Sequencing the Pancreatic Neuroendocrine Genome
By Ralph H. Hruban, M.D.
We have previously discussed the clinical and pathological features of pancreatic neurendocrine tumors (also known as islet cell tumors) in this BLOG. Here we report on a major advance in the war against these tumors.
A team of scientists at Johns Hopkins, led by Nickolas Papadopoulos, reported the results of sequencing the pancreatic neuroendocrine genome in a recent issue of the journal Science
Dr. Papadopoulos and his team sequenced all known human genes in a series of ten pancreatic neurendocrine tumors, and then validated their findings by sequencing selected genes in another 58 tumors. Since cancers, including pancreatic neuroendocrine tumors, are fundamentally caused by mutations (mistakes) in DNA, this study provided fundamental insight into what drives these tumors.
The investigators may four major findings:
1) The genes mutated in pancreatic neurendocrine tumors are completely different from the genes mutated in ductal adenocarcinoma of the pancreas (commonly known as “pancreatic cancer”). The MEN-1, ATRX, DAXX, TSC2, PTEN and PIK3CA genes are mutated in pancreatic neurendocrine tumors, while the genes KRAS, TP53, SMAD4 and p16 are mutated in ductal adenocarcinoma of the pancreas. These two tumors, both of which arise in the pancreas, are therefore fundamentally different. Indeed, as we discussed previously in this BLOG, the prognosis for patients with a pancreatic neurendocrine tumor is significantly better than the prognosis for patients with a ductal adenocarcinoma of the pancreas.
2) One-sixth of pancreatic neurendocrine tumors harbor mutations in genes coding for proteins in the mTOR pathway (these include TSC2, PTEN and PIK3CA). There are drugs currently available (“rapalogues” such as everolimus) that specifically target the mTOR pathway. One should therefore be able to identify and treat those patients who will benefit from an mTOR inhibitor (those patients who have a pancreatic neurendocrine tumor that has a mutation in one of the MTOR Pathway genes), while sparing patients who would not benefit from treatment because their tumors do not have mutations in this pathway. This finding obviously needs to be validated in large clinical trials, but it is an exciting example of “personalized medicine.”
3) Dr. Papadopoulos and his team discovered a new cancer pathway in the pancreatic neuroendocrine tumors. They discovered mutations in two genes (ATRX and DAXX) that have not been reported before in any tumor. This finding is exciting as it provides insight into the fundamental biology of neuroendocrine tumors of the pancreas, and, as we learn more about the function of the ATRX and DAXX genes, hopefully this discovery will lead to completely novel therapies.
4) The team found that tumors with both ATRX/DAXX mutations and mutations in another gene (MEN-1) have a significantly better prognosis than do tumors that lack these mutations.
We believe that this sequencing project represents a significant advance in the war against pancreatic neuroendocrine tumors. The results have both immediate and long-term impact. The next step is to bring these discoveries to patients!