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Predicting Relapse in Pancreatic Neuroendocrine Tumors

A pancreatic neuroendocrine tumor.

Researchers have found a new way to classify non-functional pancreatic neuroendocrine tumors (PNETs) in order to predict which patients will experience relapse.

Most PNETs are non-functional, meaning that they do not release excess hormones into the bloodstream. In current practice, patients whose non-functional PNETs are larger than 2 cm are considered at the highest risk of metastatic recurrence following surgery.

"As clinical behaviors [of non-functional PNETs] vary widely and distant metastases are eventually lethal, biological classifications might guide treatment," write the researchers, led by co-first authors Paloma Cejas, PhD, Research Associate in Medicine at Brigham and Women's Hospital, and Yotam Drier, PhD, Assistant Professor in the Faculty of Medicine of The Hebrew University, in their publication in Nature Medicine.

When the investigators used enhancer maps to infer gene regulatory programs, they identified two major subtypes of non-functional PNETs. One of these subtypes has epigenomes and transcriptomes that have some resemblance to healthy islet alpha cells; this subtype expresses the regulatory protein ARX. The other subtype somewhat resembles healthy islet beta cells and expresses the regulatory protein PDX1. Of 142 non-functional PNET tumor specimens, 84% expressed either ARX, PDX1, or occasionally both. Among 103 patients with non-functional PNETs, the researchers found that distant relapses occurred in patients whose tumors expressed ARX and PDX1, particularly in tumors that showed alternative lengthening of telomeres.

"These markedly different outcomes belied similar clinical presentations and histology and, in one cohort, occurred irrespective of MEN1 mutation," write the researchers. "This robust molecular stratification… accurately predicts disease course and can inform postoperative clinical decisions."

The study's senior investigator, Ramesh Shivdasani, MD, PhD, Professor of Medicine at Harvard Medical School, emphasizes the practical application of the new classification: "These patients can be monitored vigilantly for recurrent cancers, which may be treatable if detected early, while patients with the less aggressive kind of PNET can be advised that the prognosis is excellent."

For More Information

Cejas P, Drier Y, Dreijerink KMA, et al (2019). Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nat Med. [Epub ahead of print] DOI:10.1038/s41591-019-0493-4

Image credit: Nephron. Licensed under CC BY-SA 4.0

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