Scientists Map Complete Genetic Blueprint Of Deadly Cancers

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Main Category: Cancer / Oncology
Also Included In: Genetics
Article Date: 05 Sep 2008 - 10:00 PST

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In what has been heralded as a significant breakthrough in the fight against two of the world's deadliest cancers, US scientists have mapped complete genetic blueprints comprising more than 20,000 genes in 24 pancreatic cancers and 22 brain cancers, including not only individual gene mutations but also their interlinked pathways which sustain tumour development and growth.

The genetic maps were deciphered by scientists from the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, and the work is reported as two studies in the September 5, 2008 issue of Science Express. The team was the same one that led the mapping of the genomes for breast cancer and colorectal cancer last year.

Pancreatic and brain cancers have very low survival rates. This year, said the researchers, about 38,000 Americans will develop pancreatic cancer, and 95 per cent of them will die from the disease. The survival rate for brain cancers is about the same, of which there are about 20,000 new cases a year in the US.

The scientists found about a dozen core gene signalling control pathways and processes were altered for each type of tumour in the majority of the cases they studied. For pancreatic tumours, the 12 pathways were altered in 67 to 100 per cent of tumours. These included three pathways involved in DNA damage control, cell maturation, and tumour invasion.

Co-author Dr Bert Vogelstein, who is co-director of the Ludwig Center at Johns Hopkins and a Howard Hughes Medical Institute investigator, said:

"This perspective changes the way we think about solid tumors and their management, because drugs or other agents that target the physiologic effects of these pathways, rather than individual gene components, are likely to be the most useful approach for developing new therapies."

Vogelstein and colleagues also found individual gene mutations, including 83 in pancreatic and 42 in glioblastoma multiforme (GBM), the deadliest form of brain cancer. They also discovered another 70 extremely over-expressed genes that encode for proteins on cell surfaces that could be targetted for diagnosis and screening of both cancer types.

For example they found that one gene called IDH1 (isocitrate dehydrogenase 1) was often mutated in one type of GBM brain cancer. Also, it was significantly more common among younger GBM patients and linked to higher survival rates. This mutation was also in nearly all secondary GBMs the researchers investigated (where the cancer grew from a lower grade tumour that was already there), which means it might make a useful marker for spotting which low grade tumours are likely to give rise to deadly GBMs.

Co-author Dr Victor Velculescu, who is associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, said:

"Patients with IDH1 mutations seem to be different from other patients with GBM, both clinically and biologically."

"It is conceivable that these patients will ultimately benefit from different treatments, potentially by targeting IDH1," he added.

One of the most important findings to come from this and other studies that have mapped mutations and pathways is that human cancers are far more complex than scientists assumed. It is not just a case of individual genes causing direct effects, but often one that also involves complex interactions. Another co-author, Dr Kenneth W Kinzler who is co-director of the Ludwig Center at Johns Hopkins and professor of oncology said fighting cancer is becoming more like a guerilla war than a conventional one because each tumour has dozens of mutated genes:

"Individually, these mutations don't seem formidable, said Kinzler, "But working together, they form an enemy that will require us to develop novel strategies to combat them, and the best long-term strategy may be early detection of tumors, when the number of guerilla warriors is still small and more easily handled."

The researchers used several types of genetic analysis in these studies. They found gene amplifications and deletions using a method called "high -density microarrays", and they evaluated gene expression using "next-generation" sequencing technologies. They also created new algorithms to bring separate but complementary analyses together, and also used techniques that isolate harmful mutations that help cancers grow from "passenger" mutations that accumulate but don't cause any harm in cancers.

"Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses."
Siân Jones, Xiaosong Zhang, D. Williams Parsons, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, Hirohiko Kamiyama, Antonio Jimeno, Seung-Mo Hong, Baojin Fu, Ming-Tseh Lin, Eric S. Calhoun, Mihoko Kamiyama, Kimberly Walter, Tatiana Nikolskaya, Yuri Nikolsky, James Hartigan, Douglas R. Smith, Manuel Hidalgo, Steven D. Leach, Alison P. Klein, Elizabeth M. Jaffee, Michael Goggins, Anirban Maitra, Christine Iacobuzio-Donahue, James R. Eshleman, Scott E. Kern, Ralph H. Hruban, Rachel Karchin, Nickolas Papadopoulos, Giovanni Parmigiani, Bert Vogelstein, Victor E. Velculescu, and Kenneth W. Kinzler.
Science Express Published online 4 September 2008.
DOI: 10.1126/science.1164368.

Click here for Abstract.

"An Integrated Genomic Analysis of Human Glioblastoma Multiforme."
D. Williams Parsons, Siân Jones, Xiaosong Zhang, Jimmy Cheng-Ho Lin, Rebecca J. Leary, Philipp Angenendt, Parminder Mankoo, Hannah Carter, I-Mei Siu, Gary L. Gallia, Alessandro Olivi, Roger McLendon, B. Ahmed Rasheed, Stephen Keir, Tatiana Nikolskaya, Yuri Nikolsky, Dana A. Busam, Hanna Tekleab, Luis A. Diaz, Jr., James Hartigan, Doug R. Smith, Robert L. Strausberg, Suely Kazue Nagahashi Marie, Sueli Mieko Oba Shinjo, Hai Yan, Gregory J. Riggins, Darell D. Bigner, Rachel Karchin, Nick Papadopoulos, Giovanni Parmigiani, Bert Vogelstein, Victor E. Velculescu, and Kenneth W. Kinzler.
Science Express, Published online 4 September 2008.
DOI: 10.1126/science.1164382.

Click here for Abstract.

Sources: Science Express, Johns Hopkins Kimmel Cancer Center.

Written by: Catharine Paddock, PhD
Copyright: Medical News Today
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