Van Andel Research Institute (VARI) announced that the work of its scientists is featured in 27 papers focused on the output of The Cancer Genome Atlas (TCGA).
The findings are the result of a global scientific collaboration and mark the culmination of TCGA, a multi-institutional, joint effort between the National Cancer Institute (NCI) and the National Human Genome Research Institute (NHGRI) to develop a comprehensive scientific resource for better categorizing cancer. The more than decade-long initiative is the most in-depth undertaking of its kind, spanning 10,000 tumours across 33 cancer types.
“TCGA’s findings have greatly deepened our molecular understanding of the major cancer types,” said Peter W. Laird, Ph.D., a professor at VARI who led the DNA methylation analysis for TCGA Research Network and who is senior author on two of today’s papers. “It is our hope that these publications will serve as a guide for scientists who plan to harness TCGA’s robust data to develop new, more personalized methods of patient care.”
This research, which represents the project’s capstone, joins dozens of other papers that have been published since TCGA’s inception in 2005. Collectively, they provide a highly detailed description of molecular changes occurring in all major human cancers. The use of this molecular atlas is rapidly expanding, with more than 1,000 publications citing TCGA data in 2017 alone.
TCGA data may be accessed through the National Cancer Institute’s Genomic Data Commons Data Portal (portal.gdc.cancer.gov).
Along with Laird, VARI Assistant Professor Hui Shen, Ph.D., contributed to many of today’s papers, summaries of which may be found below. Shen also is one of six experts who authored retrospectives on TCGA’s legacy, which also were published.
A full list of papers may be found at www.cell.com/consortium/pancanceratlas.
Van Andel Institutewww.vai.org/news-release-4-5-2018/

Rates of inherited mutations in genes other than BRCA1/2 are twice as high in breast cancer patients who have had a second primary cancer – including, in some cases, different types of breast cancer – compared to patients who have only had a single breast cancer. But the rates of these mutations were still found to be low overall, meaning it’s difficult to assess whether and how these individual mutations may drive the development of cancer. The study from the Basser Center for BRCA in the Abramson Cancer Center of the University of Pennsylvania also investigated the use of polygenic risk scores – which have recently been added to some commercial clinical multiplex genetic testing panels. Kara N. Maxwell, MD, PhD, an instructor of Hematology-Oncology and the study’s lead author, presented the findings at the 2018 American Society of Clinical Oncology Annual.
Genetic testing can help identify patients have a genetic predisposition that puts them at risk for developing cancer. Recently, new therapies called PARP inhibitors have been FDA approved to specifically target cancers caused by certain mutations – such as BRCA1/2, which carry a lifetime breast cancer risk of as much as 85 percent and 50 percent for ovarian cancer, as well as higher risks of pancreatic, prostate and other cancers.
“We need to gain a better understanding of why patients who have multiple cancers may be susceptible to them, and that work needs to go beyond the common genes we’re already been looking at,” Maxwell said.
The team – led by Susan M. Domchek, MD, executive director of the Basser Center for BRCA, and Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center, specifically looked at patients who did not have a BRCA1/2 mutation and tested them for a panel of 15 different genetic mutations. They evaluated 891 patients who had a second primary cancer – breast or otherwise – after initial breast cancer and compared them to 1,928 who only had a single breast cancer. About eight percent of patients who had second primary cancers had mutations, compared to just four percent of patients from the single cancer cohort. The current threshold for whether or not genetic testing is recommended is five percent.
“Our data show that patients who have had multiple primary cancers should undergo genetic testing, and likely this holds true for a number of other types of second cancer,” Maxwell said. “However, the overall numbers are still low, which shows the level of uncertainty that still exists and highlights the need for further research.”
The research also evaluated polygenic risk scores, a somewhat controversial metric recently added to some commercial clinical multiplex genetic testing panels. Polygenic risk scores are determined by how many single nucleotide polymorphisms (SNPs) a person has. SNPs are common variants with smaller effect sizes, and if a patient has multiple of certain SNPs, they may be at a similar increased for cancer a as patients with a single rare mutation.
“Our study does not provide strong evidence of higher polygenic risk scores in patients with more than one breast cancer,” but many more patients will need to be studied to confirm this,” Maxwell said.

Penn Medicinewww.pennmedicine.org/news/news-releases/2018/june/beyond-brca-examining-links-between-breast-cancer-second-primary-cancer-inherited-genetic-mutations
 

Investigators at The Feinstein Institute for Medical Research discovered dozens of new genetic variations associated with a person’s general cognitive ability. The findings have the potential to help researchers develop more targeted treatment for cognitive and memory disorders.
“For the first time, we were able to use genetic information to point us towards specific drugs that might aid in cognitive disorders of the brain, including Alzheimer’s disease, schizophrenia and attention deficit hyperactivity disorder,” said Todd Lencz, PhD, senior author of the study and professor at the Feinstein Institute and the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell.  
In the largest peer-reviewed study of its kind, an international team of 65 scientists, led by Dr. Lencz, studied the genomes of more than 100,000 individuals who had their brain function measured by neuropsychological tests. These data were then combined with genomes from 300,000 people measured for the highest level of education achieved, which serves as an estimate for cognitive ability, or how the brain acquires knowledge.
While profiling cognitive ability, researchers also discovered a genetic overlap with longevity. They found when examining an individual’s family that a genetic predisposition towards higher cognitive ability was associated with longer lifespan. A new genetic overlap between cognitive ability and risk for autoimmune disease was also identified.
This study appears less than a year after Dr. Lencz and his colleagues published a similar, smaller study that was only able to identify a few key genes associated with cognitive ability.
“The field of genomics is growing by leaps and bounds,” Dr. Lencz said. “Because the number of genes we can discover is a direct function of the sample size available, further research with additional samples is likely to provide even more insight into how our genes play a role in cognitive ability.”
Feinstein Institute – Northwell Healthhttps://tinyurl.com/y8649b9o

Glaucoma, a disease that afflicts nearly 70 million people worldwide, is something of a mystery despite its prevalence. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness.
A new study from MIT and Massachusetts Eye and Ear has found that glaucoma may in fact be an autoimmune disorder. In a study of mice, the researchers showed that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore, these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body.
The discovery suggests that it could be possible to develop new treatments for glaucoma by blocking this autoimmune activity, the researchers say.
“This opens a new approach to prevent and treat glaucoma,” says Jianzhu Chen, an MIT professor of biology, a member of MIT’s Koch Institute for Integrative Cancer Research, and one of the senior authors of the study.
Dong Feng Chen, an associate professor of ophthalmology at Harvard Medical School and the Schepens Eye Research Institute of Massachusetts Eye and Ear, is also a senior author of the study. The paper’s lead authors are Massachusetts Eye and Ear researchers Huihui Chen, Kin-Sang Cho, and T.H. Khanh Vu.
One of the biggest risk factors for glaucoma is elevated pressure in the eye, which often occurs as people age and the ducts that allow fluid to drain from the eye become blocked. The disease often goes undetected at first; patients may not realize they have the disease until half of their retinal ganglion cells have been lost.
Most treatments focus on lowering pressure in the eye (also known as intraocular pressure). However, in many patients, the disease worsens even after intraocular pressure returns to normal. In studies in mice, Dong Feng Chen found the same effect.
“That led us to the thought that this pressure change must be triggering something progressive, and the first thing that came to mind is that it has to be an immune response,” she says.
To test that hypothesis, the researchers looked for immune cells in the retinas of these mice and found that indeed, T cells were there. This is unusual because T cells are normally blocked from entering the retina, by a tight layer of cells called the blood-retina barrier, to suppress inflammation of the eye. The researchers found that when intraocular pressure goes up, T cells are somehow able to get through this barrier and into the retina.
The Mass Eye and Ear team then enlisted Jianzhu Chen, an immunologist, to further investigate what role these T cells might be playing in glaucoma. The researchers generated high intraocular pressure in mice that lack T cells and found that while this pressure induced only a small amount of damage to the retina, the disease did not progress any further after eye pressure returned to normal.
Further studies revealed that the glaucoma-linked T cells target proteins called heat shock proteins, which help cells respond to stress or injury. Normally, T cells should not target proteins produced by the host, but the researchers suspected that these T cells had been previously exposed to bacterial heat shock proteins. Because heat shock proteins from different species are very similar, the resulting T cells can cross-react with mouse and human heat shock proteins.
To test this hypothesis, the team brought in James Fox, a professor in MIT’s Department of Biological Engineering and Division of Comparative Medicine, whose team maintains mice with no bacteria. The researchers found that when they tried to induce glaucoma in these germ-free mice, the mice did not develop the disease.
The researchers then turned to human patients with glaucoma and found that these patients had five times the normal level of T cells specific to heat shock proteins, suggesting that the same phenomenon may also contribute to the disease in humans. The researchers’ studies thus far suggest that the effect is not specific to a particular strain of bacteria; rather, exposure to a combination of bacteria can generate T cells that target heat shock proteins.
One question the researchers plan to study further is whether other components of the immune system may be involved in the autoimmune process that gives rise to glaucoma. They are also investigating the possibility that this phenomenon may underlie other neurodegenerative disorders, and looking for ways to treat such disorders by blocking the autoimmune response.
“What we learn from the eye can be applied to the brain diseases, and may eventually help develop new methods of treatment and diagnosis,” Dong Feng Chen says.

MITnews.mit.edu/2018/glaucoma-autoimmune-disease-0810

New research from BRC has found a way to predict rejection of a kidney transplant before it happens, by monitoring the immune system of transplant patients.
The researchers have found that a signature combination of seven immune genes in blood samples can predict rejection earlier than current techniques. Monitoring these markers in transplant patients with regular blood tests could help doctors intervene before any damage to the organ occurs, and improve outcomes for patients.
A renal transplant offers the best treatment for patients whose kidneys have failed, with around 3,000 carried out annually in the UK. Acute rejection occurs when the body’s immune system begins to attack the donated organ. This is a common complication in the first year after the transplant, affecting around 2 in 10 patients. It can affect the lifespan of the transplanted organ.
Currently, acute rejection can only be confirmed by taking a biopsy of the transplanted organ. While acute rejection can be treated, this can only be done when the organ is already affected and damage has already occurred.
Once the new technique is validated further, it has the potential to offer clinicians the use of a simple blood test to predict rejection. Being able to intervene before the event will help prevent damage to patients, and extend the life of the transplanted organ.
Dr Paramit Chowdhury, a consultant nephrologist at Guy’s and St Thomas’ and author on the paper said: “This advance could make a huge difference to our ability to monitor kidney transplant patients and treat rejection earlier. It may also save some patients from an unnecessary biopsy. It is a first step in getting a better insight into the status of a patient’s immune system, allowing better tailoring of the patient’s anti-rejection treatment.
“A big challenge at the moment is that even the best transplanted organ has a limited lifespan of up to 30 years. By being able to pick up signs of rejection early, we might increase the lifespan of the organ and help patients have a better quality of life, for longer.”
The team recruited 455 patients who received a kidney transplant at Guy’s Hospital and followed these patients over the first year of their transplant, collecting regular blood and urine samples. Using these samples and analysing the data over time, they developed a signature combination of seven genes that differentiated patients who developed rejection from those who did not.
They then tested for the signature via a blood test in a separate cohort of patients, and validated that it predicted transplant rejection.
The team also identified a six gene signature for a less common form of complication. BK-virus nephropathy can look clinically similar to acute rejection, but requires a very different therapy – reducing immunosuppression. Being able to distinguish between these complications would mean clinicians can ensure that patients receive the most appropriate treatment.
Dr Maria Hernandez Fuentes, visiting senior lecturer at King’s College London and author on the study, said: “Biomarkers are naturally occurring genes or proteins that appear in the blood, which can tell us what is happening in the body. This is vital in determining the best course of treatment for patients. We were able to monitor the genes that were being expressed in transplant patients and map how these reflected their clinical outcomes.
National Institute for Health Research
Biomedical Research Centre at Guy’shttps://tinyurl.com/y4z9k2c8