For the first time, scientists have provided unbiased estimates of the number of mutations needed for cancers to develop, in a study of more than 7,500 tumours across 29 cancer types. Researchers from the Wellcome Trust Sanger Institute and their collaborators adapted a technique from the field of evolution to confirm that, on average, 1 to 10 mutations are needed for cancer to emerge.
The results also show the number of mutations driving cancer varies considerably across different cancer types.
In the study, the team developed an approach to discovering which genes are implicated in cancer evolution and how many mutations in those genes drive cancer. In the future, such approaches could be used in the clinic to identify which few mutations in an individual patient are driving his or her cancer, from amongst the thousands of mutations present.
Over 150 years ago, Charles Darwin described how different species evolve through the process of natural selection. Cancers also develop by natural selection, acting on the mutations that accumulate in the cells of our bodies over time. In this study, scientists applied an evolutionary perspective to quantifying natural selection in 7,664 tumours across 29 different cancers.
One of the striking findings of the study was that mutations are usually well-tolerated by cells in the body. This was surprising because mutations that individuals inherit from their parents are often poorly tolerated, and are generally lost from the human species over time. In the body’s cells, however, as a cancer develops, nearly all mutations persist without impacting on the survival of the cell.
The team also catalogued the main cancer genes responsible for 29 different cancer types. Researchers discovered several new cancer genes and determined how complete the current lists of cancer genes are.
“We have addressed a long-standing question in cancer research that has been debated since the 1950s: how many mutations are needed for a normal cell to turn into a cancer cell? The answer is – a small handful. For example, about four mutations per patient on average drive liver cancers, whereas colorectal cancers typically require 10 or so driver mutations.”
Dr Peter Campbell, lead author on the study, from the Wellcome Trust Sanger Institute
“In the study, we revealed that around half of these key mutations driving cancer occur in genes that are not yet identified as cancer genes. There is already much insight into the most important genes involved in cancer; but there are many more genes yet to be discovered. We will need to bring together even larger numbers of cancers studied by DNA sequencing, into the tens of thousands, to find these elusive genes.”

Sanger Institute
www.sanger.ac.uk/news/view/1-10-mutations-are-needed-drive-cancer-scientists-find

Health scientists at the University of Leicester and University of Nottingham have heralded the discovery of a gene associated with lung fibrosis as ‘a potential new avenue of treatment for further research into this terrible disease.’
Idiopathic Pulmonary Fibrosis (IPF) is a debilitating lung disease, affecting ~6,000 new people each year, where scarring (fibrosis) of the lungs makes it difficult to breathe.
IPF, on average, results in death 3 years after diagnosis. There is no cure for IPF, and currently available drugs can only slow the disease down, and do not stop, or reverse, it. Furthermore, some patients may suffer unpleasant side-effects. A better understanding of the disease is needed to develop even more effective treatments.
Researchers Professor Louise Wain from the University of Leicester and Professor Gisli Jenkins from the University of Nottingham were lead authors of the study.  They analysed the DNA from over 2700 people with IPF and 8500 people without IPF from around the world and found that people with IPF are more likely to have changes in a gene called AKAP13.
The researchers were also able to show that these DNA changes affect how much AKAP13 protein is produced by the gene in the lungs.  Researchers know from other studies, that AKAP13 is part of a biological pathway that promotes fibrosis (or scarring) and importantly that this biological pathway can be targeted with drugs. Taken together, the findings suggest targeting this pathway with drugs in people with IPF might lead to new treatments. To confirm this, the research team now need to undertake more detailed studies into the role of AKAP13 in people with IPF.
The work was led by researchers at Leicester and Nottingham and brought together collaborators from around the world to form the largest combined analysis of people with IPF undertaken to date.

Leicester University
www2.le.ac.uk/offices/press/press-releases/2017/october/leicester-and-nottingham-scientists-discover-new-gene-associated-with-debilitating-lung-disease

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

A new five-year study of nearly 1,600 patients finds that genetic testing can help determine the safest dose of the blood thinner warfarin, with fewer side effects, in patients undergoing joint replacement surgery.
Considering a patient’s genetic makeup when prescribing warfarin—a blood thinner commonly prescribed to prevent life-threatening blood clots—can mean fewer adverse side effects like haemorrhage, researchers found.
Warfarin is a commonly prescribed, very effective anticlotting medicine — but it’s often associated with adverse complications and each patient requires a different dosage to achieve the desired treatment effect.
That unique dosing is based in part on an individual’s genetics, and great interest exists in understanding whether an individual’s genetics can guide how to best prescribe warfarin to reach the optimal therapeutic range.
Now, researchers from Intermountain Medical Center, along with four other research centers, including Washington University School of Medicine in St. Louis, which led the national study, have shown that outcomes greatly improve for older patients who undergo elective hip or knee replacement when the dose of warfarin is based on how a patient’s liver metabolizes the blood thinner, which can be discovered using a blood test.
Researchers say study findings from the GIFT study (Genetics Informatics Trial of Warfarin to Prevent Deep Venous Thrombosis) are significant. Compared to patients who received a standard dose, patients who received genetically-dosed warfarin had a 27 percent reduction in complications.
Specifically, their major bleeding was reduced by 75 percent, the incidence of excessive international normalized ratios was reduced by about 30 percent, and blood clots occurred 15 percent less often. No patients died during the study.
The findings from the GIFT study are published and could be used immediately. The Food and Drug Administration has since 2007 included language in its warfarin packaging that encourages the use of genetic guidance, if it’s available.
“Differences can be identified by looking at a patient’s genetic makeup, and specifically at the genes that are responsible for the liver’s metabolism of the drug,” said Scott Woller, MD, co-director of the Thrombosis Program at Intermountain Medical Center and principal investigator for Intermountain Healthcare.

Intermountain Healthcare
intermountainhealthcare.org/news/2017/10/genetic-testing-can-help-determine-safest-dose-of-warfarin-for-joint-surgery-patients/

What role do genes play in egg, milk, and nut allergies? A study, led by the Max Delbrück Center for Molecular Medicine (MDC) and Charité – Universitätsmedizin Berlin, has found five genetic risk loci that point to the importance of skin and mucous membrane barriers and the immune system in the development of food allergies.
An estimated five to eight percent of all children suffer from food allergies. They usually appear in the first years of life and manifest themselves in the form of itchy rashes and facial swellings, which occur shortly after food ingestion. Food allergies can, however, also cause severe allergic reactions involving breathing difficulties, vomiting, or diarrhea, and are the most frequent triggers of anaphylaxis in children. Anaphylaxis is the most extreme form of an immediate allergic reaction and can be life threatening.
In Germany, chicken eggs, cow’s milk, and peanuts are the most common causes of allergic food reactions in children. Unlike allergies to cow’s milk and chicken eggs, which often disappear after a few years, children generally do not outgrow allergies to peanuts. Peanut allergy sufferers must follow a strict diet for their entire lives and carry emergency medication with them at all times.
The causes of food allergies involve a complex interplay of genetics and environment. “Studies of twins suggest that about 80 percent of the risk for food allergies is heritable, but little is known so far about these genetic risk factors,” says Prof. Young-Ae Lee, a researcher at the MDC and head of the Charité‘s outpatient pediatric allergy clinic.
A genome-wide association study examined some 1,500 children in Germany and the United States who suffer from food allergies. The research looked at more than five million genetic variations, called single nucleotide polymorphisms or SNPs (pronounced “snips”), in each participant in the study and compared the frequency of these SNPs with that of the control subjects. The study involved researchers from Berlin, Frankfurt, Greifswald, Hanover, Wangen, and Chicago. It is remarkable not only for its size but also for its reliable diagnostic methodology.
Unlike other studies, the researchers used an oral food challenge test to confirm the allergy diagnosis. This is a complex procedure in which patients ingest small amounts of the suspected allergen in the hospital under emergency conditions to determine if they respond allergically to it. “We know from clinical practice that as many as 80 percent of presumed food allergies are not actually allergies. These food sensitivities are frequently due to food intolerance rather than an allergic response,” says Prof. Lee.
This study discovered a total of five genetic risk loci for food allergies. Four of them show a strong correlation with known loci for not only atopic dermatitis and asthma, but also for other chronic inflammatory diseases like Crohn’s disease and psoriasis as well as autoimmune disorders.

New risk locus associated with all children’s food allergies
The so-called SERPINB gene cluster on chromosome 18 was identified as a specific genetic risk locus for food allergies. It involves ten members of the serine protease inhibitor (serpin) superfamily. The genes in this cluster are expressed primarily in the skin and in the mucous membrane of the oesophagus. The researchers thus suspect that they play a major role in ensuring the integrity of the epithelial barrier function. Another important finding of the study is that four of the five identified risk loci are associated with all food allergies. The human leukocyte antigen (HLA) region, which is specific to peanut allergy cases, appears to be the only exception.
The study provides a basis for the development of better diagnostic tests for food allergies and for further investigation into their causative mechanisms and possible treatment strategies. Parents should not make decisions about avoiding specific foods on their own, but should instead seek out a specialist if their child appears to have a food allergy.
Max Delbrück Center for Molecular Medicine (MDC)
insights.mdc-berlin.de/en/2017/10/study-provides-clarity-genetic-causes-childrens-food-allergies/