Unlocking the Roles of ATRX and ZNRF3 in a Rare and Challenging Disease
Adrenocortical carcinoma (ACC) is a medical mystery—a rare and aggressive cancer with an incidence of just 1 to 2 cases per million people each year. For those diagnosed, the prognosis is daunting, with a global survival rate of less than 40% at five years 1 . What makes this cancer particularly challenging is its unpredictable behavior—some tumors grow slowly while others spread rapidly, and doctors have struggled to understand why.
In recent years, scientists have turned to genetics for answers. Through comprehensive genomic studies, two genes have emerged as crucial players in adrenocortical tumors: ATRX and ZNRF3 3 4 . These molecular actors appear to hold clues about why some adrenal cancers are so aggressive, potentially opening new avenues for diagnosis and treatment. The investigation into their roles spans from childhood tumors to adult cancers, revealing surprising differences in how these genes behave across age groups.
The ATRX gene functions as a cellular architect responsible for maintaining proper chromatin structure and telomere integrity 2 4 . Chromatin is the complex of DNA and proteins that packages genetic material within our cells, while telomeres are the protective caps at the ends of chromosomes. Think of ATRX as both a librarian who organizes genetic information and a maintenance worker who preserves the ends of our genetic "books."
When ATRX malfunctions, it can trigger a phenomenon called alternative lengthening of telomeres (ALT), which allows cancer cells to bypass normal cellular aging and become immortal 2 . This pathway is particularly dangerous because it enables tumors to grow indefinitely. Research has shown that ATRX mutations are especially prominent in pediatric adrenocortical tumors, where they often team up with TP53 mutations—another well-known cancer gene 2 .
Chromatin remodeling and telomere maintenance
ZNRF3 serves as a critical brake on cellular growth signaling 5 . This gene produces a protein that acts as a transmembrane E3 ubiquitin ligase, essentially functioning as a cellular "recycling manager" for Wnt pathway receptors. The Wnt pathway is crucial for normal cell growth and development, but when overactive, it can drive uncontrolled cancer growth.
By marking Wnt receptors for disposal, ZNRF3 ensures these growth signals don't become excessive. When ZNRF3 is lost or malfunctioning, this braking system fails, allowing Wnt/β-catenin signaling to run unchecked—like a car accelerating without brake pads 5 . This pathway becomes particularly important in adult ACC, where ZNRF3 is actually the most frequently altered gene, found in approximately 21% of cases 4 5 .
Negative regulation of Wnt signaling pathway
| Gene | Primary Function | Role in Cancer | Frequency in ACC |
|---|---|---|---|
| ATRX | Chromatin remodeling, telomere maintenance | Triggers alternative telomere lengthening, promotes genomic instability | ~9-16.6% (varies by age group) 1 |
| ZNRF3 | Negative regulation of Wnt signaling pathway | Loss leads to uncontrolled Wnt/β-catenin signaling | ~16-21% (more frequent in adults) 1 5 |
In 2020, researchers conducted a crucial investigation into ATRX and ZNRF3 patterns across different age groups, studying a Brazilian cohort of adult and pediatric patients with adrenocortical tumors 1 . This research was particularly significant because Brazil's southern region has an unusually high prevalence of a specific TP53 germline mutation (R337H), providing a unique natural laboratory for studying adrenal cancer genetics.
34 adults (median age 49 years) and 12 pediatric patients (median age 3 years) from a tertiary care center 1
The study included 34 adults (median age 49 years) and 12 pediatric patients (median age 3 years) from a tertiary care center 1
Researchers compared genetic findings with comprehensive patient data including age, tumor characteristics, TP53 mutation status, and survival outcomes 1
This multi-pronged methodology allowed the team to connect molecular findings with real-world clinical outcomes, bridging the gap between laboratory science and patient care.
Contrary to earlier studies that suggested ATRX alterations were primarily pediatric and ZNRF3 mainly adult phenomena, this research found both genes altered across age groups. Specifically, 9% of adults and 16.6% of pediatric patients showed ATRX deletions, while 16% of adults and 16.6% of pediatric patients showed ZNRF3 deletions 1 .
The study uncovered a significant relationship between ATRX expression and the famous cancer gene TP53. Reduced ATRX expression was associated with the presence of TP53 germline mutations in both pediatric and adult cohorts (p=0.028) 1 , suggesting a potential collaboration between these genetic players in driving cancer.
Unlike some previous studies, this investigation found no direct correlation between ATRX/ZNRF3 alterations and overall survival rate in their cohort 1 . This highlights the complex nature of adrenal cancer, where multiple factors interact to determine patient outcomes.
| Patient Group | ATRX Deletions | ZNRF3 Deletions | TP53 R337H Mutation |
|---|---|---|---|
| Adults (n=34) | 3/33 (9%) | 4/25 (16%) | 7/27 (25.9%) |
| Pediatric (n=12) | 2/12 (16.6%) | 2/12 (16.6%) | 10/12 (83.3%) |
The investigation into ATRX and ZNRF3 didn't stop with the Brazilian cohort. In 2021, another research team published a critical study examining the protein expression of these genes in 82 adult ACC patients, seeking to establish their prognostic value 3 4 .
This subsequent research confirmed that low protein expression of both ATRX and ZNRF3 served as negative prognostic markers 3 . The statistical analysis revealed compelling evidence:
These findings transformed ATRX and ZNRF3 from mere genetic curiosities into potential clinical tools that could help doctors predict disease course and tailor treatment strategies.
| Gene | High Expression Cut-off | Impact on Overall Survival | Impact on Recurrence-Free Survival |
|---|---|---|---|
| ATRX | >1.5 | HR: 0.521 (95% CI: 0.273-0.997) 4 | HR: 0.332 (95% CI: 0.111-0.932) for expression >2.7 4 |
| ZNRF3 | >2 | HR: 0.441 (95% CI: 0.229-0.852) 4 | HR: 0.333 (95% CI: 0.140-0.790) 4 |
HR: Hazard Ratio; CI: Confidence Interval
This technique allows scientists to detect copy number variations—whether chunks of genes are missing or duplicated. It's like taking a roll call of genetic segments to see if any are absent 1 .
A fundamental tool for measuring gene expression levels. Researchers use it to determine how actively the ATRX and ZNRF3 genes are being read and translated into proteins in tumor cells 1 .
These innovative tools contain small sections of dozens of different tumor samples arranged on a single slide, enabling high-throughput analysis of protein expression while conserving precious tissue resources 3 .
Comprehensive genomic analysis including whole genome, whole exome, and transcriptome sequencing provides researchers with a complete picture of the genetic alterations in adrenocortical tumors, allowing them to see how ATRX and ZNRF3 interact with other cancer genes 2 .
The investigation into ATRX and ZNRF3 represents a fascinating case study in modern cancer research. What began as genomic surveys identifying frequently altered genes has evolved into a nuanced understanding of how these molecular players influence cancer behavior across different age groups and populations.
These findings do more than just satisfy scientific curiosity—they pave the way for more personalized approaches to cancer care. By understanding a patient's specific genetic profile, including the status of ATRX and ZNRF3 in their tumor, oncologists may eventually tailor treatments to individual molecular characteristics rather than applying a one-size-fits-all approach.
As the authors of the Brazilian cohort study rightly noted, "prospective studies with larger cohorts are necessary to confirm the prognostic value" of these genes 1 . The journey from laboratory discovery to clinical application is long, but each study brings us closer to unlocking the mysteries of adrenocortical carcinoma and offering hope to those affected by this challenging disease.
Understanding ATRX and ZNRF3 status could enable tailored treatment approaches based on individual tumor genetics.