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Sequencing IDs Pancreatic Cancer Targets

DNA analysis graphic

(Gerd Altmann, Pixabay)

5 Mar. 2019. A genomic analysis of tumor samples from patients with pancreatic cancer, a cancer with a typically poor outlook, identified targets for early precision cancer detection and treatments. Researchers from University of Pittsburgh and its affiliated UPMC medical center, other academic labs, and the company Foundation Medicine, report the findings in the 2 March issue of the journal Gastroenterology.

Pancreatic cancer is often difficult to diagnose in its early stages, due to few unique symptoms associated with the disease, and because the pancreas is hidden among other organs in the body. As a result, it is often diagnosed in later, more advanced stages of the disease, with generally a poor prognosis for survival: 5-year survival rate of only 8 percent. American Cancer Society estimates nearly 57,000 people in the U.S. will be diagnosed with pancreatic cancer this year, leading to more than 45,000 deaths.

Making pancreatic cancer even more of a challenge to treat is the difficulty in identifying targets. The authors point out that the disease is largely defined by mutations in 4 genes — KRAS, TP53, CDKN2A, and SMAD4 — but none are considered targetable with current treatments. Moreover, apart from these 4 genes, other mutations associated with pancreatic cancer are widely distributed across the genome, with low frequencies for each target.

The team led by UPMC cancer specialist Nathan Bahary is looking for better early indicators of pancreatic cancer to improve the survival outcomes of patients. Bahary’s lab studies genetic biomarkers of cancer in gastrointestinal organs to improve detection and guide more precise treatments. The researchers include staff from Foundation Medicine, a Roche Group company in Cambridge, Massachusetts that conducts genomic analyses of cancer patients’ tumor and blood samples for diagnostics and precision treatments.

Bahary and colleagues analyzed nearly 3,600 tumor samples from pancreatic cancer patients representing all stages of the disease. The team sequenced the genomes in the tissue samples, looking for 315 genes associated with cancer and non-protein coding regions associated with 28 other genes that are rearranged in cancer cells.

The researchers, using Foundation Medicine facilities, also tested the samples for tumor mutational burden, a quantitative measure of the total number of mutations per coding error in a tumor genome. Tumors with a higher level of mutational burden are considered more likely to express immune-system targets specific to those tumors, making them better candidates for immunotherapies. In addition, the team assessed the samples for microsatellite instability, a condition where the number of short, repeated DNA sequences differ from the number of repeats in inherited DNA.

The results show pancreatic cancer samples expressed altered KRAS, TP53, CDKN2A, and SMAD4 genes as expected, but KRAS mutations were found in 88 percent of the samples. Among samples without KRAS mutations, the researchers found several types of actionable targets. In all, the findings show 17 percent of the samples containing targets treatable with currently approved drugs. The team also detected mutations in FGF23, CCND2, PIK3CA, and FGF6 genes in samples with intraductal papillary mucinous neoplasms, lesions in the pancreatic ducts that can serve as early-warning signs of tumors. In addition, the researchers found evidence of mutations in inherited genes, such as BRCA usually associated with breast cancer, among the samples.

The authors note that the these indicators can provide earlier signs of pancreatic cancer, offering more treatment options and precision therapies. “People have been looking for such markers for a long time,” says Bahary in a university statement, “and our study shows that it’s possible to break pancreatic cancer patients into different treatment buckets.”

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