Although candidate genes for hereditary pancreatic cancer have been
identified (Figure 1), namely p16 and
BRCA2, pancreatic cancer patients having an inherited
predisposition will not be easy to recognize on clinical grounds.
Genetic screening of at-risk groups, such as the Ashkenazi Jewish population
and recognized high-risk families (such as shown in Figure
2), is the currently recommended genetic testing approach to identify
patients at risk of hereditary cancer.[1,2] However, since genes such as
BRCA2 have a relatively low penetrance for causing cancer, this approach
will miss many carriers.
Even the technically straightforward process of screening Ashkenazi
Jewish patients with pancreatic cancer for the 6174 delT BRCA2 mutation
is limited by the fact that the Ashkenazi population harbors other BRCA2
Once technological advances permit, it might be preferable to screen
all consenting pancreatic cancer patients for germline BRCA2 mutations.
The main immediate benefit of such an approach would be to identify carriers
at risk of breast and other cancers so that preventive measures could be
Finally, it is still not clear how carriers of germline BRCA2 mutations
should be screened for cancer. Females who are BRCA2 carriers could be
offered an appropriate breast and ovarian cancer screening regimen. Yet
many BRCA2 carriers might inquire whether cancer screening protocols were
available specifically to detect early pancreatic cancer.
Despite improvements in the imaging of the pancreas, the low penetrance
and late age of presentation of pancreatic cancer in BRCA2 carriers imply
that screening for pancreatic cancer is probably not currently justifiable.
Using the predicted estimates of the sensitivity and specificity for a
pancreatic cancer screening test, and a low estimated risk of pancreatic
cancer in BRCA2 carriers, screening would yield far more false-positive
than true-positive test results.
Since a positive test would likely require confirmation with an invasive
procedure, the consequences of a false-positive test are currently unacceptable.
Furthermore, even a "confirmatory" test such as pancreatic biopsy
currently suffers from low sensitivity.
The development of a highly sensitive and specific screening test to
detect early pancreatic cancer would greatly benefit patients at risk of
Over the next few years, technologic advances such as DNA chip technology
will facilitate the identification of hereditary cancer families. Legislation
to protect carriers of germline mutations and regulatory controls to oversee
genetic testing services are expected to be in place. These developments
should enable clinicians to genetically screen the majority of consenting
patients with cancer.
Along with these developments, it is anticipated that additional clinical
data on the potential benefits and risks of offering genetic testing to
families with cancer will become available to assist clinicians. For certain
cancers, such as pancreatic cancer, cancer screening programs will need
to be developed to diagnose presymptomatic neoplastic lesions before gene
testing can hope to have an impact on pancreatic cancer morbidity.
Advances in molecular genetics are bringing the goal of reducing the
mortality and morbidity of hereditary cancer closer to realization.
1. The American Society of Human Genetics: Statement of the American
Society of Human Genetics on genetic testing for breast and ovarian cancer
predisposition. Am Soc Hum Genet 55:1-4, 1994.
2. The American Society of Clinical Oncology: Genetic testing for cancer
susceptibility. J Clin Oncol 14:1730-1736, 1996.
3. Oddoux C, Struewing JP, Clayton CM, et al: The carrier frequency
of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approxmately
1%. Nat Genet 13:188-190, 1996.
4. 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,
5. Hacia JG, Brody LC, Chee MS, et al: Detection of heterozygous mutations
in BRCA1 using high density oligonucleotide arrays and two-colour fluorescence
analysis. Nat Genet 14:441-447, 1996.