Every year, just over 1000 people are diagnosed with kidney cancer in Sweden. The three most common variants are clear cell, papillary and chromophobe renal cancer. Researchers compare the gene expression in tumour cells from a kidney cancer patient with cells from healthy tissue to figure out in which part of the kidney the cancer began and what went wrong in these cells. Now, a research team at Lund University in Sweden has discovered that in the Cancer Genome Atlas database, the gene expression in reference samples from normal tissue varies, depending on where in the kidney the samples happen to have been taken. The analyses can be improved by clarifying which samples correspond to the correct tissue.
The part of the kidney which purifies the blood and generates urine is called the nephron and functions as a kind of tubing system. Each kidney contains around a million nephrons which collectively filter 180 litres of primary urine (waste products, water and salts) every day. This results in 1.5 litres of concentrated liquid, which is excreted through urination.
“Everything is very specifically regulated and the cells have different gene expression and hence properties depending on their location in the tubing.”, explains Håkan Axelson, research team leader and professor of molecular tumour biology.
When a tumour biopsy is taken from a patient and compared with healthy kidney tissue, it serves to map how the various genes are expressed so as to clarify what has gone wrong in the tumour cells.  The Cancer Genome Atlas – an international database containing almost 1000 samples from kidney tumours and healthy tissue – is a tool in this process.
“But when our research team studied the samples from the database, we noticed a great range of gene expressions between normal tissue samples. It emerged that the samples in the Cancer Genome Atlas were taken at different depths in the kidney and therefore contain different types of cells, which means that their gene expressions also vary”, says Håkan Axelson.
The normal reference samples thus contain various types of cells depending on where in the kidney they happen to have been taken. Since the Atlas does not state the location in the kidney the reference sample was collected, the comparison risks being unreliable and sometimes completely incorrect.
“Since the gene expression in the cells varies depending on their location, it is important that the normal samples contained in the database should also be taken from the location corresponding to that of the patient’s tumour”, says David Lindgren, who is the lead author of the study.
As an example, it was previously suspected that clear cell tumours occur in the first part of the nephron, but if these tumour cells are compared with a normal sample taken deeper inside the nephron, the cells will not correspond to the tumour sample. The gene expression is thereby different. Although each patient is unique, the various types of tumours have different specific genetic changes which occur as a consequence of properties in the cell in which the tumour originated.
“It is extremely important to know what characterises the cells in which the tumour occurs. Through better understanding of this interaction, we can increase our understanding of the course of the disease, which could be significant for diagnostics and, in the longer term, also for the choice of treatment”, concludes Håkan Axelson.

Lund University
www.lunduniversity.lu.se/article/improved-analysis-of-kidney-cancer

Notch is one of the most frequently mutated genes in chronic lymphocytic leukaemia (CLL), the most common leukaemia in adults in the United States. It is also often mutated in other common B cell tumours, such as mantle cell lymphoma. However, the role of Notch in these cancers has been uncertain. Now, a collaborative effort between investigators at the Perelman School of Medicine at the University of Pennsylvania and the Harvard Medical School provides new insights into how Notch drives the growth of B-cell cancers.
The researchers found that in B cell tumours, mutated overactive versions of the Notch protein directly drive the expression of the Myc gene and many other genes that participate in B cell signalling pathways. Myc is a critical gene in governing cell proliferation and survival, activities that it carries out by regulating the expression of other genes involved in cell metabolism.
B cell signalling pathways are the current targets of several therapies used to treat B cell malignancies such as CLL. “An important translational implication of this research is that we hope that by combining Notch inhibitors with drugs that target B-cell signalling we can better treat these B-cell cancers,” said senior author Warren Pear, MD, PhD, a professor of Pathology and Laboratory Medicine at Penn Medicine. “Although this is true of many transcription factors, it has been difficult to develop therapeutics that directly target the Myc protein, an alternative approach may be to target the proteins that regulate Myc expression.” Notably, multiple Notch inhibitors are in various stages of clinical development as potential cancer therapies.
The mechanism used by Notch to regulate Myc in B cells is distinct from the mechanism used in other cell types, such as T cells, where Notch also regulates Myc. The team found that Notch uses different regulatory switches in the genome, called enhancers, in different cell types. This raises the issue of why evolution would select for this complexity. One reason may be that Myc needs to be under very tight control in each cell. For example, in the mouse model of Notch-induced T-cell leukemia, the Penn group previously found that the difference between inducing a T cell tumor or not is a doubling of Myc transcription by Notch. As Notch appears to use cell type-specific machinery to regulate Myc, it may be possible to target the Notch-Myc signaling path in a way that does not disrupt this path in other cell types.
Another surprising finding was the direct link between Notch and genes involved in other B cell signalling pathways. For example, Notch activates genes involved in B cell receptor signalling, which is an established drug target in these B cell cancers. The challenge now will be to understand what this might mean for treatment of patients with Notch-activated B-cell leukemias and lymphomas. The team plans to test the synergy between Notch and B-cell signaling inhibitors. If they find a relationship, the next step would be to stimulate interest in a clinical trial.

Penn Medicine
www.pennmedicine.org/news/news-releases/2017/october/penn-study-links-mutations-in-notch-gene-to-role-in-b-cell-cancers

Leading rheumatologist and Feinstein Institute for Medical Research Professor Betty Diamond, MD, may have identified a protein as a cause for the adverse reaction of the immune system in patients suffering from lupus. A better understanding of how the immune system becomes overactive will help lead to more effective treatments for lupus and potentially other autoimmune diseases.
Lupus is an autoimmune disease that causes the immune system to lose the ability to differentiate between foreign agents and healthy tissue. It becomes hyperactive and attacks healthy tissue, causing inflammation and damage to joints, skin, and internal organs. Previous studies have shown that a polymorphism or variation in the gene PRDM1 is a risk factor for lupus. PRDM1 enacts the production of a protein called Blimp-1. In this study, Dr. Diamond and her team were looking to examine how Blimp-1 regulates the immune system.
"A healthy immune system is able to identify organisms that are not normally in the body and activate cells like T-Cells to attack them," said Dr. Diamond. "In the case of patients with an autoimmune disease like lupus, the immune system has started to identify healthy cells as something to target. Our study found that a low level of or no Blimp-1 protein in a particular cell type led to an increase in the protein CTSS which caused the immune system to identify healthy cells as something to attack – particularly in females."
In an animal model, Dr. Diamond’s team was able to show that females with reduced production of Blimp-1 caused an increase in CTSS, a protein that helps the immune system see microbes, or a microorganisms that causes disease. This resulted in an immune system which attacked healthy cells. Male animals with the reduced production of Blimp-1 showed no change in their immune system. Though more study is required to confirm that the risk gene PRDM1 could lead to a hyperactive immune system in human females, this is a significant discovery to better understanding the causes and potential treatments for lupus.

EurekAlert
www.eurekalert.org/pub_releases/2017-07/nh-fii071417.php

Researchers at the University of Helsinki have found a genetic variation, which associates with the damage caused by maternal alcohol consumption. This genetic variation clarifies the role of genetic factors in the alcohol-induced developmental disorders and could be useful in future diagnostics.
The effects of prenatal alcohol exposure (PAE) on placental genes involved in growth and on the size of affected newborns were explored in the study performed at the University of Helsinki and Helsinki University Hospital in Finland. The researchers observed that alcohol alters epigenetic marks on the placenta and also the head size of newborn, depending on the genetic variation inherited from the parents.
Epigenetic marks are molecules, which bind to DNA sequence. They regulate the activity of genes and thus production of proteins in the cells.
The research material was 39 alcohol-exposed and 100 control placentas. They were collected from mothers who gave birth in the Helsinki University Hospital and had given approval for their participation in the study.
It is already known that in addition to neuronal disorders and birth defects, alcohol causes retarded growth. Therefore the researchers focused on two genes, insulin-like growth hormone 2 (IGF2) and H19, which locate near each other and regulate the growth of the placenta and embryo.
There is a common genetic variation in the Finnish population in the DNA region which regulates the function of these genes. The genetic variants that an individual inherits from the parents have been shown to associate with the amount of epigenetic marks on this region. This led the researchers to examine this intensively studied genomic region in a novel way.
– We divided all our samples in four groups according to the inherited genetic variations. We observed that there were different quantities of epigenetic marks in the groups of alcohol-exposed placentas compared with controls, explains Adjunct Professor Nina Kaminen-Ahola, the leader of the research team at the University of Helsinki.
– This finding led us to explore if there are changes in the gene expression and newborns’ birth measurements that would associate with the variation. We observed that expression of the negative growth controller H19 was significantly increased compared to expression of the growth supporter IGF2 in certain variant groups of the alcohol-exposed placentas.
The birth measurements were analysed by using new Finnish growth charts. Previous studies have shown that alcohol particularly affects the head growth and thus head circumference has been used as a mark of alcohol-induced damage. However, this study indicated that the head circumferences of alcohol-exposed newborns vary significantly depending on the genetic variations inherited from parents.
– We do not know yet if this variation is connected with alcohol-induced neuronal disorders. However, this could explain earlier study results concerning decreased correlation between HCs and brain size, as well as between HCs and cognitive skills among alcohol-exposed children. This suggests that alcohol causes damage in the brain in all genotypes, but this cannot be always seen in the head size, Kaminen-Ahola states.

University of Helsinki
www.helsinki.fi/en/news/a-candidate-genetic-factor-for-the-effects-of-prenatal-alcohol-exposure-has-been-found

Couples who are undergoing pre-implantation genetic diagnosis (PGD) in order to avoid transmission of inherited diseases, such as Duchenne muscular dystrophy or cystic fibrosis, should also have their embryos screened for abnormal numbers of chromosomes at the same time, say Italian researchers.
By doing this, only embryos that are free not only of the genetic disease, but also of chromosomal abnormalities (aneuploidy), would be transferred to a woman’s womb, giving her the best chance of achieving a successful pregnancy, and avoiding the risk of implantation failure, miscarriage, or even live births that could be affected by conditions such as Down syndrome (in which there is an extra chromosome) or Turner syndrome (in which a girl has only one x chromosome rather than the normal two).
In a study reporting on the world’s largest series of double genetic tests the researchers carried out simultaneous PGD and pre-implantation genetic screening (PGS) on cells taken in a single biopsy.
They took between five and ten cells from the outer layer of 1122 blastocysts (the early collection of cells that begin to form about five days after an egg has been inseminated with sperm and which go on to develop into an embryo) and, after PGD and PGS, 218 blastocysts were transferred to the women’s wombs, resulting in 99 pregnancies and the birth of 70 healthy babies by January 2017, when the paper was written. This is a pregnancy rate of 49%, which is higher than the average clinical pregnancy rate of between 22-32% reported in the general population of couples undergoing in vitro fertilisation (IVF). At the time of writing the paper, 13 further pregnancies were ongoing and now 12 have resulted in the birth of healthy babies, while one miscarried. This gives a delivery rate of 38.6%. A total of 91 healthy blastocysts remain frozen awaiting transfer.
Dr Maria Giulia Minasi, laboratory director at the Centre for Reproductive Medicine, European Hospital, Rome, Italy, and first author of the study, said: “Importantly, we found that while 55.7% of the biopsied blastocysts did not carry a genetic disease or changes in the structures of chromosomes, only 27.5% of them also had the right number of chromosomes. Without performing pre-implantation genetic screening for aneuploidy, 316 blastocysts, which appeared to be healthy but had abnormal numbers of chromosomes, could have been transferred, leading to implantation failures, miscarriages or sometimes live births of babies affected by aneuploidy. For the couples involved, and particularly the women, these outcomes can be emotionally devastating.”
As a result of their findings, Dr Minasi and her colleagues believe that when couples undergo PGD, they should also have PGS.

The European Society of Human Reproduction and Embryology
www.eshre.eu/Press-Room/Press-releases-2017/Simultaneous-PGD-and-PGS-screening-on-cells-in-a-single-biopsy.aspx