Digital NGS can detect cancerous mutations in pancreatic juice

Reuters Health Information: Digital NGS can detect cancerous mutations in pancreatic juice

Digital NGS can detect cancerous mutations in pancreatic juice

Last Updated: 2017-06-02

By Marilynn Larkin

NEW YORK (Reuters Health) - Digital next-generation sequencing (NGS) can detect certain cancer-causing mutations in pancreatic juice, showing promise for screening and surveillance efforts, researchers in Maryland say.

The molecular progression of pancreatic ductal neoplasia involves acquisition of mutations in multiple genes - such as KRAS and GNAS in low-grade pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), and TP53 and SMAD4 in higher-grade lesions and invasive pancreatic ductal adenocarcinoma.

MRI/MR cholangiopancreatography and endoscopic ultrasound can identify certain lesions, but precancerous lesions such as PanINs are generally too small to be detected by these modalities.

To see whether digital NGS could help, Dr. Michael Goggins and colleagues at Johns Hopkins Medical Institutions in Baltimore, Maryland used the technology to compare mutation profiles of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) versus IPMN versus controls, first in a discovery set of pancreatic juice samples from 53 patients, and then in a validation set of 62 patients.

Samples were obtained by infusing participants with synthetic secretin intravenously for about a minute and collecting pancreatic juice (typically, 5 to 10 mL) from the duodenal lumen for about five minutes.

Dr. Goggins told Reuters Health, “Digital NGS can be used to identify cancer-associated mutations at lower concentrations (0.1 to 1%) than conventional NGS methods - concentrations typically found in the circulation or pancreatic fluid.”

“Digital NGS analysis has the potential to detect occult pancreatic neoplasms not detectable by endoscopy,” he added.

As reported in Gut, online May 18, in the combined set of 115 patients tested, digital NGS detected as least one mutation in 91.2% of samples from those with PDAC and 91.1% of those with an IPMN without PDAC (p=0.001), compared with 54.2% of controls (p<0.001).

Mutant DNA concentrations were higher in those with PDAC compared with IPMN (p=0.003) or controls (p<0.001).

TP53 and/or SMAD4 mutations were commonly detected in samples from patients with PDAC but not from controls (p<0.0001); mutant TP53/SMAD4 concentrations could distinguish PDAC from IPMN cases with 32.4% sensitivity and 100% specificity (area under the curve, 0.73, p=0.0002), and from controls (AUC 0.82, p<0.0001).

In two of four patients who developed pancreatic cancer despite close monitoring, cancer-related SMAD4/TP53 mutations were detected in juice samples collected in the 18 months prior to their pancreatic cancer diagnosis, when no suspicious pancreatic lesions were detected by imaging.

The results “highlight the potential of using pancreatic juice analysis to detect worrisome mutations that could help in the surveillance and risk stratification of patients undergoing pancreatic screening and surveillance,” the authors conclude.

“Digital NGS is a more laborious and technically demanding method than conventional NGS,” Dr. Goggins acknowledged, “but it uses standard NGS protocols and therefore could be introduced into and validated in clinical molecular diagnostic laboratories that perform NGS as a test to identify low-abundance mutations.”

Dr. Christopher DiMaio, director of Therapeutic Endoscopy at the Icahn School of Medicine at Mount Sinai in New York City, called the study, “an exciting step forward in improving our ability to better identify patients at increased risk of developing pancreatic cancer.”

“Accurate biologic and genetic markers are a critical addition to the diagnostic tools we currently use, such as (MR cholangiopancreatography and endoscopic ultrasound), in the evaluation of patients who may be at an elevated risk of pancreatic cancer,” he told Reuters Health.

“One advantage of the method described in this paper is that pancreatic fluid samples were collected by an easy, safe, and minimally invasive method,” he said by email.

“Furthermore, because the fluid collected is theoretically representative of the entire pancreatic ductal system, it allows an opportunity to better ‘screen’ the entire gland,” he said, “as opposed to taking small biopsies from one or two spots.”

“This study represents only a first step, however,” he continued. “It should be noted that the gene mutations of interest were not present in all cases with cancers or pre-cancerous lesions.”

“Furthermore,” he added, “it remains unclear how we should manage patients who have detectable mutations in their pancreatic ductal fluid, but do not have any identifiable lesions on (imaging studies) that could otherwise be surgically removed.”

“Further studies are needed to better address these issues,” Dr. DiMaio concluded, “and better understand how such a test could reliably fit in with current management practices.”


Gut 2017.

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