Cancer Control Research
5R03CA070837-02
Goodfellow, Paul J.
EARLY DETECTION OF PANCREATIC ADENOCARCINOMAS
AbstractDESCRIPTION
This is an application to develop new methods to detect mutations in the
CDKN2 tumor suppressor gene to investigate the sensitivity, reliability and
specificity of CDKN2 mutation analysis in identifying neoplastic cells in
biopsy specimens from patients at high risk for pancreatic cancer. Earlier
detection of these cancers will allow for earlier surgical resection and as
a consequence will positively influence patient outcome.
Pancreatic carcinoma has a particularly poor prognosis and is considered to
be one of the deadliest malignancies. Less than 20 percent of pancreatic
cancer patients survive one year after diagnosis, and the overall five-year
survival rate is only three percent. Early detection and curative surgery
for patients with stage I or H disease increases five-year survival to up to
50 percent. At present the detection of early-stage tumors, followed by
surgical resection, is the cornerstone of pancreatic cancer therapy.
Diagnostic markers are urgently needed for earlier detection of this
aggressive cancer.
Several lines of evidence suggest that the CDKN2 gene is a good candidate
for the development of DNA-based tests to distinguish pancreatic cancers
from other pancreatic masses and to identify neoplasms earlier than is
currently possible. In order to determine the effectiveness of the
detection of CDKN2 mutations in pancreatic cancers we propose the following:
(1) development of sensitive and reliable methods for the detection of CDKN2
mutations in clinical specimens (detection of specific mutations will be
accomplished by dot blot hybridization with oligonucleotides specific for
mutations, polymerase chain reaction (PCR) amplification and restriction
digestion assays and by testing for premature protein truncation (PTT). The
sensitivity and specificity of each of these assays will be carefully
investigated. (2) We will determine whether CDKN2 mutations are present in
chronic pancreatitis through the evaluation of a collection of DNAs prepared
from fresh and archivel specimens. DNA prepared from specimens from
patients with simple chronic pancreatitis and from patients with co-existing
pancreatitis and adenocarcinoma will be investigated for CDKN2 mutation.
(3) We will apply newly devised CDKN2 mutation detection systems to the
study of prospectively acquired biopsy specimens from patients at high risk
for the development of pancreatic adenocarcinomas. Fresh biopsy specimens
will be evaluated for CDKN2 mutations, using what are determined to be the
most sensitive and reliable methods based on our investigations of archival
and fresh pancreatitis specimens.
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