As the result of a six-year long research process, Fredrick R. Schumacher, PhD, a cancer epidemiology researcher at Case Western Reserve University School of Medicine, and an international team of more than 100 colleagues have identified 63 new genetic variations that could indicate higher risk of prostate cancer in men of European descent. The findings contain significant implications for which men may need to be regularly screened because of higher genetic risk of prostate cancer. The new findings also represent the largest increase in genetic markers for prostate cancer since they were first identified in 2006.
The changes, known as genetic markers or SNPs ("snips"), occur when a single base in the DNA differs from the usual base at that position. There are four types of bases: adenine (A), thymine (T), guanine (G), and cytosine (C). The order of these bases determines DNA’s instructions, or genetic code. They can serve as a flag to physicians that a person may be at higher risk for a certain disease. Previously, about 100 SNPs were associated with increased risk of prostate cancer. There are three billion base pairs in the human genome; of these, 163 have now been associated with prostate cancer.
One in seven men will be diagnosed with prostate cancer during their lifetimes.
“Our findings will allow us to identify which men should have early and regular PSA screenings and these findings may eventually inform treatment decisions,” said Schumacher. PSA is a blood test used to screen for prostate cancer. It measures the amount of prostate-specific antigen (PSA) in the blood. PSA is a protein produced by both cancerous and noncancerous tissue in the prostate.
Adding the 63 new SNPs to the 100 that are already known allows for the creation of a genetic risk score for prostate cancer. In the new study, the researchers found that men in the top one percent of the genetic risk score had a six-fold risk-increase of prostate cancer compared to men with an average genetic risk score. Those who had the fewest number of these SNPs, or a low genetic risk score, had the lowest likelihood of having prostate cancer.
In a meta-analysis that combined both previous and new research data, Schumacher, with colleagues from Europe and Australia, examined DNA sequences of about 80,000 men with prostate cancer and about 60,000 men who didn’t have the disease. They found that men with cancer had a higher frequency of 63 different SNPs (also known as single nucleotide polymorphisms) that men without the disease did not have. Additionally, the more of these SNPs that a man has, the more likely he is to develop prostate cancer.
The researchers estimate that there are about 500-1,000 genetic variants possibly linked to prostate cancer, not all of which have yet been identified. “We probably only need to know ten percent to twenty percent of these to provide relevant screening guidelines,” continued Schumacher, who is an associate professor in the Department of Population and Quantitative Health Sciences at Case Western Reserve School of Medicine.
Currently, researchers don’t know which of the SNPs are the most predictive of increased prostate cancer risk. Schumacher and a number of colleagues are working to rank those most likely to be linked with prostate cancer, especially with aggressive forms of the disease that require surgery, as opposed to slowly developing versions that call for “watchful waiting” and monitoring.
The research lays a foundation for determining who and how often men should undergo PSA tests. “In the future, your genetic risk score may be highly indicative of your prostate cancer risk, which will determine the intensity of PSA screening,” said Schumacher. “We will be working to determine that precise genetic risk score range that would trigger testing. Additionally, if you have a low score, you may need screening less frequently such as every 2-5 years.” A further implication of the findings of the new study is the possibility of precise treatments that do not involve surgery. “Someday it may be feasible to target treatments based on a patient’s prostate cancer genetic risk score,” said Schumacher.

Cape Western Reserve University School of Medicine
casemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=1297&news_category=8

Mutations in the gene ANT1 may confer a risk for bipolar disorder through a complex interplay between serotonin and mitochondrial signalling in the brain. These two pathways have been separately implicated in bipolar disorder, but the link between levels of the neurotransmitter serotonin and mitochondrial dysfunction had not been established. Researchers at the RIKEN Center for Brain Science (CBS) in Japan now report that mitochondrial dysfunction affects the activity of serotonergic neurons in mice with mutations of ANT1.
Mitochondria are the vital organelles that deliver energy to all cells and mitochondrial damage has been found, for example, in brain imaging of bipolar patients and in post-mortem brains. Roughly 20% of patients with mitochondrial disease also have bipolar disorder, a major psychiatric disease characterized by manic and depressive episodes. Altered serotonin functioning, on the other hand, seems to be involved in bipolar disorder because drugs that target serotonin levels can effectively treat the condition. "Our study suggests that mitochondrial dysfunction can alter activity of serotonergic neurons in bipolar disorder, and this is the first time these two lines of evidence have been linked," says Tadafumi Kato, research group leader at CBS.
The study started by identifying ANT1 mutations in patients with bipolar disorder. Kato and colleagues then looked at mice lacking the ANT1 gene in the brain only. Compared with non-mutant mice, the mitochondria in these knockout mice could not retain calcium and had leakier pores. The ANT1-mutant mice also showed lower impulsivity in behaviour tests, and consistent with this, their brains showed elevated serotonin turnover. This hyper-serotonergic state is likely a result of a cascade of changes that starts with the loss of the ANT1 gene and the resulting dysfunctional mitochondria. Enhanced serotonergic activity may then further impair mitochondria in a vicious cycle.
Serotonergic neurons were found to deteriorate in a brain area called the dorsal raphe, which is a region also affected in Parkinson’s disease–another condition that may have its roots in mitochondrial dysfunction. The ANT1 mutation does not cause bipolar disorder, says Kato, but is associated with elevated risk. The implication of this research is that emerging therapies for the underlying mitochondrial dysfunction could one day treat bipolar disorder more successfully than today’s variable serotonin-targeting drugs.

EurekAlert
www.eurekalert.org/pub_releases/2018-06/r-mlb060818.php

A new study from BUSM and BUSPH identifies a pattern of inflammation associated with cardio-metabolic risks among participants in the Black Women’s Health Study, as well as two independent groups of vulnerable women. These findings could help underserved patients benefit from precision medicine and personalized profiles of disease risk.
According to the researchers, body mass index alone is an imperfect measure of obesity-associated disease risks, such as for Type 2 diabetes, because there are some individuals with chronic obesity who are apparently protected from cardio-metabolic complications and lean individuals with high cardiovascular and diabetes risks. Abnormal, unresolved inflammation in blood and adipose (fat) tissue, rather than obesity per se, is thought to be important for development of disease. Certain biomarkers show promise in predicting obesity-associated diabetes risk; however, the clinical utility of single biomarkers is limited for complex disease phenotypes such as these.
The research team took a data-driven, systems biology approach to discover six cytokine signatures associated with Type 2 diabetes risk in a vulnerable population: African American women with obesity and varying degrees of metabolic health. These six distinct signatures are patterns of sixteen cytokines/chemokines that promote or reduce inflammation.
Analyses of plasma samples from participants in the Black Women’s Health Study, formed the basis for the discovery dataset, which was then validated in two separate groups, African American women volunteers with obesity who had donated plasma to the Komen Tissue Bank, and African American women with obesity who were breast reduction surgical patients at a safety net hospital in Greater Boston. The patterns or signatures in the validation cohorts closely resembled the distributions in the discovery cohort.
“These findings are highly relevant to an understudied and underserved population that experiences elevated risks for co-morbidities of obesity. The overall impact of this report is high because of the potential utility of the new signatures just discovered and validated, which could assist clinical decision making with more personalized information,” explained corresponding author Gerald V. Denis, PhD, Associate Professor of Pharmacology and Medicine at BUSM.

Boston University School of Medicine
www.bumc.bu.edu/busm/2018/05/08/new-study-provides-insight-into-blood-signatures-of-inflammation/

An international team of researchers from the Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), the European Molecular Biology Laboratory (EMBL) and the German Cancer Consortium (DKTK) together with colleagues at the St. Jude Children’s Research Hospital in Memphis and the Hospital for Sick Children in Toronto has summarized hereditary gene defects which can trigger the development of certain malignant brain tumours (medulloblastoma). From their findings, the team has derived recommendations for routine genetic screening in medulloblastoma patients.
Medulloblastoma is a rare malignant tumour of the cerebellum and occurs predominantly in children. Scientists believe that in many cases hereditary gene defects trigger the development of this malignant disease. However, there are no standards for routine genetic screening of patients, nor are there guidelines and a corresponding nationwide infrastructure for genetic counselling of affected families.
Scientists have now been able to characterize medulloblastoma more accurately and to derive recommendations for genetic testing based on analysis of 1022 patients with medulloblastoma. "We analysed genes that have been previously implicated in predisposition to any type of paediatric and adult cancer", says Sebastian Waszak from the EMBL Heidelberg who is one of the study’s lead authors. It turned out that six genes were also frequently affected by genetic alterations in patients with medulloblastoma.
Considering the six significantly enriched genes, about five percent of patients had an increased risk of cancer. Taking into account all cancer risk genes, about eleven percent of the patients had an increased cancer risk. Looking at a particular tumour subgroup, the so called "SHH-activated medulloblastoma", even 20 percent were identified to harbour a genetic predisposition to cancer.
These predisposing mutations occur in every single cell of the patient and can be also passed on to offspring. "Mutations of this kind often indicate a familial predisposition to cancer and therefore place special demands on the treatment of patients and the counselling of families", said Paul Northcott from the St. Jude Children’s Research Hospital in Memphis, who shares the lead authorship. The results are particularly important because both, materials from previous studies and patient data from four current or recently completed clinical trials were included in the analysis.
Based on these findings and other tumour features, the scientists developed criteria for routine genetic screening. "Hereditary disease factors usually have a significant impact on the whole family of the patient, We want to make genetic analysis available as a standard of care for patients with specific medulloblastoma", says Stefan Pfister, KiTZ director, scientist at the German Cancer Research Center, and senior physician at the Heidelberg University Hospital. To make this possible, Stefan Pfister and Christian Kratz from the Hannover Medical School have created a registry for patients with a hereditary cancer predisposition and a website that contains information for patients, families, and physicians (www.krebs-praedisposition.de).

The German Cancer Research Center (DKFZ)
www.dkfz.de/en/presse/pressemitteilungen/2018/dkfz-pm-18-30-Genetic-analysis-for-certain-childhood-brain-tumors-soon-a-standard-of-care.php

Rheumatoid arthritis (RA) is an autoimmune disorder that occurs when the immune system mistakenly attacks the body’s tissues. Unlike the wear-and-tear damage of osteoarthritis, rheumatoid arthritis affects the lining of the joints, causing painful swelling that can eventually result in bone erosion and joint deformity.
Most RA patients are positive for anticitrullinated protein antibodies (ACPA), and these antibodies are highly specific for RA diagnosis. ACPA recognizes various citrullinated proteins, such as fibrinogen, vimentin and glucose- 6-phosphate isomerase. Citrullinated proteins are proteins that have the amino acid arginine converted into the citrulline, which is not one of the 20 standard amino acids encoded by DNA in the genetic code. Autoreactivity to citrullinated protein may increase susceptibility to RA.
While many candidate citrullinated antigens have been identified in RA joints, the involvement of citrullinated proteins in blood serum remains mostly uninvestigated. To that end, a team of University of Tsukuba-centred researchers set out to explore the expression and commonality of citrullinated proteins in peptide glucose-6-phosphate isomerase-induced arthritis (pGIA) and patients with RA, and went one step further to investigate its correlation with RA disease activity.
"We examined serum citrullinated proteins from pGIA by western blotting, and the sequence was identified by mass spectrometry. With the same methods, serum citrullinated proteins were analysed in patients with RA, primary Sjögren’s syndrome, systemic lupus erythematosus, and osteoarthritis as well as in healthy subjects," study corresponding author Isao Matsumoto explains. "In patients with RA, the relationship between the expression of the identified protein inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) and clinical features was also evaluated, and the levels of citrullinated ITIH4 were compared before and after biological treatment."
The researchers found that citrullinated ITIH4 was highly specific to patients with RA, compared with patients with other autoimmune and arthritic diseases or in healthy subjects, indicating a potential role for citrullinated ITIH4 in RA pathogenesis. Notably, its levels were decreased in correlation with the reduction of disease activity score after effective treatment in patients with RA. Moreover, antibody response to citrullinated epitope in ITIH4 was specifically observed in patients with RA.
"Our results suggest that citrullinated ITIH4 might be a novel biomarker to distinguish RA from other rheumatic diseases and for assessing disease activity in patients with RA," Matsumoto says. "To our knowledge, this is the first report of its kind in the literature."

MedicalXpressmedicalxpress.com/news/2018-04-discovery-biomarker-remarkable-specificity-rheumatoid.html