Objective
To identify the genetic changes underlying the development of human pancreatic neuroendocrine tumors by sequencing the pancreatic neuroendocrine tumor genome.
As with other cancers, the discovery of mutated genes is essential to understand pancreatic neuroendocrine cancer. Delayed diagnosis, and the lack of good prognostic markers and new treatments can be attributed to the fact that the pathogenesis of pancreatic neuroendocrine tumors is not understood.
Dr. Papadopoulos’ team of experts proposes to sequence all 21,000 protein-coding genes in a series of pancreatic neuroendocrine tumors. Investigators will first define the genes that are mutated in a sample of twelve tumors and then determine the prevalence of the most promising mutations by sequencing the relevant genes in additional tumors.
By identifying the genetic signature of pancreatic neuroendocrine tumors, Dr. Papadopoulos’ study will lead directly to new diagnostic tools and gene-specific therapies. Additionally, the discoveries made in this study will create opportunities for advancement in the field of pancreatic neuroendocrine tumor research.
Research Objectives
- To identify the genetic changes underlying the development of human pancreatic neuroendocrine tumors
- To use discoveries for the development of diagnostics and new targeted therapies
Abstract
Simply put, cancer is a genetic disease. Mutations in certain genes promote the growth of cancer cells. Discovery of the mutated genes is the critical step in understanding any form of cancer. Moreover, the mutations that are identified can be used to develop novel diagnostic tools and highly specific, targeted therapies. Despite their importance, little is known about the genetics of pancreatic endocrine neoplasms (pancreatic neuroendocrine tumors). The pancreatic research team at Johns Hopkins is proposing to identify the genes that are mutated in pancreatic endocrine neoplasms by sequencing all the genes that code for proteins using state-of-the-art technologies. It is our hope that this study will not only lead directly to new diagnostic tools and gene-specific therapies, but that it will also open the door to other investigators to follow-up on the discoveries we make.
Research
In January 2011, Dr. Papadopoulos and his team uncovered the set of genetic alterations present among patients with non-functional pancreatic neuroendocrine tumors. They also uncovered a prognostic set of mutations and a rapid way of prioritizing patients for treatments with mTOR inhibiting drugs.
Dr. Papadopoulos says, “One of the most significant things we have learned is that each patient with this form of pancreatic cancer has a unique genetic code that predicts how aggressive the disease is and how sensitive it is to specific treatments.”
Dr. Papadopoulos and his team found that in patients with non-functional pancreatic neuroendocrine tumors, those with specific mutations lived at least 10 years from diagnosis, while more than 60% of patients without these mutations died within five years of diagnosis. These findings, published online in Science Express, suggest new approaches for treating patients with pancreatic neuroendocrine tumors.
Alan Meeker, Ph.D., assistant professor at the Johns Hopkins Kimmel Cancer Center and a member of Dr. Papadopoulos’ team, pursued these mutations and published data suggesting that both of these genes are also linked to why the ends of cellular DNA (known as “telomeres”) lengthen in patients with cancer. These results were published in Science Express in June 2011.
“Finding the genes responsible for alternative lengthening of telomeres is the first step in understanding this process and provides opportunities to develop new drug therapies,” says Dr. Papadopoulos.
“If the correlation holds up, we could use alternative lengthening of telomeres and ATRX/DAXX mutations as a method of determining a patient’s prognosis in addition to developing treatments that target these genes,” says Dr. Meeker.
With few treatment options currently available for pancreatic neuroendocrine tumor patients, these findings represent important advances toward improving treatment options for these patients.
Determined genetic landscape of PNETs by sequencing all protein coding genes. Found DAXX and ATRX gene mutations, which are genes associated with lengthening of telomeres, but have never before been implicated with cancer. He also identified mutations in the mTOR pathway, which could be used for personalized medicine for neuroendocrine patients. Through his work, he acknowledged epigenetics as key area for further study.
Pancreatic neuroendocrine tumors are the second most-common pancreatic malignancy. The ten year survival rate of patients with pancreatic neuroendocrine tumors is only 40%. Virtually all the biologic properties of cancer cells are governed by the genetic changes present in them. Dr. Papadopoulos determined the genetic landscape of these tumors by sequencing all of the genes that code for proteins. His main findings are as follows. 1) Close to 65% of tumors have mutations in genes that alter the epigenetic state of the cells. 2) Almost half (44%) of the tumors have mutations in MEN1 and 43% in either ATRX or DAXX. 3) There are other genes that are mutated, but in lower frequency. In the genomic medicine era, such mutations are important because they could suggest response to targeted therapies. For example, some patients have mutations in genes that are part of the mTOR pathway, which is activated in the tumor cells. These patients should benefit with therapies against the pathway. 4) Mutations in ATRX and DAXX have prognostic value and are associated with changes in the telomeres of the cancer cells. This has sparked a line of investigation to identify new therapies that can target the tumors with these mutations. If successful, this would have a profound impact on the management of this disease.
Research Publications
DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors
Altered Telomeres in Tumors with ATRX and DAXX Mutations
References
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