Pancreatic Cancer: Recognizing an Hereditary Predisposition

Although candidate genes for hereditary pancreatic cancer have beenidentified (Figure 1), namely p16 andBRCA2, pancreatic cancer patients having an inheritedpredisposition will not be easy to recognize on clinical grounds.

Genetic screening of at-risk groups, such as the Ashkenazi Jewish populationand recognized high-risk families (such as shown in Figure2), is the currently recommended genetic testing approach to identifypatients at risk of hereditary cancer.[1,2] However, since genes such asBRCA2 have a relatively low penetrance for causing cancer, this approachwill miss many carriers.

Even the technically straightforward process of screening AshkenaziJewish patients with pancreatic cancer for the 6174 delT BRCA2 mutation[3]is limited by the fact that the Ashkenazi population harbors other BRCA2mutations.[4]

Once technological advances permit, it might be preferable to screenall consenting pancreatic cancer patients for germline BRCA2 mutations.The main immediate benefit of such an approach would be to identify carriersat risk of breast and other cancers so that preventive measures could beinitiated.

Finally, it is still not clear how carriers of germline BRCA2 mutationsshould be screened for cancer. Females who are BRCA2 carriers could beoffered an appropriate breast and ovarian cancer screening regimen. Yetmany BRCA2 carriers might inquire whether cancer screening protocols wereavailable specifically to detect early pancreatic cancer.

Despite improvements in the imaging of the pancreas, the low penetranceand late age of presentation of pancreatic cancer in BRCA2 carriers implythat screening for pancreatic cancer is probably not currently justifiable.Using the predicted estimates of the sensitivity and specificity for apancreatic cancer screening test, and a low estimated risk of pancreaticcancer in BRCA2 carriers, screening would yield far more false-positivethan true-positive test results.

Since a positive test would likely require confirmation with an invasiveprocedure, the consequences of a false-positive test are currently unacceptable.Furthermore, even a "confirmatory" test such as pancreatic biopsycurrently suffers from low sensitivity.

The development of a highly sensitive and specific screening test todetect early pancreatic cancer would greatly benefit patients at risk ofhereditary disease.

Conclusion

Over the next few years, technologic advances such as DNA chip technology[5]will facilitate the identification of hereditary cancer families. Legislationto protect carriers of germline mutations and regulatory controls to overseegenetic testing services are expected to be in place. These developmentsshould enable clinicians to genetically screen the majority of consentingpatients with cancer.

Along with these developments, it is anticipated that additional clinicaldata on the potential benefits and risks of offering genetic testing tofamilies with cancer will become available to assist clinicians. For certaincancers, such as pancreatic cancer, cancer screening programs will needto be developed to diagnose presymptomatic neoplastic lesions before genetesting can hope to have an impact on pancreatic cancer morbidity.

Advances in molecular genetics are bringing the goal of reducing themortality and morbidity of hereditary cancer closer to realization.

References:

1. The American Society of Human Genetics: Statement of the AmericanSociety of Human Genetics on genetic testing for breast and ovarian cancerpredisposition. Am Soc Hum Genet 55:1-4, 1994.

2. The American Society of Clinical Oncology: Genetic testing for cancersusceptibility. J Clin Oncol 14:1730-1736, 1996.

3. Oddoux C, Struewing JP, Clayton CM, et al: The carrier frequencyof the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approxmately1%. Nat Genet 13:188-190, 1996.

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

5. Hacia JG, Brody LC, Chee MS, et al: Detection of heterozygous mutationsin BRCA1 using high density oligonucleotide arrays and two-colour fluorescenceanalysis. Nat Genet 14:441-447, 1996.