Zodiac (Case 14): IL1RAP — A NEW Marker for Alzheimer’s Disease and an OLD Fella for Cancer — Supports Negative Correlation between Alzheimer and Cancer!

This is the 14th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

There is a news report about a new biomarker for Alzheimer, a gene called IL1RAP

The report stated that ” Older adults and Alzheimer’s patients who are carrying a specific variant of the IL1RAP gene were found to have higher rates of amyloid plaque accumulation in the brain, which is one of the key drivers of the disease. Not only could the discovery lead to quicker diagnoses and better identification of at-risk patients, but researchers suggest that by manipulating the IL1RAP immune pathway they could figure out how to either slow the progression of the disease, or perhaps stop it altogether.”

IL1RAP is related to a gene called IL-1 (Interleukin 1) family, which induces synthesis of acute phase and proinflammatory proteins during infection, tissue damage, or stress, by forming a complex at the cell membrane with an interleukin 1 receptor and an accessory proteinIL1RAP is the gene that encodes an interleukin 1 receptor accessory protein.

IL-1 is intensely produced by tissue macrophages, monocytes, fibroblasts, and dendritic cells, but is also expressed by B lymphocytes, NK cells and epithelial cells. They form an important part of the inflammatory response of the body against infection. These cytokines increase the expression of adhesion factors on endothelial cells to enable transmigration (also called diapedesis) of immunocompetent cells, such as phagocytes, lymphocytes and others, to sites of infection.

In my previous blog post Zodiac (Case 11), I raised a question of whether there is a similarity between cancer and neural disorders, such as Alzheimer. I showed evidence supporting the similarity between two diseases, and concluded that “I start to suspect that many ill-functioned inter-cellular mechanisms in cancer might be also present in neural degenerate diseases such as Alzheimer. I wonder if any cancer therapies targeting these mechansims could be tested on neurodisorders, at least in cell lines and mice.”

Here I am again, finding a newly discovered disease biomarker for Alzheimer potentially related to cancer as well. Let’s take a look at IL1RAP in the literature. Just a few months ago, the prestigious journal PNAS published a paper showing an antibody suppressing IL1RAP expression show therapeutic effects in xenograft models of acute myeloid leukemia (AML). The gene has been shown to be a therapeutic target for leukemia and auto-immune diseases such as rheumatoid arthritis, in which IL1RAP is typically over expressed. Interestingly, the problem in Alzheimer is the opposite. IL1RAP is believed to be under expressed and the under expression causes disease progression.

Therefore, based on the IL1RAP gene, there should be a negative correlation of some cancer, such as leukemia, and Alzheimer, since the expression of IL1RAP decreases in Alzheimer and increases in leukemia. Is it true?

Turns out this negative correlation has been reported extensively in the literature, with a most recent report published in August, 2015: through a meta-analysis and systemic review, an “inverse relationship” is found between Alzheimer and cancer, where individuals with a cancer history having 40% reduced risk than those without. The study is based on a retrospective review of publications in PubMed, Web of knowledge and the Cochrane library databases.

As to which genes are associated with IL1RAP in Zodiac, here is a quick summary. In short, a lot of important cancer genes!

First, in the genes with strong copy number — copy number association with IL1RAP, a couple of genes stand out.

CLDN1 Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands.

CLDN1 is related to sealing the blood brain barrier (BBB), which is critical to many neural disorders.

MAP3K13 The protein encoded by this gene is a member of serine/threonine protein kinase family. This kinase contains a dual leucine-zipper motif, and has been shown to form dimers/oligomers through its leucine-zipper motif. This kinase can phosphorylate and activate MAPK8/JNK, MAP2K7/MKK7, which suggests a role in the JNK signaling pathway.

This gene is interesting since JNK pathway has been targeted for several neural disorders.

Second, I looked up genes that co-express with IL1RAP in Zodiac. Not surprisingly, many immune and cancer related genes showed up.

POU5F1 This gene encodes a transcription factor containing a POU homeodomain that plays a key role in embryonic development and stem cell pluripotency. Aberrant expression of this gene in adult tissues is associated with tumorigenesis. This gene can participate in a translocation with the Ewing’s sarcoma gene on chromosome 21, which also leads to tumor formation.

OGT This gene encodes a glycosyltransferase that catalyzes the addition of a single N-acetylglucosamine in O-glycosidic linkage to serine or threonine residues. Since both phosphorylation and glycosylation compete for similar serine or threonine residues, the two processes may compete for sites, or they may alter the substrate specificity of nearby sites by steric or electrostatic effects. The protein contains multiple tetratricopeptide repeats that are required for optimal recognition of substrates.

Remark: Note that “serine” is an amino acid and a form of serine has been described as a potential early diagnostic marker for Alzheimer!

BRCA2 Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair.

FCGR2A This gene encodes one member of a family of immunoglobulin Fc receptor genes found on the surface of many immune response cells. The protein encoded by this gene is a cell surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes.

KRT6C Keratins are intermediate filament proteins responsible for the structural integrity of epithelial cells and are subdivided into epithelial keratins and hair keratins.

Remark: KRT6C seems another suspect related to neural disorders.

Genes such as CD58 and REL also showed up; they are related to T- and B-lymphocytes.

In conclusion, IL1RAP seems to be a gene that plays key roles in both cancer and Alzheimer. However, it appears to be over expressed in leukemia and under expressed in Alzheimer, which supports the negative associations of the two diseases.

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