Surreal illustration of a child's face with a neural network formed by stars, symbolizing neuroblastoma research.

Unlocking Neuroblastoma: How a Gene Discovery Could Change Everything

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Elliot Brynn in Health & Wellness August 2025 • 5 min read.

"Groundbreaking research identifies NKAIN2 as a potential key in understanding and treating this childhood cancer, offering new hope for families."


Neuroblastoma (NB), a cancer that develops from immature nerve cells, primarily affects young children. While most cases occur sporadically, a small percentage are familial, sparking a quest to identify the genes that predispose individuals to this disease. Researchers have already linked genes like ALK and PHOX2B to familial NB, yet these genes don't fully explain why some individuals develop the cancer while others don't, suggesting that additional genetic factors are at play.

A recent study has shed light on a previously unappreciated gene, NKAIN2 (Na/K transporting ATPase interacting 2), as a potential contributor to neuroblastoma development. The study, published in PLOS ONE, details how high-resolution array Comparative Genomic Hybridization (CGH) profiling led to the identification of NKAIN2 as a predisposing candidate gene. This discovery could refine our understanding of NB and pave the way for novel diagnostic and therapeutic strategies.

The researchers focused on an Italian family with a history of neuroblastoma, where multiple members were affected by the disease. By analyzing the genetic makeup of these individuals, they uncovered a specific genetic alteration involving the NKAIN2 gene, prompting further investigation into its role in neuroblastoma.

Decoding NKAIN2: What the Research Reveals About Neuroblastoma

Surreal illustration of a child's face with a neural network formed by stars, symbolizing neuroblastoma research.

The study began with an Italian family affected by neuroblastoma. Three members, two siblings and a first cousin, all carried a germline mutation in the ALK gene, known to increase susceptibility to neuroblastoma. Interestingly, this mutation was inherited from their mothers, who did not have the disease. This observation underscored the need for additional genetic factors to trigger tumor development.

To identify these factors, the researchers conducted a high-resolution array CGH analysis, a technique that detects copy number variations (CNVs) in DNA. By comparing the DNA of affected siblings, they discovered a germline gain at the NKAIN2 locus in one sibling. This gain, meaning an extra copy of the gene, was inherited from a parent without the ALK mutation. This was unexpected, and suggested NKAIN2 might be important.

  • Germline Gain: One sibling showed a germline gain at the NKAIN2 locus, inherited from a parent without the ALK mutation.
  • NKAIN2 Expression: Surprisingly, the sibling without the genomic gain also showed high NKAIN2 expression, suggesting other regulatory mechanisms.
  • MYCN Amplification: High levels of NKAIN2 were found in MYCN-amplified NB cell lines, known for aggressive behavior.
  • Differentiation: NKAIN2 expression decreased during all-trans retinoic acid (ATRA) differentiation in NB cell lines.
The researchers then looked at how the NKAIN2 gene was expressed. Surprisingly, both affected siblings had high levels of NKAIN2, even the one without the extra copy of the gene. This meant there was something else turning on the NKAIN2 gene. Further, high levels of NKAIN2 were also found in neuroblastoma cell lines that are known to be aggressive, particularly those with MYCN amplification, a well-known driver of neuroblastoma. Finally, when neuroblastoma cells were treated with retinoic acid to make them more mature (differentiated), NKAIN2 levels decreased. These findings all pointed to a potential role for NKAIN2 in neuroblastoma development.

What Does This Mean for the Future of Neuroblastoma?

The identification of NKAIN2 as a potential player in neuroblastoma opens new avenues for research. Further studies are needed to fully understand its role and how it interacts with other genes and pathways involved in the disease. However, this discovery could eventually lead to the development of new diagnostic tools to identify individuals at higher risk of developing neuroblastoma, as well as targeted therapies that specifically address the role of NKAIN2 in tumor growth and differentiation, offering a more effective and less toxic approach to treating this devastating childhood cancer.

About this Article -

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Everything You Need To Know

1

What exactly is neuroblastoma?

Neuroblastoma (NB) is a cancer that originates from immature nerve cells, predominantly affecting young children. The causes can be sporadic or, in a smaller number of cases, familial. Research has identified genes like ALK and PHOX2B associated with familial NB, but these don't fully explain the development of the cancer. The recent research highlights NKAIN2 as another potential factor, potentially leading to new diagnostic and therapeutic strategies.

2

Why is the discovery of NKAIN2's role in neuroblastoma considered important?

The discovery of NKAIN2's role is significant because it provides a new target for understanding and potentially treating neuroblastoma. The research suggests that NKAIN2 may contribute to tumor growth and differentiation. Understanding its function could lead to new diagnostic tools for identifying high-risk individuals and to the development of targeted therapies that specifically address NKAIN2's role in the disease, potentially providing more effective and less toxic treatments.

3

What is Array Comparative Genomic Hybridization (CGH), and how was it used in this research?

Array Comparative Genomic Hybridization (CGH) is a technique used to detect copy number variations (CNVs) in DNA. In this context, it was used to compare the DNA of siblings affected by neuroblastoma to identify genetic differences that might contribute to the disease. The researchers used high-resolution array CGH profiling to identify NKAIN2 as a predisposing candidate gene. This method allowed them to uncover a germline gain at the NKAIN2 locus in one sibling, indicating an extra copy of the gene.

4

What is MYCN amplification, and what does it have to do with NKAIN2?

MYCN amplification refers to an increase in the number of copies of the MYCN gene in neuroblastoma cells. MYCN is a well-known driver of neuroblastoma, and its amplification is associated with aggressive tumor behavior. The research found that high levels of NKAIN2 were present in neuroblastoma cell lines with MYCN amplification, suggesting a connection between NKAIN2 and aggressive neuroblastoma development. This connection implies that NKAIN2 may play a role in the pathways that drive tumor growth in MYCN-amplified neuroblastoma.

5

What is all-trans retinoic acid (ATRA) differentiation, and how does it relate to NKAIN2?

All-trans retinoic acid (ATRA) differentiation is a treatment approach used to make neuroblastoma cells more mature or differentiated. The study found that when neuroblastoma cells were treated with ATRA, the levels of NKAIN2 decreased. This suggests that NKAIN2 expression is linked to the immature state of neuroblastoma cells and that reducing NKAIN2 levels may contribute to the differentiation process. This finding is important because differentiation therapy aims to slow or stop cancer growth by promoting the maturation of cancer cells.

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