The Sol Goldman Pancreatic Cancer Research Center

What's New 1996

Hopkins Scientists Discover that as many as 7% of Patients with Pancreatic Cancer are Born with a Defective Copy of the Breast Cancer Gene
December 2, 1996

The second breast cancer gene, called BRCA2 was recently discovered by Michael Stratton. As described in the February 15, 1996 "What's New", scientists at Johns Hopkins played a major role in the identification of this gene when they discovered that a small piece of DNA missing from a pancreas cancer was right in the middle of the region in which Dr. Stratton and other scientists were hunting for the BRCA2 gene.

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.

If you are interested in finding out more about genetic testing for cancer and whether it would be appropriate for you or your family, please contact Karen Johnson, MS, CGC.

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.

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Hopkins Researchers Help Identify the Structural Basis for Genetic Changes in Pancreatic Cancer
November 5, 1996

Two approaches can be used to identify the genes which are important in the development of a cancer. "Classical cytogenetics" (a technique similar to the tests performed on fluid obtained by amniocentesis from pregnant women to determine the health of their babies) can be used to visualize and examine individual chromosomes in a cancer. With "molecular techniques", DNA probes specific for each chromosome arm are used to identify specific pieces of DNA that have been lost in a cancer. The lost pieces of DNA are often the sites of mutated genes called "Tumor Suppressor Genes".

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.

Reference:
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.

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.

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.

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.

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.

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Hopkins Researchers Show DPC4 Gene as Harboring Special Importance for Pancreatic Cancer
July 1996

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.

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:
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.

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Hopkins Researchers Help Identify Precursor to Invasive Pancreas Cancer
April 25, 1996

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.

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.

Reference:
DiGiuseppe JA, Hruban RH, Offerhaus GJA, et al: Detection of K-ras mutations in mucinous pancreatic duct hyperplasia from a patient with a family history of pancreatic carcinoma. Am J Pathol 144:889-895, 1994.

DiGiuseppe JA, Hruban RH, Goodman SN, et al: Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol 101:684-688, 1994.

Day JD, DiGiuseppe JA, Yeo C, Lai-Goldman M, Anderson SM, Goodman SN, Kern SE, and Hruban RH: Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Human Pathology 27(2):119-124, 1996.

Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: correlation of relapse and survival with amplification of the erbB-2/neu oncogene. Science 235:177-182, 1987.

Akiyama T, Sudo C, Ogawa H, et al: The product of human c-erbB-2 gene: a 185 kilodalton glycoprotein with tyrosine kinase activity. Science 232:1644-1646, 1986.

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Pancreatic Cancer Gene Discovered at Johns Hopkins
February 27, 1996

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.

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).

Reference:
Hahn SA, Schutte M, Hoque ATMS, Moskaluk CA, daCosta LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE. DPC4, a candidate tumor-suppressor gene at human chromosome 18q21.1. Science 271:350-353, 1996.

O'Brien C. New tumor suppressor found in pancreatic cancer. Science 271:294, 1996.

Hahn SA, Hoque ATMS, Moskaluk CA, daCosta LT, Schutte M, Rozenblum E, Seymour AB, Weinstein CL, Yeo CJ, Hruban RH, Kern SE. Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res 56:490-494, 1996.

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Hopkins Research in Pancreas Cancer Aids in the Discovery of the Second Breast Cancer Gene
February 15, 1996

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).

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).

Reference:
Wooster R, Bignell G, Lancaster J, et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789-792, 1995.

Marx J. A second breast cancer susceptibility gene is found. Science 271:30-31, 1996.

Schutte M, daCosta LT, Hahn SA, et al. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BRCA2 region. Proc Natl Acad Sci USA 92:5950-5954, 1995.

Schutte M, Rozenblum E, Moskaluk CA. An integrated high-resolution physical map of the DPC/BRCA2 region at chromosome 13q12. Cancer Res 55:4570-4574, 1995.

Tulinius H, Olafsdottir GH, Sigvaldason H, et al. Neoplastic diseases in families of breast cancer patients. J Med Genet 31: 618-621, 1994.

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Aggressive Surgical Approach for Carcinoma of the Pancreas Improves Survival
January 8, 1996

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.

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.

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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