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Genetic Studies Offer Clues to Pancreatic Cancer Progression

By Andrea Anderson

NEW YORK (GenomeWeb News) – A pair of new genetic studies appearing online today in Nature suggest pancreatic cancer is genetically diverse, but typically takes more than a decade to develop into metastatic disease.

In the first of these studies, an American research team analyzed sequence data on pancreatic cancer metastases taken from seven individuals to look at how mutations in these metastases compared with those found in primary tumors and metastases from other sites. Their results suggest that many of the genetic changes present in pancreatic cancers occur relatively early in the disease's progression, though the cancer overall takes years to fully develop and spread to other parts of the body.

"It takes at least two decades from when a normal cell in the pancreas develops the very first mutation that starts it down the path of becoming a pancreatic cancer," senior author Christine Iacobuzio-Donahue, a pathology and oncology researcher at the Sol Goldman Pancreatic Cancer Research Center at the Johns Hopkins Medical Institutions, told GenomeWeb Daily News.

When she arrived at Johns Hopkins in 2003, she explained, Iacobuzio-Donahue helped to initiate a rapid autopsy program for patients with pancreatic cancer that involves collecting tumor and metastatic samples from individuals who have consented to be autopsied immediately after their death.

Metastatic tumors from seven individuals in the rapid autopsy database were included in a broader exome sequencing study of pancreatic cancer done by researchers at Johns Hopkins in 2008.

To build on these results and explore the relationships between primary and metastatic tumors, Iacobuzio-Donahue and her co-workers decided to look at whether mutations in the metastases were also present in primary tumors and additional metastases from the same individuals.

Based on their analysis of sequence data and genotype information generated with the Illumina Infinium II Whole Genome genotyping array, the researchers found that primary pancreatic cancers can harbor various sub-clonal populations.

Overall, though, their results indicated that many of the mutations found in pancreatic cancer tend to be shared between primary and metastatic tumors, suggesting the changes occurred prior to the cancer's spread beyond the pancreas.

Iacobuzio-Donahue and her colleagues have not yet identified mutations to specific genes that trigger this metastasis or steer it to specific sites in the body, though she explained that it might be possible to learn more about the genetics of these processes by examining samples from additional patients.

Given the number and type of mutations in the tumors, though, the team concluded that it typically takes up to two decades for a normal pancreatic cell to progress to advanced or metastatic pancreatic cancer.

They estimated that it takes about 11.7 years, on average, from when tumorigenesis starts to when an initial cancer cell forms and then an average of 6.7 years more before the tumor has the potential to spread. Patients typically survive an additional 2.7 years after this so-called index lesion occurs, the researchers explained.

"The diagnosis is being made so late for the tumor," Iacobuzio-Donahue said. "If we could simply diagnose earlier, we could have a lot more cures and a lot more people surviving from pancreatic cancer."

Similarly, a second Nature paper by some members of the same team offered additional genetic evidence that pancreatic cancer develops slowly, with many mutations occurring relatively early.

The Wellcome Trust Sanger Institute-led effort relied on a combination of sequencing and phylogenetic analyses to assess rearrangement patterns in pancreatic cancers from 13 individuals.

"Each metastasis is its own tumor, each evolving, each striving for dominance, each adapting to life outside the pancreas," co-lead author Peter Campbell, a researcher affiliated with the Sanger Institute and the University of Cambridge, explained in a statement. "When we treat cancer that has spread through the body, we're not just treating one tumor, we might be treating tens of genetically distinct tumors."

Using paired-end sequencing followed by PCR screening, the researchers found 381 somatic rearrangements in samples from the patients, as well as 177 germline rearrangements.

Although the precise rearrangements and genes varied from one individual to the next, researchers explained, more than half of the rearrangements were shared in primary and metastatic tumors from the same individual.

That suggests that it might eventually be possible to pin down pancreatic cancer biomarkers for tracking an individual's cancer progression and treatment response, Iacobuzio-Donahue noted.

For their part, she and her team plan to continue exploring genetic patterns by examining samples in additional pancreatic cancer patients. They are also continuing to collect rapid autopsy samples for their repository, which currently contains samples from about 120 patients.

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