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Now that the BRCA2 gene has been discovered and its sequence determined, Hopkins scientists have examined the role that this gene plays in the development of pancreas cancer. Dr. Michael Goggins and colleagues at Johns Hopkins studied 245 patients with pancreas cancer and found that as many as 7% of these patients had a defective copy of the BRCA2 gene. Remarkably, this defective copy was present in the patient's "germline" DNA (normal tissue from the patients). The finding of a germline DNA change in these patients means that these patients were born with a defective copy of the BRCA2 gene and that they inherited this defective copy from one of their parents. This discovery is quite remarkable because it suggests: (1) that there is a link between pancreas and breast cancer; (2) that patients born with defective copies of the breast cancer gene may develop pancreas cancer; and (3) that there is now the ability to selectively test patients for an inherited susceptibility to develop pancreas cancer. Patients found to carry a defective BRAC2 gene can be carefully watched and if they do develop a cancer it could potentially be caught earlier.
While further studies are clearly needed to identify how common the defective copies of the BRCA2 gene are in the general population, and how many patients with defective copies of the breast cancer gene go on to develop pancreas and breast cancer, the findings by Dr. Goggins and his colleagues provide one of the first opportunities for scientists to identify patients who are at an increased risk for pancreas cancer using molecular-based tests.
REFERENCE:
Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360-5364.
Dr. Daniel Brat and his colleagues at The Johns Hopkins University analyzed a series of pancreatic cancers using both of these techniques. They found that most (65%) losses of DNA identified using molecular techniques could also be seen in the classical cytogenetic analyses. Importantly, this study provided Dr. Brat and his colleagues with the unique opportunity to determine the mechanism by which the DNA losses were occurring. For example, Dr. Brat was able to show that 123 of "losses of heterozygosity" (losses of DNA) identified at the molecular level were caused by whole chromosome losses in 83 instances, by partial deletions of a chromosome in 18 cases, by the formation of the structures called isochromosomes in 9 tumors, by the addition of parts of a chromosome in 8 cancers, and by translocation (the movement of a piece of DNA from one chromosome to another) in 5 cancers.
This study advances our understanding of the mechanisms by which genes are lost in pancreatic cancer. Researchers at Johns Hopkins are now expanding this study to look at more pancreatic cancers and to look at specific chromosomes in greater detail.
REFERENCES:
1. Brat DJ, Hahn SA, Griffin CA, Kern SE, Hruban RH. A comparison of karyotypic abnormalities and allelic loss in surgically resected human pancreatic adenocarcinoma. Presented at the United States and Canadian Academy of Pathology Meetings, 1996. Laboratory Investigation 74:134A:779, 1996.
2. Brat DJ, Hahn SA, Griffin CA, Kern SE, Hruban RH. The structural basis of molecular genetic deletions: An integration of classical cytogenetic and molecular analyses in pancreatic adenocarcinoma. Am J Pathology (in press), 1996.
3. Griffin CA, Hruban RH, Long PP, Morsberger LA, Douna-Isssa R, Yeo CJ. Chromosome abnormalities in pancreatic adenocarcinoma. Genes Chrom Cancer 9:93-100, 1994.
4. Griffin CA, Hruban RH, Morsberger LA, Ellingham T, Long PP, Jaffee EM, Hauda KM, Bohlander SK, Yeo CJ. Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res 55:2394-2399, 1995.
5.
Hahn SA, Seymour AB, Hoque ATMS, Schutte M, daCosta LT, Redston MS, Caldas
C, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. Allelotype of
pancreatic adenocarcinoma using xenograft enrichment.
Cancer Res 55:4670-4675, 1995.
A recent study suggested one such clue. A gene named DPC4 (for deleted in
pancreatic carcinoma, locus 4) was recently isolated by Hopkins
researchers. It was found to be mutated in half of pancreatic cancers. To
follow up this finding, Mieke Schutte, of Dr. Kern's molecular genetics
laboratory, worked in collaboration with investigators of multiple
departments at Hopkins and investigators at the NIH National Center for
Human Genome Research to investigate the DPC4 gene in other tumor types.
She found that, of 338 tumors derived from 12 distinct anatomic sites
outside the pancreas, only two had mutations involving the DPC4 gene. When
her exhaustive study is combined with some earlier data, we now know that
DPC4 is indeed occasionally inactivated in other tumor types, including
bladder, breast, ovarian, biliary, and colorectal cancers. But for the
other sites studied to date, it appears that DPC4 mutations are distinctly
uncommon, involving less than 10% of the tumors occurring outside the
digestive tract.
With this study, we begin to show some very clear differences between
pancreatic cancer and other common cancer types at the genetic level. It
is hoped that through this approach to uncover what is distinctive about
pancreatic cancer, we should eventually understand better the special
nature of the disease.
Reference:
Now John Day, M.D., Joseph DiGiuseppe, M.D., Ph.D. and colleagues at Johns
Hopkins have helped identify how these intraductal lesions gain a growth
advantage over normal pancreatic ducts (3). They examined the expression
of HER-2/neu in pancreata with infiltrating cancers. HER-2/neu expression
was examined because upregulation or amplification of HER-2/neu has been
associated with a poor prognosis in breast, ovarian, and gastric cancers
(4). Nineteen cases were examined and HER-2/neu expression essentially
was absent in normal pancreatic ducts and ductules, but, by contrast,
HER-2/neu was expressed in 82% of ducts with flat duct lesions, 86% of
ducts with papillary duct lesions without atypia, and 92% of ducts with
atypical papillary duct lesions and in all specimens with carcinoma in
situ. The HER-2/neu proto-oncogene encodes for a 185 kilodalton
transmembrane glycoprotein with tyrosine kinase activity. The protein is
closely related to the epidermal growth factor (EGF) receptor. When
specific ligands, which include EGF and transforming growth factor -alpha,
bind to the EGF receptor, the tyrosine kinase activity of the EGF receptor
is increased, and the resulting intracellular signals that are generated
stimulate cell growth (5). The finding of HER-2/neu overexpression in
pancreatic duct lesions suggests that HER-2/neu expression may provide
duct lesions with a growth advantage over adjacent non-neoplastic
epithelium, thereby promoting the development of adenocarcinoma.
Furthermore, it suggests that anti-HER-2/neu monoclonal antibodies or
inhibitory ligands that block HER-2/neu could be used to interrupt the
proliferative cycle of these intraductal lesions, potentially preventing
the development of invasive carcinoma.
Thus, it appears that intraductal lesions are the precursors to invasive
pancreatic cancer. These lesions harbor clonal mutations in codon 12 of
K-ras and they overexpress the p53 gene product. The demonstration that
these duct lesions also overexpress the epidermal growth factor receptor
homologue, HER-2/neu, provides further evidence for the hypothesis that
lesions formally regarded as various grades of hyperplasia instead may
represent neoplasms with the potential for subsequent invasion and
metastasis. It is hoped that a better understanding of these early
pancreatic neoplasms will lead to the development of tests to detect and
treat pancreatic cancers at earlier stages.
References:
Besides providing a better understanding of the events which give rise to
the development of cancer of the pancreas, the discovery of this gene may
one day form the basis of a molecular test for cancer of the pancreas.
Furthermore, if drugs can be developed to restore its missing suppressor
effects, then this gene may provide a new approach to more effective
treatments for pancreas cancer (2,3).
The story of the discovery of this gene is the subject of a brief
"News and Views" article which appeared in the January 19, 1996
issue of Science (2).
References
It turns out that scientists at Johns Hopkins studying a resected cancer
of the pancreas played a crucial role in the discovery of BRCA2. As
described in detail in Science (2), Mieke Schutte in the
Kern
Pancreas Cancer Research Laboratory here at
Hopkins found that a small piece of DNA was missing
(deleted from) a pancreas cancer. This finding was reported in the
journal The Proceedings of the National Academy of Science (3,4).
Using the technique of "representational difference analyses"
(RDA), Mieke identified a small deletion of chromosome 13q21.2 in a
sporadic pancreas cancer. The deletion of less than 200 Kb of DNA
involved both copies of chromosome 13, and it was in the region in which
other scientists were hunting for the BRCA2 gene. Such deletions often
signal the locations of "tumor-suppressor genes", which when
lost can lead to cancer. Indeed, the discovery and mapping of this
deletion (in a pancreatic cancer!) provided a critical collaboration with
Michael Stratton's team, who prioritized this deletion region for the
successful gene search for the BRCA2 gene. Indeed, some of the markers
previously published by the Hopkins effort included portions of the BRCA2
gene (exon 2 and intron 24). This is an exciting finding, not only
because researchers here at Hopkins studying pancreas cancer were able to
help in the discovery of the second familial breast cancer gene, but also
because there have been some reports suggesting that the risk of pancreas
cancer is increased in families with members afflicted with breast cancer
(5).
A retrospective review from The Johns Hopkins pancreatic carcinoma
database was performed which identified sixty-four consecutive patients
undergoing pancreaticoduodenectomy for pancreatic carcinoma with gross
and/or microscopic evidence of adenocarcinoma at the surgical resection
margin. This group of patients was compared retrospectively with
sixty-two consecutive patients found to be unresectable at the time of
laparotomy due to local invasion without evidence of metastatic disease.
Combined gastric and biliary bypass were performed in 87% of these
patients. No patients in either group had evidence of either liver
metastases or serosal implants. The two groups were similar with respect
to age, gender, race and presenting symptoms.
The hospital mortality was identical in both groups. Fifty-eight percent
of patients undergoing pancreaticoduodenectomy had an uncomplicated
postoperative course, compared to sixty-eight percent of patients
undergoing palliative bypass (not significant). The length of hospital
stay following pancreaticoduodenectomy was 18.4 days which was
significantly longer (p<0.05) than for the patients undergoing
palliative bypass (15.0 days). The overall actual survival (Kaplan-Meier)
was significantly improved in patients undergoing pancreaticoduodenectomy
(p<0.02). Postoperative chemo- or radiation therapy improved survival
in both groups.
This study supports the role of an aggressive surgical approach for
carcinoma of the pancreas. Pancreaticoduodenectomy can be performed with
similar perioperative morbidity and mortality and only a minimal increase
in hospital stay when compared to traditional surgical palliation. It
would appear that pancreaticoduodenectomy with postoperative chemo- and
radiation therapy can be associated with improved long-term survival when
compared to patients treated with surgical bypass.
Hopkins Researchers Show DPC4 Gene as Harboring
Pancreatic cancer has an especially aggressive behavior compared to many
other cancer types. This has been a source of frustration for clinicians
and researchers, since in many respects pancreatic cancer is very similar
to these other tumors. Like most cancers, it is of epithelial origin. It
is an "adenocarcinoma", or gland-forming cancer, and thus rather
similar to other adenocarcinomas of the breast, colon, rectum, and
prostate. Even the known genetic changes of pancreatic cancer often
involve the same genes as those found in the other cancer types. But
these other tumors can often be cured by surgery, while pancreatic cancer
rarely affords a total cure. These considerations suggested that
additional clues should be sought, those which distinguished pancreatic
cancer from other malignancies.
Special Importance for Pancreatic Cancer
July 1996
Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova
GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA Jr, Meltzer PS,
Hahn SA, Kern SE. DPC4 gene in various tumor types. Cancer Res
56:2527-2530, 1996.
Hopkins Researchers Help Identify Precursor to
One of the keys to developing tests to detect cancer of the pancreas
earlier is to understand the precursor lesions which give rise to invasive
pancreatic cancer. A growing body of evidence suggests that
"intraductal lesions" are the precursors to invasive pancreatic
cancer. We have previously shown that some intraductal lesions in the
pancreas have clonal mutations in codon 12 of the K-ras oncogene, and that
many of these intraductal papillary lesions overexpress the p53 gene
product (1,2). These findings suggest that these lesions are neoplastic.
In addition, we have recently seen a remarkable case that suggests that
there is a progression from these intraductal lesions to infiltrating
adenocarcinoma of the pancreas. In 1984 a 57 year old man had a distal
pancreatectomy and splenectomy at our hospital for irregularities
identified within his pancreatic ducts on ERCP. Histologic examination of
the resected pancreas revealed chronic pancreatitis and multiple atypical
intraductal papillary lesions. The patient did well until 9 years later
(1993) when he was diagnosed with an infiltrating adenocarcinoma of the
head of the pancreas. This patient's clinical course suggests that
intraductal papillary lesions in the pancreas can give rise to
infiltrating carcinomas of the pancreas, providing further support for the
hypothesis that duct lesions are the precursors of infiltrating
adenocarcinoma of the pancreas.
Invasive Pancreas Cancer
April 25, 1996
Pancreatic Cancer Gene Discovered at Johns Hopkins
In the January 19, 1996 issue of the journal Science, scientists
at The Johns Hopkins University School of Medicine announced the discovery
of a new pancreas cancer gene (1). Dr. Stephan Hahn, working in the
laboratory of Dr. Scott Kern, discovered this gene and named it
"DPC4" for Deleted in Pancreas
Cancer 4. DPC4 belongs to a group of genes called
"tumor suppressor genes". Tumor suppressor genes are those genes
that when lost or inactivated contribute to the development of cancer, and
DPC4 is mutated or lost in almost half of all pancreas cancers. The new
gene is located on chromosome 18, and it may play a vital role in cell
function, as it is highly conserved in a variety of species. For example,
the DPC4 protein resembles a fruit fly protein called "mad". The
gene also appears to function with the transforming growth factor beta
(TGFß) family of genes. This family of genes normally inhibits cell
growth and one can speculate that loss of the gene would lead to loss of
this inhibition and therefore to unrestrained cell growth.
February 27, 1996
Hopkins Research in Pancreas Cancer
Just as is true for pancreas cancer, breast cancer seems to run in
families. Almost 15 months ago researchers discovered the first breast
cancer gene, called "BRCA1". This gene causes hereditary breast
cancers when it is mutated, but unfortunately it accounts for only half of
the cases of hereditary breast cancer. Now, in the December 21/28, 1995
issue of Nature Michael Stratton and his team in the United
Kingdom announced the discovery of the second breast cancer gene, called
"BRCA2" (1).
Aids in the Discovery of the Second Breast Cancer Gene
February 15,
1996
References:
Aggressive Surgical Approach for Carcinoma
The decreases in perioperative morbidity and mortality and improved
long-term survival associated with pancreaticoduodenectomy for pancreatic
cancer have clearly established a role for this operation when performed
with curative attempt. Yet, most surgeons remain hesitant to perform
pancreaticoduodenectomy unless surgical margins are widely clear, choosing
rather to perform palliative biliary and gastric bypass. This study seeks
to determine the role of surgical resection performed as a palliative
procedure in patients with small residual carcinoma left at the surgical
margins.
of the
Pancreas Improves Survival
January 8, 1996
Reference:
Lillemoe KD, Cameron JL, Yeo CJ, Sohn TA, Nakeeb A, Sauter PK, Hruban RH,
Abrams RA, Pitt HA. Pancreaticoduodenectomy: does it have a role in the
palliation of pancreatic cancer?
Ann Surg 1996
Jun;223(6):718-28
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