Research Update from the MCM team (July 2024)


We continue to characterise lung cancer biomarkers identified in the MCM1 project. This update focuses on ASTN2, a protein involved in neuronal migration. It is expressed across several tissue types, and has been implicated in various cancers.

Project: Mapping Cancer Markers

Published on: 10 Jul 2024

Terminology

- Chiari malformation type I: A malformation in which part of the brain bulges through a normal opening in the skull where it joins the spinal canal, putting pressure on the brain and spinal cord.

- Chronic obstructive pulmonary disease (COPD): A group of diseases that cause airway blockage and breathing-related problems.

- Glioblastoma: A type of cancer which forms from cells called astrocytes in the brain or spinal cord.

- Astrocytes: A type of cell in the central nervous system which play many critical roles to support neurons.

Background

Identifying molecular markers and their combination (signatures) enables us to detect disease earlier (diagnostic signatures) and stratify patients into subgroups based on disease progression patterns (prognostic signatures). The final group of markers helps identify which patients will benefit from specific treatment options (predictive signatures). The Mapping Cancer Markers project analyses data sets with millions of data points collected from patients with cancers to find such diagnostic, prognostic and predictive signatures.

Since November 2013, World Community Grid volunteers have donated over 905,700 CPU years to the project, helping analyse data on lung and ovarian cancer and sarcoma, much more thoroughly than otherwise possible. We are immensely grateful for this continued support.

Focusing on characterising the 26 top-scoring genes in lung cancer, we have already discussed VAMP1, FARP1, GSDMB, ADH6, IL13RA1, PCSK5, TLE3, HSD17B11, and KLF5 in previous MCM updates. Here, we outline information on ASTN2.

ASTN2 Research

ASTN2 (Astrotactin-2), is a protein that mediates the recycling of ASTN1 (Astrotactin-1), which is a neuronal cell adhesion molecule. This process involves promoting ASTN1 being internalised back into the neuron, and enabling its transport throughout the neuron, during neuronal migration (Uniprot).

Given ASTN2’s role in the central nervous system, it is understandable that it has been implicated in emotional and cognitive functions[1]. Evidence suggests that ASTN2 has a role in disorders linked to the brain and cognition, such as Alzheimer’s disease[2], psychiatric disorders[3], intellectual disability[4], migraine suceptibility[5], and Chiari malformation type I[6]. That said, ASTN2 has low tissue specificity and is expressed across all tissue types examined in the Human Protein Atlas. Correspondingly, ASTN2 has been implicated in kidney function[7], endometriosis[8], osteoarthritis[9], cardiometabolic traits[10,11], and chronic obstructive pulmonary disease (COPD)[12]. Interestingly, this link to COPD is a female-specific association[12]. The potential role of ASTN2 in COPD is noteworthy because studies have demonstrated that COPD and lung cancer are closely linked at a molecular level[13].

Figure 1. ASTN2 expression across different tissue types (Human Protein Atlas).

In line with the other genes we have presented, high expression of ASTN2 is associated with longer survival in lung cancer (Figure 2A). Notably, this relationship is present in females only (Figure 2B), not males (Figure 2C).

A

BC

Figure 2. (A) Survival curves for lung cancer patients with low and high expression of ASTN2 (KMplot), (B) for females only, and (C) for males only.

While our focus is on lung cancer, we further examined whether ASTN2 is also linked to other cancer types. As shown in Figure 3, comparing cancer tissues with normal tissues, ASTN2 is differentially expressed in 13 of the 22 cancers analyzed (indicated by red text). Notably, ASTN2 is upregulated in 8 of these cancers, while it is only downregulated in 5. Within the literature, the link between ASTN2 and cancer appears to be underresearched, with very few published articles on the topic. However, one study suggested that ASTN2 is linked to lung function[14], and another study found that ASTN2 expression is elevated in glioblastoma cell lines compared with normal human astrocytes[15].

Figure 3. Expression of ASTN2 in normal and cancer tissue for multiple cancer types. Red text represents a significant difference between expression in cancer tissue compared with normal tissue (TNMplot).

If you have any questions or comments, please leave them in this thread for us to answer!

WCG Support Team

References

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  2. Wang KS, Tonarelli S, Luo X, Wang L, Su B, Zuo L, Mao C, Rubin L, Briones D, Xu C. Polymorphisms within ASTN2 gene are associated with age at onset of Alzheimer's disease. J Neural Transm (Vienna). 2015 May;122(5):701-8. doi: 10.1007/s00702-014-1306-z. Epub 2014 Nov 21. PMID: 25410587.
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