Adenocarcinoma of the pancreas is
the fifth leading cause of cancer death in the United States. It has
a lifetime incidence of approximately one in 150 persons in the United
States and a male-to-female ratio of approximately 1.3 to 1.
Most patients present with advanced inoperable disease, and the overall
survival is less than 5% at five years. However, for patients presenting
early, without clinical evidence of metastasis, pancreaticoduodenectomy
can result in a five-year survival of approximately 25%.
Techniques to detect early cancer in at-risk patients, before they develop
inoperable disease, could save many lives. Pancreatic cancer has a significant,
although generally under-recognized, hereditary predisposition, and patients
with this hereditary predisposition constitute an at-risk population to
which screening techniques could be applied.
For many hereditary cancers, such as familial polyposis coli, hereditary
nonpolyposis colon cancer (HNPCC), or familial breast cancer, a familial
tendency toward cancer development can often be easily identified on the
basis of a pattern of autosomal dominant inheritance with high penetrance.
In contrast, even for patients with pancreatic cancer in whom a hereditary
predisposition has been identified, clinical features alone often fail
to raise suspicion of hereditary cancer. Despite these difficulties, several
genes responsible for at least part of this hereditary predisposition have
recently been identified.
Once the genes responsible for an inherited predisposition are characterized,
they can be used to identify and manage gene carriers. Indeed, commercial
testing for hereditary-cancer-predisposing genes is becoming increasingly
available. However, until technologic advances enable routine genetic testing
of virtually all cancer patients, the most important task for the clinician
considering cancer patients for genetic testing will remain the identification
of those patients who carry a hereditary predisposition.
The molecular genetic profile of pancreatic cancer has been relatively
well characterized, compared with that of some other cancers. Infiltrating
adenocar-cinoma of the pancreas has a unique genetic profile, with somatic
mutations of the K-ras gene (more than 90% of tumors)[5,6] and the p53
gene (50% to 75%), and genetic inactivation of the p16 gene (approximately
80%) and the DPC4 (SMAD-4) gene (50%).
Unlike colorectal cancers, pancreatic cancers do not have APC mutations.[10,11]
Similarly, microsatellite instability suggestive of an inherited defect
in one of the mismatch repair genes is an unusual finding in pancreatic
The genes mutated in sporadic cancers are frequently also responsible
for hereditary cancers. Thus, this understanding of the molecular genetics
of infiltrating pancreatic cancer provides a foundation for examining the
molecular basis for hereditary pancreatic cancer, which will be reviewed
in the next article in this series.
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