Pancreatic Tumors take nearly 20 years to become Lethal after the first Genetic Perturbations – Discovery @ The Johns Hopkins University
Reporter: Aviva Lev-Ari, PhD, RN
Bert Vogelstein, MD – The Scientist in the Lab
Professor of Oncology and Pathology, Investigator, Howard Hughes Medical Institute
Director, Ludwig Center for Cancer Genetics & Therapeutics
Revising the Timeline for Deadly Pancreatic Cancer
Summary
A new study reveals that many pancreatic tumors take nearly 20 years to become lethal after the first genetic perturbations appear, suggesting an opportunity for early diagnosis.
Pancreatic tumors are one of the most lethal cancers, with fewer than five percent of patients surviving five years after diagnosis. But a new study that peers deeply into the genetics of pancreatic cancer presents a bit of good news: an opportunity for early diagnosis. In contrast to earlier predictions, many pancreatic tumors are, in fact, slow growing, taking nearly 20 years to become lethal after the first genetic perturbations appear.
“There have been two competing theories explaining why pancreatic cancers are so lethal,” says Bert Vogelstein, the Howard Hughes Medical Institute investigator who helped lead the new study. “The first is that pancreatic tumors are aggressive right from the get-go and spread to other organs very quickly. The second theory is that pancreatic tumors are, in fact, not more aggressive than other tumors, but that symptoms appear so late in the process that patients have little chance of surviving. We were surprised and pleased to discover that this second theory is correct, at least for a major fraction of tumors. It means that there is a window of opportunity for early detection of pancreatic cancer.”
For disease control in the future, this finding is paramount. It gives us hope that we will eventually be able to reduce morbidity and mortality from pancreatic cancer through earlier detection.
Bert Vogelstein, MD
The new work is published in the October 28, 2010, issue of the journal Nature. Christine Iacobuzio-Donahue, a pathologist at Johns Hopkins University School of Medicine, is the senior author of the paper.
Working with Iacobuzio-Donahue, Vogelstein obtained samples of primary pancreatic tumors from seven autopsied patients, as well as metastatic lesions from their lungs, liver, and other organs. Their team sequenced the DNA of every gene in each metastatic tumor as well as in the primary tumor. These genetic read-outs provided data to compare the genetic mutations found in each patient’s metastatic lesions with the mutations found in the primary tumor.
The investigators found that each metastatic lesion contained, on average across all patients, 61 cancer-related genetic mutations. Further, the majority of these mutations—64 percent on average—were also present in the primary tumor. The researchers then worked with Martin Nowak, an evolutionary biologist at Harvard, to estimate how long it took these mutations to accumulate. Using a “molecular clock” technique commonly used in evolutionary biology, it is possible to generate a hypothesis about when a mutation occurred. By comparing the genomes of, say, monkeys and man, evolutionary biologists can estimate how long ago the two species diverged.
Similarly, each genetic mutation seen in a cancer cell represents a tick of the molecular clock. Because such mutations accumulate at a steady rate—as observed in cancer cells growing in petri dishes—Vogelstein and his colleagues could estimate how long it took for all of the mutations seen in each metastatic lesion to appear.
The technique showed that it took a surprisingly long time—11.7 years on average—for a mature pancreatic tumor to form after the appearance of the first cancer-related mutation in a pancreatic cell. Another 6.8 years passed, on average, before the primary tumor sent out a metastatic lesion to another organ. From that point, another 2.7 years went by, on average, before the patient died. In total, more than 20 years elapsed between the appearance of the first mutated pancreatic cell and death.
“This time scale is similar to what we’ve previously seen in colorectal cancers,” says Vogelstein. “These tumors evolve over long periods—decades.”
Unlike other cancers, though, pancreatic tumors usually produce no symptoms until they’ve spread. Jaundice is often the first symptom, but that arrives only after a pancreatic tumor has metastasized to the liver. But Vogelstein says the new data suggest that a blood or stool test might be able to pick up early cancer-causing mutations. His team is already examining the efficacy of such tests for detecting early signs of colorectal cancer.
“For disease control in the future, this finding is paramount,” Vogelstein says. “It gives us hope that we will eventually be able to reduce morbidity and mortality from pancreatic cancer through earlier detection.”
The research also provided a glimpse into how pancreatic tumors evolve. In the pancreatic tumors of two of the patients, Iacobuzio-Donahue sectioned the tumors into smaller pieces, and then examined the genetics of each section. Surprisingly, she found that each tumor comprised genetically distinct sub-tumors. That is, the tumor continued to accumulate genetic mutations after the tumor first appeared.
“We saw a whole lot of evolution within the primary tumor, producing what looked like a series of generations of tumor clones – fathers, grandfathers, great-grandfathers, you could say,” Vogelstein says. “The primary tumor is, in fact, not a single tumor but an accretion of several genetically distinct tumors. Moreover, we could find a subclone within the primary tumor that gave rise to each metastasis,” Vogelstein says. “That’s fascinating from a basic science perspective and gives us some deep insights into how these tumors evolve.”
SOURCE
http://www.hhmi.org/news/revising-timeline-deadly-pancreatic-cancer
Research Summary
Bert Vogelstein is interested in identifying and characterizing the genes that cause cancer and the application of this knowledge to the management of patients.
Tumors of the colon and rectum are a major health problem: in 2006 alone, a million new cancer cases occurred in the world, resulting in ~590,000 deaths. Half of the population of the United States will develop at least one benign colorectal tumor, and in one-tenth of these, the tumors will eventually become malignant. Our research is aimed at understanding the molecular basis of colorectal neoplasia, in the hope that this knowledge can be used to improve the diagnosis and therapy of this disease.
Pathways That Control Tumorigenesis
A pathway is defined by a set of genes that regulate a specific cellular function. Two kinds of pathways have been shown to drive the process of colorectal neoplasia. One kind contains oncogenes and tumor-suppressor genes that directly regulate cell birth and cell death. In the normal colon, the rate of cell birth precisely equals that of cell death, resulting in a constant number of colon cells. When a particular growth-controlling pathway gene is altered through mutation, the rate of cell birth exceeds that of cell death, and a tumor is initiated. These tumors progress, becoming larger and more dangerous as mutations in other growth-controlling pathway genes accumulate during the tumorigenic process. When several such pathways are altered by mutation, a malignancy is likely to form (see figure).
Figure 1: Pathways that control colorectal tumorigenesis…
Genes that participate in the second kind of pathway, called stability genes, do not directly control cell birth or cell death, but rather control the rate of mutations of other genes, including growth-controlling genes. When stability genes are genetically altered, the cell accumulates mutations at a high rate and the tumorigenic process is accelerated. Members of our laboratory and others have discovered several stability genes that appear to be important for colorectal neoplasia. These include the mismatch repair genes MSH2, MSH6, MLH1, and PMS2, whose alterations result in subtle DNA changes, and BUBR1, MRE11, and CDC4, whose alterations can result in gross chromosomal abnormalities.
Initiation and Progression of Colorectal Neoplasia
The APC (adenomatous polyposis coli) pathway must be altered for colonic tumors to form. Patients with inherited mutations of the APC gene develop thousands of benign tumors of the colon, called adenomas. Our group has helped discover the mechanisms through which APC regulates colon cell growth. APC binds to another protein, called β-catenin, and stimulates its phosphorylation. In cells with an APC mutation, this phosphorylation does not take place and β-catenin is activated. The intracellular location of β-catenin changes upon APC mutation; it migrates to the nucleus, interacts with transcription factors, and induces the expression of genes that stimulate cell birth.
Mutations in APC or β-catenin are sufficient to initiate the growth of a small benign tumor but are not sufficient to make such tumors progress to more advanced forms. Several other pathways participate in this progression. One of these pathways involves transforming growth factor β (TGFβ) family members, a group of small polypeptide hormones that negatively control colon cell growth through regulation of transcription factors such as SMAD4. A second critical pathway involved in tumor progression involves TP53, a gene that is inactivated not only in colorectal cancers but also in most other cancer types. Activation of the normal TP53 gene inhibits cell growth by blocking the cell cycle and by stimulating cellular suicide (apoptosis). Our group has discovered several of the genes that mediate these effects. Thep21WAF1 and 14-3-3σ genes control cell birth by regulating passage through various phases of the cell cycle. The PUMA gene is a powerful stimulator of apoptosis whose product is located in mitochondria and binds to homologous proteins, like BAX, that control cell death.
The studies described above were generally performed through the analysis of single genes that appeared useful on the basis of functional evidence or gross chromosomal changes in cancers. Recently we have developed technologies that allow detailed analysis of all of the protein-coding genes within the human genome. We have found that a typical solid tumor (such as that of the colon, breast, pancreas, or brain) contains 50–100 genetic alterations with major effects on one or more genes. The complex picture that emerges from these studies can be simplified by the realization that the most important of these alterations can be grouped into a smaller number of pathways. The dozen or so pathways that are genetically altered in each tumor are apparently responsible for most of the known properties of tumors. Although detailed understanding of these pathways will require much future research, their recognition is already providing novel approaches to diagnosis, prognosis, and treatment.
Practical Applications
Knowledge of the pathogenesis of tumors has already had a significant impact on the management of patients. For example, our group has developed sensitive blood tests to identify patients with inherited mutations of APCor of the mismatch repair genes. These tests are now routinely used in the clinic to help advise families with hereditary forms of colorectal cancer predisposition. When combined with genetic counseling and surveillance measures, these diagnostic tests can ameliorate much of the anxiety and suffering previously encountered by these families and help affected members achieve normal life spans.
Deaths from colorectal cancer can almost always be prevented if the tumors are detected prior to the onset of metastasis. We have designed new approaches for such early detection that employ DNA purified from stool specimens or blood samples. Our most recent advance in this area is the development of an assay that can efficiently query each of tens of thousands of single DNA molecules for mutations in APC and other genes. This assay, called BEAMing for its four principal components (beads, emulsions, amplifications, magnetics), has been used to show that more than 60 percent of patients with early, presumably curable forms of colorectal cancers can be identifiedthrough the analysis of routine blood samples. Moreover, the number of mutant molecules in the blood of patients with colorectal cancer following treatment provides an objective measure of residual disease.
In addition to improving diagnosis, the new understanding of cancer can guide therapeutic development. We are attempting to develop chemotherapeutic drugs that inhibit the lipid kinase activity of the PIK3CA gene product. Mutations in this gene were discovered through the unbiased genomic analyses methods described above. Additionally, we are attempting to develop C. novyi-NT, a genetically modified strain of Clostridium novyi, as a new therapeutic agent. These bacteria are exquisitely sensitive to oxygen. When C. novyi-NT spores are injected into animals with human tumors, the spores germinate in the poorly oxygenated regions of cancerous tissues but not in normal tissues. This poor oxygenation results from aberrations of the signaling pathways that are genetically altered in the cancers. We have recently begun a clinical trial of C. novyi-NT in patients with advanced cancers.
Grants from the National Institutes of Health provided support for some of these studies.
As of May 30, 2012
SOURCE
http://www.hhmi.org/research/molecular-basis-colorectal-cancer-and-its-implications-patients
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