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Genomes of Advanced Neuroendocrine Neoplasms Unveil Subtypes, Treatment Clues

NEW YORK – With the help of whole-genome sequencing, a research team from the Netherlands has uncovered subtype-specific features and potentially targetable driver mutations in locally advanced or metastatic neuroendocrine neoplasms (aNEN) — malignancies stemming from neuroendocrine cells in the pancreas, gastrointestinal tract, lung, or other parts of the body.

"Historically, [neuroendocrine neoplasm] has long been considered as a difficult malignancy to diagnose, monitor, and treat due to presentation of an inherently wide spectrum of disease progression, cellular differentiation, and low mutational burden, resulting in few targetable mutations and a relatively stable tumor genome," co-senior and co-corresponding author Bianca Mostert, a cancer researcher at Erasmus MC Cancer Institute, and her colleagues wrote.

For a paper published in Nature Communications on Thursday, the researchers sequenced the genomes of biopsy samples from 85 individuals with locally advanced or metastatic neuroendocrine neoplasms, including 70 samples taken from metastatic lesions and 15 samples representing the patients' primary tumor. A dozen samples came from cases with unknown primary tumor sites.

The team's results highlighted subsets of aNENs with genomic features that varied depending on the related primary tumor site, tumor subtype, and tumor grade. In contrast to the relatively low levels of tumor mutational burden, or TMB, in the neuroendocrine tumors on the whole, for example, the team saw higher-than-usual TMB in neuroendocrine carcinomas, along with recurrent alterations in genes such as TP53, KRAS, RB1, MYC, and APC.

"In our aNEN cohort," the authors reported, "it is apparent that the molecular landscape of [advanced neuroendocrine carcinomas] is markedly dissimilar from that of the more differentiated [advanced neuroendocrine tumors], in terms of mutational burden (median TMB of 5.45 versus 1.09, respectively), genomic stability, and distinct mutant (driver) genes."

The researchers also distinguished driver mutations based on the primary site of the aNEN cases. While samples associated with neuroendocrine tumors that turned up in the midgut tended to contain somatic alterations affecting the CDKN1B gene, cases involving pancreatic neuroendocrine tumors had recurrent mutations in genes such as ATRX, MEN1, DAXX, DMD, and CREBBP.

By digging into the tumor sequence data further, the team flagged possible treatment targets in nearly half of the advanced tumors they studied.

"We observed 42 aNEN (49 percent) harboring one or more target-specific or general somatic aberrations which are known as possible (and responsive) druggable targets against currently available (or under development) treatments," the authors wrote.

In one of the aNENs originating in the pancreas, the team detected particularly high levels of TMB, along with a mutational signature previously linked to exposure to alkylating agents such as temozolomide that may reflect the patient's past treatment with a drug combination that included the antineoplastic alkylating agent streptozotocin.

Although streptozotocin treatment has not been linked to such hypermutation in the past, the researchers explained, the results in this aNEN case point to the possibility of boosting response to immune checkpoint inhibitor treatments by prompting enhanced TMB with treatments that bump up tumor mutation levels.

Still other aNEN cases contained mutations that are being targeted in other cancer types, or had high TMB levels that might correspond with checkpoint blockade response, they noted. However, the effects of the targeted treatments suggested by the tumor mutation patterns have yet to be explored in the clinical setting of aNEN.

"The major advantages of characterizing the genomic landscape of metastatic NEN lie within the identification of potentially actionable targets and treatment-induced (resistance) mechanisms within the late-stage disease," the authors wrote.

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