Neuroendocrine neoplasms (NENs) can show up anywhere in the body and can impact any organ system. These tumors originate in diverse sites, according to the authors of a recently published paper in Endocrine Reviews, which kind of makes them moving targets.
Authors of the paper, “Epigenetics and disease progression in neuroendocrine neoplasms,” led by Madson Q. Almeida, MD, PhD, of the University of Sao Paulo in Brazil, write that although clinical, biochemical, and pathological features have been associated with metastatic potential, the reliable prediction of disease progression and prognosis in NENs remains a major challenge.
The review then discusses epigenetics and how epigenetic regulation is mediated. The authors write: Epigenetic regulation is mediated through several interrelated molecular mechanisms: DNA methylation, histone modification, ATP-dependent chromatin remodeling, non-coding RNA-mediated regulation, and higher-order chromatin architecture.
The authors point to the technologies that have given rise to what Almeida and colleagues call “one of the most transformative tools in rare disease diagnostics”: DNA methylation episignatures that the authors describe as genome-wide methylation patterns that are uniquely and reproducibly associated with specific Mendelian syndromes. “Their utility lies in their ability to serve as a downstream readout of functional disruption in the epigenetic machinery, effectively bridging the gap between genetic variant identification and phenotypic consequence,” the authors write.
Turns out, the authors write, these circulating epigenetic biomarkers are emerging as promising non-invasive tools for early diagnosis, risk stratification, and disease monitoring. “Epigenetic mechanisms are dynamic and reversible, which makes them good candidates for therapeutic targeting,” the authors write. “The clinical translation of these insights is rapidly evolving.”
Epigenetic regulation is mediated through several interrelated molecular mechanisms: DNA methylation, histone modification, ATP-dependent chromatin remodeling, non-coding RNA-mediated regulation, and higher-order chromatin architecture.
The review describes several neoplasms, including pheochromocytomas/paragangliomas (PPGLs), gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), lung neuroendocrine neoplasms (LNENs), medullary thyroid carcinoma (MTC), and pituitary NETs (PitNETs). It also describes emerging epigenetic therapies, like global DNA methyltransferases inhibitors,
Medications like azacitidine and decitabine block DNMT activity and have been evaluated as a potential treatment for NETs. Pre-clinical studies have indicated that DNMT inhibitors (DNMTi) may have particular efficacy in PPGLs with SDH pathogenic variants and can reduce both proliferation and metastasis. HDAC (histone deacetylases) inhibitors can inhibit cell growth and cell motility. Studies have shown that HDAC inhibitor. “Pre-clinical studies in GEP-NETs have also shown HDACi to decrease proliferation, inhibit cell cycle progression, and increase apoptosis, as well as increase SSTR2 expression, therefore providing both anti-tumor agent and agent to aid in increasing radioligand expression.”
And while these new therapeutic options are promising, the authors write there’s more work to be done. Identifying epigenetic biomarkers across a large, diverse population is imperative. “With sustained technological advances and rigorous clinical validation,” the authors conclude, “the epigenome is poised to transition from a research focus to a cornerstone of precision medicine in neuroendocrine oncology.”
