# The Prognostic Significance and Mechanistic Determination of Chromatin Remodeling Biomarkers in Non-Functional Pancreatic Neuroendocrine Tumor

> **NIH NIH R37** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $613,156

## Abstract

Project Summary/Abstract
Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) are a heterogeneous group of neoplasms with increasing
incidence and ill-defined pathobiology. While many NF-PanNETs are indolent and remain stable for years, a significant
subset may behave aggressively and metastasize widely. Thus, the increasing and frequent detection of NF-PanNETs
presents a treatment dilemma. Current prognostic parameters and systems are susceptible to interpretation errors, sampling
issues, and do not accurately reflect the clinical behavior of these neoplasms. Hence, additional biomarkers are needed to
improve the prognostic stratification of patients with NF-PanNETs. Previously, we and others have reported recurrent
genomic alterations in ATRX and DAXX are associated with metastatic progression of NF-PanNETs. Mutations in these
genes result in loss of their respective proteins and coincide with the alternative lengthening of telomeres (ALT), a
telomerase-independent maintenance mechanism. We have also shown that loss of ATRX/DAXX and ALT correlate with
the development of metastases, are prognostic biomarkers for shorter disease-free survival and are independent of other
prognostic clinicopathologic parameters. Thus, ATRX/DAXX and ALT represent promising biomarkers. However, they
have not been evaluated prospectively nor in preoperative specimens, where prognostic stratification is important for patient
management. In addition, only 50% of metastatic NF-PanNETs harbor inactivation of ATRX/DAXX and the presence of
ALT. To identify additional biomarkers, we recently profiled ATRX/DAXX wild type metastatic NF-PanNETs and reported
recurrent alterations in SETD2/H3K36me3 and ARID1A, which similar to ATRX and DAXX are chromatin regulating genes.
We therefore hypothesize that the metastatic progression of NF-PanNETs is characterized by changes in chromatin
regulation and determining the key genomic and epigenomic hallmarks will not only improve the prognostic stratification
of patients with NF-PanNETs, but advance our understanding of the pathogenesis of this increasingly prevalent disease.
Aim 1 will be to develop and clinically validate preoperative prognostic biomarker assays for NF-PanNETs. Through both
retrospective and prospective studies, we will determine the prognostic performance and significance of ATRX, DAXX,
ALT, H3K36me3 and ARID1A. For Aim 2, we plan to define the chromatin patterns at different epigenetic states in the
metastatic progression of NF-PanNETs. Considering ATRX, DAXX, SETD2 and ARID1A are chromatin regulators, we will
evaluate the nanoscale chromatin structure and affected molecular pathways of various NF-PanNET states using
PathSTORM and CUT&RUN/RNA-seq assays. Finally, Aim 3 will investigate the adaptive response of ATRX/DAXX
inactivation and ALT initiation. We have discovered that the histone chaperone, HIRA, can reconstitute telomeric chromatin
and function of ATRX/DAXX deficiency ALT cancer cells. Within this aim...

## Key facts

- **NIH application ID:** 10279379
- **Project number:** 1R37CA263622-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Aatur Dilip Singhi
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $613,156
- **Award type:** 1
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10279379

## Citation

> US National Institutes of Health, RePORTER application 10279379, The Prognostic Significance and Mechanistic Determination of Chromatin Remodeling Biomarkers in Non-Functional Pancreatic Neuroendocrine Tumor (1R37CA263622-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10279379. Licensed CC0.

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