Dr. Sawicki earned his medical degree from the Medical College of Georgia in 1987. He then completed his general surgery residency training at UCLA, spending three years in the laboratory studying molecular genetics and assisting in the characterization of the genetic defect in gastrinomas. He was recruited to the faculty at UCLA in the Division of General Surgery in July 1995, with primary clinical responsibility at the West Los Angeles VA Medical Center. There he has continued his basic research in gastrinomas and has been involved with multiple research committees at the VA. He also serves as consultant to the Alfred E. Mann Foundation for Scientific Research. During the past year, Dr. Sawicki has become clinically active in the Bariatric Surgery Program, as well as assuming responsibility at the VA for the directorship of the Surgical Intensive Care Unit and as Chief of the General Surgery Service.
This research program focuses on the molecular mechanisms which regulate pancreatic endocrine tumor (PET) cell growth. These pancreatic tumors secrete hormones, such as insulin, gastrin, and glucagon, which frequently cause characteristic symptoms. For example, patients with an insulin secreting tumor (insulinoma) have symptoms of dangerously low blood glucose. During severe episodes, these patients may suffer seizures and brain injury from profound hypoglycemia. Other secreted hormones produce more pedestrian symptoms, such as peptic ulcer disease in patients with a gastrin secreting tumor (gastrinoma), or diabetes in patients with a glucagon secreting tumor (glucagonoma). When malignant, these tumors can be very aggressive and difficult to manage. Surgery in such cases is not curative and, unfortunately, none of the current chemotherapy regimens is very effective in patients with metastatic disease.
PETs occur incidentally in the population and less commonly in families with an inherited genetic abnormality. The inherited forms occur as part of the familial tumor syndromes called multiple endocrine neoplasia type 1 (MEN1) and von Hipple Lindau (VHL) disease. Although uncommon, these tumors provide a unique opportunity to study multistep carcinogenesis. Clearly, there are benign and malignant forms of these tumors, but little is known about the specific genes causing the malignant tumors to be more aggressive. Surprisingly, genes which are commonly implicated in other more common tumors, such as colon or breast cancer, do not play a significant role in these tumors. Consequently, understanding the genetic abnormalities in these tumors and elucidating the pathways leading to pancreatic endocrine cancer will likely lead to discovery of novel genes important for regulating cell growth. The primary goal is to unravel the molecular biology of these tumors and to identify the defective genes which contribute to the malignant behavior of these tumors.
Tumor Suppressor Gene Which Predicts Prognosis
Thus far, studies in this laboratory have identified three genetic abnormalities in these tumors. All of these abnormalities involve tumor suppressor genes. Protein products of this class of tumor-associated genes normally act to slow cell growth. When these genes are inactivated by mutation they no longer slow cell growth and result in tumorigenesis. Some of the most important cancer genes identified to date, such as BRCA1 (inherited breast cancer) and p53 (many types of tumors), function as tumor suppressors. The most frequent abnormality in PETs affects a tumor suppressor gene region on chromosome 11 in approximately 40% of these tumors. At least one gene called MENIN from this chromosome region has been shown to be mutated in these tumors. The second major alteration involves another tumor suppressor gene region on chromosome 1 where deletion of this chromosome is associated with progression to malignancy. The specific gene, however, is yet to be identified. The third abnormality involves the tumor suppressor p53, but mutation of this key gene is infrequent in these tumors.
MENIN Gene Mutation as an Early Event in Pancreatic Cancer
The main thrust of this effort is to understand the role of the MENIN tumor suppressor gene in PETs. The chromosomal location of this gene was identified in this laboratory in 1989, by studying sporadic pancreatic endocrine tumors for mutations of known oncogenes and tumor suppressor genes. This broad sweep gene analysis identified one common abnormality, namely deletion of chromosome 11, in many of the tumors studied. These results suggested the presence of a tumor suppressor gene located on this chromosome, but gave no specific clues to its function. This was an important finding, as tumor suppressor genes are thought to play a major role in carcinogenesis. Intensive investigation of these tumors with many DNA markers from chromosome 11 narrowed down the location of this gene to a small region of a few megabases.
At the same time, other investigators had come to the same conclusion through a different line of investigation. Several groups, including the Karolinska Institute in Sweden and the NIH, were studying patients with an inherited tumor syndrome called multiple endocrine neoplasia type 1 (MEN1). These patients have a genetic tendency to develop several types of endocrine tumors, in particular PETs, at a high frequency. The predisposing gene, now referred to as MENIN, mapped to the same chromosome region previously identified as being deleted in sporadic tumors. The convergence of these two independent lines of research led to the same conclusion: a tumor suppressor gene on chromosome 11 was responsible for both sporadic and inherited PETs.
Information from the tumor analysis was used to search for the specific gene deleted in the tumor samples. Approximately 1,500,000 base pairs of DNA were cloned and 29 genes were mapped to the region thought to harbor the gene (Fig 1). Each gene then needed to be tested to determine whether it was mutated in these tumors. This was much like a search for a needle in a haystack. A few of the genes which had been previously cloned, and their function known, were easily excluded from further analysis, others had no known function. Two genes had been cloned in mice, but the human form was yet to be identified. These latter two genes were the most interesting, because their function in the mouse suggested they may indeed behave as tumor suppressor genes. While these two genes were pursued, another gene in the area was identified as the sought-after tumor suppressor gene MENIN by Francis Collins and his colleagues at the NIH.
This laboratory has now embarked upon a detailed analysis of MENIN in sporadic PETs. Results indicate that both benign and malignant tumors have this gene mutated early in their development (Fig 2). Not all sporadic tumors, however, harbor MENIN mutations, suggesting that other genetic events bypass this mechanism and lead to tumor formation. To date, this is the only gene known to be frequently mutated in these tumors. Other commonly mutated tumor suppressor genes have been studied, such as p53, and only one tumor with inactivation of this gene has been identified.
Candidate Tumor Suppressor Gene in Pancreatic Cancer
Along similar lines of investigation, another important PET tumor suppressor gene locus on chromosome 1 has been identified. In a very detailed analysis, frequent deletions of all or part of this chromosome in malignant sporadic PETs were found. Perhaps, most fascinatingly, this only occurs in tumors with liver metastases, but not in tumors found in lymph nodes. This finding may lead credence to the controversial hypothesis that surgical removal of so-called "nodal tumors" may be curative. This is the first such study demonstrating this finding. Remarkably, other investigators have searched, but were unable to identify any association between this chromosome and these tumors. Chromosome 1 is widely studied, because several types of tumors have deletions of this chromosome in their pathogenesis. This finding poses a unique opportunity to identify a gene which predisposes to malignancy and will provide insight into this poorly understood process.
These tumor suppressor gene studies will lead to a better understanding of the molecular mechanisms responsible for PET formation. In addition, the exploding repertoire of genes which regulate cell growth will be increased. It is also hypothesized that these tumors arise from stem cells related to human islets. On this basis, it is believed that these studies will ultimately lead to new discoveries about islet cell growth. Without a doubt, such information will be useful to enhance islet cell growth in the treatment of diabetes. With this point of view in mind, studying these unusual tumors will have a broader impact than the tumors themselves.