Zodiac (case 11): Are there similarities in genetic interactions between Cancer and Neurological Disorders?

This is the 11th-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.

Today I want to raise a bold question: Are genetic interactions between cancer and neurological disorders, such as Alzheimer disease (AD), similar? My current belief is that there are definitely similar genetic interactions between cancer and neurodisorders. In my previous two articles (here and here) I showed, as side notes, that some immune cancer biomarkers are related to genes with critical neurological functions. Today, I came across a Nature article published on Aug. 31, 2015, revealing a new physiological APP (this is the gene I will talk about) processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. This potentially has translational relevance for therapeutic strategies targeting APP processing in AD.

I learned from this article that APP is a critical gene for AD. So I looked up APP in Zodiac, which contains genome-wide gene-pair interactions in cancer. I did not expect to see much since Zodiac s is a database in cancer, not AD. Well, the top gene that co-express with APP is

PCDHB2 This gene is a member of the protocadherin beta gene cluster, one of three related gene clusters tandemly linked on chromosome five. The gene clusters demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The beta cluster contains 16 genes and 3 pseudogenes, each encoding 6 extracellular cadherin domains and a cytoplasmic tail that deviates from others in the cadherin superfamily. The extracellular domains interact in a homophilic manner to specify differential cell-cell connections. Unlike the alpha and gamma clusters, the transcripts from these genes are made up of only one large exon, not sharing common 3′ exons as expected. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins. Their specific functions are unknown but they most likely play a critical role in the establishment and function of specific cell-cell neural connections.

OK. I learned that the top gene “talks” with APP in cancer is PCDHB2, which is a member of a gene cluster related to cadherin. Cadherin is a critical protein that properly adheres cells together, so that they don’t wonder around in mature organs or tissues. Apparently, this is important physiologically. In cancer, cells do not properly bind to each other, and therefore become ill-shaped, like a tumor. Maybe when cells do not adhere to each other in brain, we get neural disorders, like Alzheimer?

Moving down the list, the second gene with top co-expression with APP is TMTC1. Humans know nothing about this gene.

The third gene is

FAT4 The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2.

It is a gene that regulate how cells shape in the space, which is called planar cell polarity. Surprisingly, FAT4 is a gene of the same protcadherin family as PCDHB2, the top gene above! This starts to give me goosebumps! Essentially the top two genes interact with APP are from the same gene family regulating spacing of cells. And neurodisorders like AD are affected by spacing of neural cells.

Moving on, the next gene is

GPRASP2 The protein encoded by this gene is a member of a family that regulates the activity of G protein-coupled receptors (GPCRs). The encoded protein has been shown to be capable of interacting with several GPCRs, including the M1 muscarinic acetylcholine receptor and the calcitonin receptor.

So it is a G protein-coupled receptor, or GPCR! What is a GPCR? It is a protein that has been awarded at least seven Nobel Prizes, including The 2012 Nobel Prize in Chemistry, awarded to Brian Kobilka and Robert Lefkowitz for their work that was “crucial for understanding how G protein–coupled receptors function.” It is apparently a very important protein and has been linked to at least the following nine physiological functions in human, among which 1, 2, 3, 4, 6, 7 are related to neural functions. Also, 5, 7 and 9 are related to cancer as well!

  1. The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose
  2. The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter- and sweet-tasting substances.
  3. The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
  4. Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate
  5. Regulation of immune system activity and inflammation: Chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation and directly involved in suppression of TLR-induced immune responses from T cells.[20]
  6. Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
  7. Cell density sensing: A novel GPCR role in regulating cell density sensing.
  8. Homeostasis modulation (e.g., water balance).[21]
  9. Involved in growth and metastasis of some types of tumors.[22]

The next top gene co-expresses with APP in Zodiac is

NDN This intronless gene is located in the Prader-Willi syndrome deletion region. It is an imprinted gene and is expressed exclusively from the paternal allele. Studies in mouse suggest that the protein encoded by this gene may suppress growth in postmitotic neurons.

NDN is related to neurons.

At this point, I am convinced that Zodiac, albeit a database computed using cancer data, can reveal relationships of genes in neural disorders as well. This seems to suggest that disease-related genetic interactions in cancer and neural disorders might have overlaps.

As I move down the list in Zodiac, genes related to neural functions continue to show up such as PTPRKPIEZO2 and HEY2. Below is a Zodiac visual summary of all the genes mentioned in this article.

APP

To avoid making an overly long article, I decide to stop here. 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.

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Zodiac (Case 9): Zodiac Shows Potential Utility in AutoImmune Deficiency

This is the 9th-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.

This piece will be a short one since I am stepping out of my main domain, cancer. In this piece, I will briefly talk about a recent negative trial for treating systemic lupus erythematosus (SLE), also known as Lupus. It is an autoimmune disease currently with no cure. UCB, a Belgium-based biopharmaceutical company announced a devastating statement that its phase III trials (EMBODY 1&2) failed to meet its primary endpoint. The candidate drug is a monoclonal antibody called epratuzumab, which targets CD22 in the mature B-cell, a biomarker with elevated expression in Lupus patients.

I searched CD22 in Zodiac and found that the top 5 genes might shed new light about the CD22 mechanism. The majority of these genes are related neuro-disorders. It is interesting that Zodiac, a primary database for cancer, links genes in neuro-disorders.

SYN2 This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Polymorphisms in this gene are associated with abnormal presynaptic function and related neuronal disorders, including autism, epilepsy, bipolar disorder and schizophrenia.

KCNH4 Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. This gene encodes a member of the potassium channel, voltage-gated, subfamily H. This member is a pore-forming (alpha) subunit. The gene is brain-specific, and located in the neocortex and the striatum. It may be involved in cellular excitability of restricted neurons in the central nervous system.

ST3GAL5 Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome.

F5 This gene encodes an essential cofactor of the blood coagulation cascade. This factor circulates in plasma, and is converted to the active form by the release of the activation peptide by thrombin during coagulation. This generates a heavy chain and a light chain which are held together by calcium ions. The activated protein is a cofactor that participates with activated coagulation factor X to activate prothrombin to thrombin. Defects in this gene result in either an autosomal recessive hemorrhagic diathesis or an autosomal dominant form of thrombophilia, which is known as activated protein C resistance. (Note: this gene is related to thrombin/prothrombin. According to Wiki, activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant also known as antiphospholipid syndrome).

HIST2H2BE Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene encodes a replication-dependent histone that is a member of the histone H2B family, and generates two transcripts through the use of the conserved stem-loop termination motif, and the polyA addition motif. The protein has antibacterial and antifungal antimicrobial activity. (Note: This is a histone gene, with essential epigenetic functions. According to KEGG, this gene is in the Lupus disease pathway. See here)

These are the top five genes found in Zodiac that are strongly associated with CD22, and they seem to be related to auto-immune deficiencies. One striking finding is that none of these genes have any cancer terms in their descriptions, even though Zodiac is generated using cancer data.

Zodiac (case 7): CD33 as A Target of Immunotherapy Myeloid Leukemia

This is the 7th-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.

CD33 has been used as a cell surface target for treating myeloid leukemia. Lintuzumab is currently an investigational monoclonal antibody (mAB) that targets CD33 for treating myeloid leukemia. Other mABs are also being developed although efficacy has not been impressive so far. There is a renewed interest in targeting CD33, using activated Natural Killer (NK) cells, which are considered as a type of innate immune cells. I took a look at CD33 in Zodiac and found the following genes that are associated with CD33 with strong co-expression.

First, CD33 is positively associated with several other “CD” markers, namely

CD163 The protein encoded by this gene is a member of the scavenger receptor cysteine-rich (SRCR) superfamily, and is exclusively expressed in monocytes and macrophages. It functions as an acute phase-regulated receptor involved in the clearance and endocytosis of hemoglobin/haptoglobin complexes by macrophages, and may thereby protect tissues from free hemoglobin-mediated oxidative damage. This protein may also function as an innate immune sensor for bacteria and inducer of local inflammation.

CD53 The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins. It contributes to the transduction of CD2-generated signals in T cells and natural killer cells and has been suggested to play a role in growth regulation. Familial deficiency of this gene has been linked to an immunodeficiency associated with recurrent infectious diseases caused by bacteria, fungi and viruses.

CD86 This gene encodes a type I membrane protein that is a member of the immunoglobulin superfamily. This protein is expressed by antigen-presenting cells, and it is the ligand for two proteins at the cell surface of T cells, CD28 antigen and cytotoxic T-lymphocyte-associated protein 4. Binding of this protein with CD28 antigen is a costimulatory signal for activation of the T-cell. Binding of this protein with cytotoxic T-lymphocyte-associated protein 4 negatively regulates T-cell activation and diminishes the immune response.

CD37 The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein that is known to complex with integrins and other transmembrane 4 superfamily proteins. It may play a role in T-cell-B-cell interactions.

Apparently, these CD-markers all have a role in immune defense, some directly related to NK cells. The following genes also strongly co-express with CD33 in tumor samples. Their functions are related to immune defense as well. For example, SAMHD1 directly involves in the regulation of innate immune response.

ITGAM This gene encodes the integrin alpha M chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This I-domain containing alpha integrin combines with the beta 2 chain (ITGB2) to form a leukocyte-specific integrin referred to as macrophage receptor 1 (‘Mac-1’), or inactivated-C3b (iC3b) receptor 3 (‘CR3’). The alpha M beta 2 integrin is important in the adherence of neutrophils and monocytes to stimulated endothelium, and also in the phagocytosis of complement coated particles.

IFI30 The protein encoded by this gene is a lysosomal thiol reductase that at low pH can reduce protein disulfide bonds. The enzyme is expressed constitutively in antigen-presenting cells and induced by gamma-interferon in other cell types. This enzyme has an important role in MHC class II-restricted antigen processing.

SAMHD1 This gene may play a role in regulation of the innate immune response. The encoded protein is upregulated in response to viral infection and may be involved in mediation of tumor necrosis factor-alpha proinflammatory responses. Mutations in this gene have been associated with Aicardi-Goutieres syndrome.

Lastly, interestingly Zodiac showed three genes that co-express with CD33 and are related to neurological functions.

PVALB The protein encoded by this gene is a high affinity calcium ion-binding protein that is structurally and functionally similar to calmodulin and troponin C. The encoded protein is thought to be involved in muscle relaxation. See also a paper here.

ADORA3 This gene encodes a protein that belongs to the family of adenosine receptors, which are G-protein-coupled receptors that are involved in a variety of intracellular signaling pathways and physiological functions. The receptor encoded by this gene mediates a sustained cardioprotective function during cardiac ischemia, it is involved in the inhibition of neutrophil degranulation in neutrophil-mediated tissue injury, it has been implicated in both neuroprotective and neurodegenerative effects, and it may also mediate both cell proliferation and cell death. Alternative splicing results in multiple transcript variants. This gene shares its 5′ terminal exon with some transcripts from overlapping GeneID:57413, which encodes an immunoglobulin domain-containing protein.

TNFRSF1B The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways.

In summary, Zodiac confirms the close relationship between CD33 and immune cells. The suggested genes maybe further evaluated. A few genes that co-express with CD33 also relate to neurological functions.