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.
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, the Peutz-Jeghers
syndrome, hereditary relapsing acute pancreatitis, and the Li-Fraumeni
syndrome. 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.
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.
Such mutations appear to account for only a small percentage of all
familial pancreatic cancers, and they should be suspected in a patient
with pancreatic cancer and a strong family history of melanoma.
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.
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. Of interest, pancreatic cancer in these
patients with germline BRCA2 mutations does not usually present at an early
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.
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.
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
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
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
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.
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
In contrast, Couch et al found no pancreatic cancers in 11 families
with 36 breast cancers. 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
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.
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. Apart
from colon cancer, where DPC4 is somatically inactivated in approximately
20% of cancers, most tumor types are rarely associated with inactivation
of this gene. Moskaluk et al screened 18 families that had two or more
members with pancreatic cancer and found no germline DPC4 mutations.
Patients with Li-Fraumeni syndrome due to germline mutations of the
p53 gene have only a 1.2% risk of pancreatic cancer. 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. 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
Familial Pancreatic Cancer Registry
To register a family or an individual with a history of pancreatic cancer,
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 ).
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