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Hereditary Pancreatic Cancer: Part II. Candidate Genes

Hereditary Pancreatic Cancer: Part II. Candidate Genes

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.

Before the genetic basis for a familial predisposition to a cancer can be 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 carcinoma have a hereditary susceptibility for the disease,[1-7] and a Canadian population-based epidemiologic study found that approximately 8% of pancreatic cancer patients have a first-degree relative with pancreatic cancer.[3]

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

Since most familial clusters of pancreatic cancer are not associated with a recognized syndrome, interest has therefore shifted to a "candidate gene" approach. In this approach, patients with a familial clustering of pancreatic cancer, but without a recognized cancer syndrome, are examined for germline mutations in genes found to be mutated in sporadic pancreatic cancer (see Part I, June 1997).

Mutations of p16

The p16 gene (CDKN2) is frequently inactivated in sporadic pancreatic cancer. It was the first gene identified for which germline mutations could be associated with an increased risk of developing pancreatic cancer.[10] These p16 mutations were first identified as predisposing to a high risk of melanoma,[11,12] but carriers of germline p16 mutations also have a 13-fold increased risk of developing pancreatic cancer.[10]

Such mutations appear to account for only a small percentage of all familial pancreatic cancers,[13] and they should be suspected in a patient with 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 homozygous deletion in a sporadic pancreatic cancer. Germline BRCA2 mutations also contribute to the hereditary predisposition to pancreatic cancer. For example, in our recent examination of a large series of unselected patients with pancreatic cancer, we found that 7% had germline BRCA2 mutations.[14]

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

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

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

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

The increased risk of developing pancreatic and breast cancer associated with germline BRCA2 mutations is particularly noteworthy because of the widespread availability of clinical testing for these mutations.

Based on the relative risk of breast cancer in Ashkenazi Jewish BRCA1 or BRCA2 mutation carriers, the penetrance of early-onset breast cancer in BRCA2 mutant carriers is approximately one third that of their BRCA1 counterparts.[19]

The lifetime risk of breast cancer in BRCA2 mutant carriers is less certain, but is probably significantly less than the 80% to 90% risk for BRCA1 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 additional factors, including the type of mutation, its position within the gene, the inheritance of unknown modifier genes, and environmental factors. For example, the cancer risk of most missense mutations will be difficult to predict, as their effects on protein function are generally unknown.

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

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

The exact risk of pancreatic cancer in a carrier of a germline BRCA2 mutation is not known at present, but an approximation may be constructed from the currently available data. Among 21 BRCA2 families, Thorlacius et 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 breast cancer.[15]

In contrast, Couch et al found no pancreatic cancers in 11 families with 36 breast cancers.[24] As these families were recruited to help identify the BRCA2 gene, there was clearly a selection bias toward those families with breast as opposed to pancreatic cancer. However, these data suggest that, in a carrier of a germline BRCA2 mutation, pancreatic cancer may be approximately one tenth as common as breast cancer. Thus, the lifetime risk of pancreatic cancer in BRCA2 mutant carriers is probably in the range of 5%.

This low penetrance at which germline BRCA2 mutations result in pancreatic cancer may explain the previously described observation that 7% of apparently sporadic 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 germline mutations if these mutations have a low penetrance.

Other Genes

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

Hahn et al identified the DPC4 tumor suppressor gene and demonstrated that it is somatically inactivated in 50% of pancreatic cancers.[30] Apart from colon cancer, where DPC4 is somatically inactivated in approximately 20% of cancers,[31] most tumor types are rarely associated with inactivation of this gene.[32] Moskaluk et al screened 18 families that had two or more members with pancreatic cancer and found no germline DPC4 mutations.[33]

Patients with Li-Fraumeni syndrome due to germline mutations of the p53 gene have only a 1.2% risk of pancreatic cancer.[9] Similarly, an association between hereditary pancreatic cancer and germline K-ras mutations has never been documented in the human germline.

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

Johns Hopkins Registry

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

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 Hopkins Hospital, Meyer 7-181, Department of Pathology, 600 Wolfe St., Baltimore, MD 21287, or visit the Registry's web site at http://www.path.jhu.edu/pancreas.

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

The small number of affected members in most families, the short life expectancy of most pancreatic cancer patients, and concerns about low penetrance would mandate that a large number of pancreatic cancer families be studied in order for this approach to be successful. The NFPTR is therefore actively trying to identify and register additional families in which there is an aggregate of pancreatic cancer (see box ).

References

1. Lynch HT: Genetics and pancreatic cancer. Arch Surg 129:266-268, 1994.

2. Lynch HT, Fusaro L, Lynch JF: Familial pancreatic cancer: A family study. Pancreas 7:511-515, 1992.

3. Ghadirian P, Boyle P, Simard A, et al: Reported family aggregation of pancreatic cancer within a population-based case-control study in the Francophone community in Montreal, Canada. Int J Pancreatol 10:183-196, 1991.

4. Lynch HT, Voorhees GJ, Lanspa SJ, et al: Pancreatic carcinoma and hereditary non-polyposis colorectal carcinoma: A family study. Br J Cancer 52:271-273, 1985.

5. Fernandez E, La Vecchia C, D'Avanzo B, et al: Family history and the risk of liver, gallbladder, and pancreatic cancer. Cancer Epidemiol Biomarkers Prev 3:209, 1994.

6. Lumadue JA, Griffin CA, Osman M, et al: Familial pancreatic cancer and the genetics of pancreatic cancer. Surg Clin North Am 75:845, 1995.

7. Giardiello FM, Welsh SB, Hamilton SR, et al: Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511, 1987.

8. Whitcomb DC, Gorry MC, Preston RA, et al: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141, 1996.

9. Kleihues P, Schauble B, zur Hausen A, et al: Tumors associated with p53 mutations: A synopsis of 91 families. Am J Pathol 150:1-13, 1997.

10. Goldstein AM, Fraser MC, Struewing JP, et al: Increased risk of pancreatic carcinoma in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med 333:970-974, 1995.

11. Kamb A, Shattuck-Eidens D, Eeles R, et al: Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 8:22-26, 1994.

12. Hussussuan CJ, Struewing JP, Goldstein AM, et al: Germline p16 mutations in familial melanoma. Nat Genet 8:15-21, 1994.

13. Moskaluk CA, Rhuban RH, Lietman A, et al: Low prevalence of p16INK4a and CDK4 mutations in familial pancreatic carcinoma. Human Mutation (in press).

14. Goggins M, Schutte M, Lu J, et al: Germline BRCA2 mutations in patients with apparently sporadic pancreatic cancer. Cancer Res 56:5630-5651, 1996.

15. Phelan CM, Lancaster JM, Tonin P, et al: Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 13:120-122, 1996.

16. Tonin P, Weber B, Oint K, et al: Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families. Nat Med 2:1179-1183, 1995.

17. Tulinius H, Olafsdottir GH, Sigvaldason H, et al: Neoplastic diseases in families of breast cancer patients. J Med Genet 31:621, 1994.

18. Kerber RA, Slattery ML: The impact of family history on ovarian cancer risk. Arch Intern Med 155:905, 1995.

19. 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 13:188-190, 1996.

20. Gayther SA, Mangion J, Russell P, et al: Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15:103-105, 1997.

21. Roa BB, Boyd AA, Voichik K, et al: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14:185-187, 1996.

22. Easton DF, Ford D, Bishop DT: Breast Cancer Linkage Consortium: Breast and ovarian cancer incidence in BRCA1-mutation carriers. Am J Hum Genet 56:265-271, 1995.

23. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al: A single BRCA2 mutation in male and female breast carcinoma families from Iceland with varied cancer phenotypes. Nat Genet 13:117-119, 1996.

24. Couch FJ, Farid LM, DeShano ML, et al: BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 13:123-125, 1996.

25. Teng DH-F, Bogden R, Mitchell J, et al: Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet 13:241-244, 1996.

26. Takahashi H, Chits HC, Bandera CA, et al: Mutations of the BRCA2 gene in ovarian carcinomas. Cancer Res 56:2738-2741, 1996.

27. Lancaster JM , Wooster R, Mangion J, et al: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet 13:238-240, 1996.

28. Foster KA, Harrington P, Kerr J, et al: Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res 56:3622-3625, 1996.

29. Miki Y, Katagiri T, Kasumi F, et al: Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet 13:245-247, 1996.

30. Hahn SA, Hoque ATMS, Schutte M, et al: DPC4, a candidate tumor suppressor gene at human chromosome 18q2l.1. Science 271:350-353, 1996.

31. Thiagalingam S, Lengauer C, Leach FS, et al: Evaluation of candidate tumour suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 13:343-347, 1996.

32. Schutte M, Hruban RH, Hedrick L, et al: DPC4 gene in various tumor types. Cancer Res 56:2527-2530, 1996.

33. Moskaluk CA, Hruban RH, Schutte M, et al: Polymerase chain reaction and cycle sequencing of DPC4 in the analysis of familial pancreatic carcinoma. Diagnostic Molec Pathol 6:85-90, 1997.

34. Hruban R, Yeo CJ, Kem SE: Pancreatic cancer, in McKusick V, Vogelstein B (eds): Mendelian and Metabolic Basis of Inherited Disease. CD-ROM edition. New York, McGraw-Hill, 1997.

 
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