Scientists Crack Rare Pancreatic Cancer Genetic Code And Highlight Role Of Epigenetics

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Main Category: Pancreatic Cancer
Also Included In: Cancer / Oncology;  Genetics;  Biology / Biochemistry
Article Date: 21 Jan 2011 - 2:00 PDT


In cracking the genetic code and certain "epigenetic" features of a rare pancreatic cancer called neuroendocrine or islet cell tumors, scientists at Johns Hopkins in the US have discovered clues as to why some patients live twice as long as others, bolstering the idea that perhaps cancers should be classified by the type of genes involved and not just by organ or cell type.

The researchers said their findings also show the importance of targeting the "epigenetics" of cancer, that is the processes that influence what genes do but occur outside of the underlying DNA chemistry of genes, when developing genetic treatments for the disease.

You can read how Dr Nickolas Papadopoulos, associate professor at the Johns Hopkins Kimmel Cancer Center and director of translational genetics at Johns Hopkins' Ludwig Center in Baltimore, Maryland, and colleagues came to their findings in the 20 January online issue of Science.

Papadopoulos told the press that:

"One of the most significant things we learned is that each patient with this kind of rare cancer has a unique genetic code that predicts how aggressive the disease is and how sensitive it is to specific treatments."

Pancreatic neuroendocrine tumors (also called PanNETs) are a rare but clinically important form of pancreatic cancer and account for about 5 per cent of all pancreatic cancers.

Some PanNETs release hormones that cause significant changes in the body, including variations in blood sugar levels, weight gain, and skin rashes. In contrast, without these effects, the hormone-free tumors grow silently in the pancreas.

Co-author Dr Ralph Hruban, professor of pathology and oncology, and director of the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins, said the hormone-free tumors were often difficult to distinguish from other pancreatic cancer types.

For their study, Papadopoulos, Hruban and colleagues, who have previously mapped six other cancer types, mapped the genetic code of non-hormonal pancreatic neuroendocrine tumors in 68 male and female patients:

They found that patients whose tumors contained mutations in three genes: MEN-1, DAXX and ATRX, lived at least 10 years after diagnosis, while over 60 per cent of patients whose tumors did not have them, died within 5 years of diagnosis.

The genetic map they produced provides clues as to how tumors develop, grow and spread.

The "alphabet" of the genetic code is made up of "letters" called nucleotides, and pairs of nucleotides form genes that give instructions that guide cell behavior. Changes to nucleotide pairs (a bit like "spelling" errors), or mutations, lead to coding errors that can screw up instructions to cells and make them cancerous.

For this study, the researchers carried out two sets of experiments. In the first they sequenced nearly all the protein-encoding genes in 10 of the 68 PanNET samples and compared these sequences with each patient's normal DNA, to find the mutations that were specific to the PanNETs.

In the second experiment they searched the remaining 58 PanNETs to establish how often these mutated genes appeared.

"... we determined the exomic sequences of ten nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs," they wrote.

The most prevalent mutation was in the MEN-1 gene, and they found it in more than 44 per cent of all 68 PanNETs.

MEN-1 has been associated with many cancers; it guides the making of proteins that control how long strands of DNA are twisted and assembled into dense packets that open and close depending on which genes are to be activated (a process that scientists describe as "epigenetic" because it involves proteins and chemicals that operate outside of genes).

The two other genes they found, DAXX and ATRX, have not been linked to cancer before, but they also have "epigenetic" effects on the reading of DNA. The proteins they code for relate to specific sections of DNA and change the reading of its nucleotide "letters".

In this study, the researchers found DAXX in 25 per cent of the samples, and ATRX in 17.6 per cent.

Co-author Dr Kenneth Kinzler, professor of oncology at the Johns Hopkins Kimmel Cancer Center and co-director of the Ludwig Center at Johns Hopkins, said:

"To effectively detect and kill cancers, it may be important to develop new diagnostics and therapeutics that take aim at both epigenetic and genetic processes."

The researchers also found that 14 per cent of the PanNETs contained mutations in a family of genes called mTOR (mammalian target of rapamycin), which controls cell signalling.

Drugs that inhibit the action of mTOR exist, and Papadopoulos said that these might prove also to be suitable for patients with PanNETs.

Hruban said this was a good example of how personalized cancer therapy might work:

"Patients who are most likely to benefit from a drug can be identified and treated, while patients whose tumors lack changes in the mTOR pathway could be spared the side effects of drugs that may not be effective in their tumors," he explained.

"DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors."
Yuchen Jiao, Chanjuan Shi, Barish H. Edil, Roeland F. de Wilde, David S. Klimstra, Anirban Maitra, Richard D. Schulick, Laura H. Tang, Christopher L. Wolfgang, Michael A. Choti, Victor E. Velculescu, Luis A. Diaz, Jr., Bert Vogelstein, Kenneth W. Kinzler, Ralph H. Hruban, and Nickolas Papadopoulos.
Science 1200609 Published online 20 January 2011.
DOI:10.1126/science.1200609.

Additional source: Johns Hopkins Medicine (press release, 20 Jan 2011).

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

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