-characterized syndromes, however, probably accountfor only a small proportion of the familial pancreatic carcinoma burden.[1-7]

Since most familial clusters of pancreatic cancer are not associatedwith a recognized syndrome, interest has therefore shifted to a "candidategene" approach. In this approach, patients with a familial clusteringof pancreatic cancer, but without a recognized cancer syndrome, are examinedfor germline mutations in genes found to be mutated in sporadic pancreaticcancer (see Part I, June 1997).

Mutations of p16

The p16 gene (CDKN2) is frequently inactivated in sporadic pancreaticcancer. It was the first gene identified for which germline mutations couldbe associated with an increased risk of developing pancreatic cancer.[10]These p16 mutations were first identified as predisposing to a high riskof melanoma,[11,12] but carriers of germline p16 mutations also have a13-fold increased risk of developing pancreatic cancer.[10]

Such mutations appear to account for only a small percentage of allfamilial pancreatic cancers,[13] and they should be suspected in a patientwith pancreatic cancer and a strong family history of melanoma.[13]

Role of BRCA2

The search for the BRCA2 gene was aided by the identification of a homozygousdeletion in a sporadic pancreatic cancer. Germline BRCA2 mutations alsocontribute to the hereditary predisposition to pancreatic cancer. For example,in our recent examination of a large series of unselected patients withpancreatic cancer, we found that 7% had germline BRCA2 mutations.[14]

Remarkably, this hereditary risk for cancer could not have been predictedfrom the patients' clinical histories. Of four BRCA2 mutation carriers,none had a family history of pancreatic cancer, and only one had a first-degreerelative with breast cancer.[14] Of interest, pancreatic cancer in thesepatients with germline BRCA2 mutations does not usually present at an earlyage.[14,15]

The contribution of germline BRCA2 mutations to pancreatic cancer mayaccount for previous epidemiologic data that identified an increased prevalenceof pancreatic cancer in families of patients with breast and ovarian cancer.

For example, breast cancer families with germline BRCA2 mutations havea higher than expected number of members with pancreatic cancer,[15,16]and Tulinius et al found an increased relative risk of pancreatic cancerin male first-degree relatives of breast cancer patients.[17]

Furthermore, in their analysis of the Utah Population Database, Kerberand Slattery found that a family history of pancreatic cancer is significantlyassociated with an increased risk of ovarian cancer.[18]

The increased risk of developing pancreatic and breast cancer associatedwith germline BRCA2 mutations is particularly noteworthy because of thewidespread availability of clinical testing for these mutations.

Based on the relative risk of breast cancer in Ashkenazi Jewish BRCA1or BRCA2 mutation carriers, the penetrance of early-onset breast cancerin BRCA2 mutant carriers is approximately one third that of their BRCA1counterparts.[19]

The lifetime risk of breast cancer in BRCA2 mutant carriers is lesscertain, but is probably significantly less than the 80% to 90% risk forBRCA1 mutation carriers, and may be on the order of 25% to 35%.[19,20]

Low Penetrance of BRCA2

Penetrance will vary within individual families depending on additionalfactors, including the type of mutation, its position within the gene,the inheritance of unknown modifier genes, and environmental factors. Forexample, the cancer risk of most missense mutations will be difficult topredict, as their effects on protein function are generally unknown.

Most of the known mutations of BRCA2, including those found commonlyin the Ashkenazi population, would generate truncated proteins. However,not all truncating mutations of the BRCA2 gene would necessarily have anequivalent effect.

For example, mutations in certain regions of the BRCA1 and BRCA2 genesmight be more likely to cause ovarian cancer than would other mutations.[21,22]Similarly, it is possible that mutations of certain regions of the BRCA2gene might, in particular, predispose carriers to the development of pancreaticcancer.

The exact risk of pancreatic cancer in a carrier of a germline BRCA2mutation is not known at present, but an approximation may be constructedfrom the currently available data. Among 21 BRCA2 families, Thorlaciuset al observed 100 patients with breast cancer and 11 with pancreatic cancer.[23]Similarly, in a report of eight families with germline mutations of BRCA2,Phelan et al found four patients with pancreatic cancer and 48 with breastcancer.[15]

In contrast, Couch et al found no pancreatic cancers in 11 familieswith 36 breast cancers.[24] As these families were recruited to help identifythe BRCA2 gene, there was clearly a selection bias toward those familieswith breast as opposed to pancreatic cancer. However, these data suggestthat, in a carrier of a germline BRCA2 mutation, pancreatic cancer maybe approximately one tenth as common as breast cancer. Thus, the lifetimerisk of pancreatic cancer in BRCA2 mutant carriers is probably in the rangeof 5%.

This low penetrance at which germline BRCA2 mutations result in pancreaticcancer may explain the previously described observation that 7% of apparentlysporadic pancreatic cancer patients have germline mutations in BRCA2.

This figure compares well with the rates seen for "apparently sporadic"breast cancers (less than 4%) and ovarian cancers (less than 4%).[25-29]Thus, even apparently sporadic cancers may, in fact, be caused by germlinemutations if these mutations have a low penetrance.

Other Genes

Of the other genes found to be somatically inactivated in pancreaticcancer, none has been found in the germline of pancreatic cancer patients.

Hahn et al identified the DPC4 tumor suppressor gene and demonstratedthat it is somatically inactivated in 50% of pancreatic cancers.[30] Apartfrom colon cancer, where DPC4 is somatically inactivated in approximately20% of cancers,[31] most tumor types are rarely associated with inactivationof this gene.[32] Moskaluk et al screened 18 families that had two or moremembers with pancreatic cancer and found no germline DPC4 mutations.[33]

Patients with Li-Fraumeni syndrome due to germline mutations of thep53 gene have only a 1.2% risk of pancreatic cancer.[9] Similarly, an associationbetween hereditary pancreatic cancer and germline K-ras mutations has neverbeen documented in the human germline.

It seems likely that one or more additional genes for hereditary pancreaticcancer-specific susceptibility exist but have yet to be identified. Thissuspicion is based on the identification of many pancreatic cancer familieswhose pedigrees do not suggest a BRCA2 or p16 family. Such families havebeen reported by Lynch and coworkers.[1,2]

Johns Hopkins Registry

Pancreatic cancer families that lack a BRCA2 or p16 pedigree are typicalof most families in the National Familial Pancreatic Tumor Registry (NFPTR)at Johns Hopkins.[34] The registry has already enrolled more than 70 familiesin which more than one first-degree relative has pancreatic cancer. Appropriatefamilies are screened initially for germline mutations in "candidategenes."

Familial Pancreatic Cancer Registry

To register a family or an individual with a history of pancreatic cancer,write to the National Familial Pancreatic Tumor Registry, The Johns HopkinsHospital, Meyer 7-181, Department of Pathology, 600 Wolfe St., Baltimore,MD 21287, or visit the Registry's web site at

Although linkage analysis has historically been used to establish theloci of most of the inherited tumor suppressor genes in other tumor types,the detection of a familial pancreatic cancer gene by use of a linkageanalysis approach will be difficult.

The small number of affected members in most families, the short lifeexpectancy of most pancreatic cancer patients, and concerns about low penetrancewould mandate that a large number of pancreatic cancer families be studiedin order for this approach to be successful. The NFPTR is therefore activelytrying to identify and register additional families in which there is anaggregate of pancreatic cancer (see box ).


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