This month in Breast Cancer Research and Treatment, Khalil and his colleagues at Case Western Reserve University proved the power of persistence; from a pool of more than 30,000 possibilities, they found 38 genes and molecules that most likely trigger HER2+ cancer cells to spread.

By narrowing what was once an overwhelming range of potential culprits to a relatively manageable number, Khalil and his team dramatically increased the chances of identifying successful treatment approaches to this particularly pernicious form of breast cancer. The HER2+ subtype accounts for approximately 20 to 30 percent of early-stage breast cancer diagnoses, which are estimated to be more than 200,000 new breast cancer diagnoses each year in this country, leading to approximately 40,000 deaths annually. Several cancer chemotherapy drugs do work well at early stages of the disease — destroying 95 to 98 percent of the cancer cells in HER2+ tumors.

“Eventually though, many of these patients develop resistance to the drugs, and the 2 to 5 percent of the remaining breast cancer cells begin to grow and cause tumours again,” said Khalil, assistant professor in the Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine. “We want to develop a strategy to target the genes responsible for enhancing HER2 oncogenic activity and increase the chances of eliminating the tumour entirely at the early stages of the disease.”

In this study, Khalil, also a member of the Case Comprehensive Cancer Center, and colleagues chose an innovative approach that went beyond merely comparing gene expression in normal and in HER2+ cancer-affected breast tissue. Other scientists tried such a straightforward comparison but found themselves swamped by hundreds and even thousands of gene expression differences. Instead, Khalil designed a study where the offending genes would stand out. He and colleagues compared gene expression differences among HER2+ breast cancer tissues of uncontrolled HER2 activity with those having greatly diminished HER2 activity. Ultimately their work revealed 35 genes and three long intervening noncoding RNA (lincRNAs) molecules were most associated with the active HER2+ cells.

To obtain special breast cancer tissues in HER2-active and HER2-diminished states, Khalil collaborated with oncologist Lyndsay Harris, MD, who had served as correlative science principal investigator for a clinical trial of the drug trastuzumab, which involved Brown University, Yale University and Cedars-Sinai. Harris, now professor of medicine, CWRU School of Medicine, and director of the Breast Cancer Program, University Hospitals Seidman Cancer Center, obtained the preserved HER2+ breast cancer tissues for Khalil’s study from two intervals — before and then during the trastuzumab clinical trial. The drug works by disrupting HER2 activity, which in turn prevents this recalcitrant protein from launching uncontrolled cell growth.

From this collection of HER2+ breast cancer tissue, Khalil and colleagues got to work on determining which genes and other genetic components stood out. First, they applied RNA sequencing and then compared the sequences in tissues collected before trastuzumab curtailed HER2 activity with those collected later when HER2 activity declined sharply. Next, investigators grew the HER2+ breast cancer tissue cells in the laboratory and examined genes prominent in the cell culture (in vitro) model of the disease. Forty-four genes stood out during this portion of the investigation. Finally, Khalil and colleagues obtained publically available RNA-sequence data sets comparing HER2+ breast cancer with matched normal tissue and found that 35 of those 44 genes passed through this third filter.

“In our investigation, we essentially went from thousands of genes and narrowed it down to 35 genes,” Khalil said. “A lot of those genes made sense in terms of carcinogenesis. When they become upregulated because of increased HER2 activity, many of these genes are involved in increased transcription and increased cell proliferation, which are hallmarks of cancer cells.”

The investigators applied the same comparative analysis — RNA sequencing, growing cells in culture and inhibiting HER2 protein — to observe the role of lincRNAs. Khalil and colleagues only discovered this special group of RNA genes in humans in 2009, and scientists now are slowly unraveling the mystery of lincRNAs. For this study, investigators uncovered three standout lincRNAs that are modulated in activity when subjected to increased HER2 activity.

“For the first time, we have shown that these lincRNAs can also contribute to this HER2+ breast cancers,” Khalil said. “So we added another layer of complexity to the disease with lincRNAs. However, these lincRNAs could potentially open the door for RNA-based therapeutics in HER2+ breast cancer, a therapeutic strategy that has great potential but has not been fully tested in the clinic yet.” Case Comprehensive Cancer Center

With more than 200 million global users of statins, these medications are the very definition of ‘blockbuster.’ By stopping a substance the body uses to make cholesterol, statins can help stave off heart attacks and strokes — the top two causes of death worldwide. But in a significant percent of patients — up to 30 percent by some reports — statins can also eat away muscle tissue, causing weakness, muscle pain and in rare cases, potentially deadly kidney and liver damage.

And the problem could grow larger. Under the most recent heart disease prevention guidelines issued by the American Heart Association and American College of Cardiology, the potential number of candidates for statin therapy in the US jumped from 43 million to 56 million.

‘As doctors follow the current guidelines, we expect that nearly half of Americans ages 40 to 75 and most men over 60 may be prescribed a statin,’ said Joseph Kitzmiller, MD, PhD an associate director of the Center for Pharmacogenomics at The Ohio State University Wexner Medical Center. ‘We currently have a limited ability to predict clinical outcomes and potential side effects for any of those individual patients — many of whom will be on a statin for the rest of their lives. In general and for most patients, statins are largely beneficial. Unfortunately, not all patients benefit and some are harmed by statins.’

Kitzmiller, who has devoted his career to untangling the many ways that genetics influence how patients respond to their medications, thinks that statin dosage recommendations need also to consider common genetic variants the affect drug exposure.

‘The muscle toxicity associated with statins is largely about exposure, and exposure is significantly affected by a patient’s genetics,’ Kitzmiller explained. ‘If you give two people 20 milligrams of a statin, and one of them has a polymorphism, or gene variation that changes the way the body processes that statin, it may be as though you’ve given them two or three times as much medication.’

Kitzmiller is team, which is primarily studying simvastatin, have already identified a gene variation that decreases statin metabolism — making people more susceptible to adverse events.

‘For our patients carrying this genetic variant, simvastatin doesn’t break down as much in the liver. This means more of the drug is in their bloodstream, increasing their exposure and potential for muscle toxicity,’ said Kitzmiller. ‘For these people, a lower dose of simvastatin could potentially deliver the same benefits while causing fewer side effects.’

Kitzmiller also found that a patient’s likelihood for carrying a genetic polymorphism depends on their race. Recent work by his research team suggests that the effect size also varies significantly across racial groups. One genetic variant resulted in a nearly 3-fold increase in simvastatin concentrations for African-Americans but only a modest increase for Caucasians.

‘That can have incredible clinical significance, especially since African-Americans often suffer higher rates of drug adverse outcomes and higher disease mortality rates despite receiving similar or even identical treatment,’ said Kitzmiller, who is also an associate professor in the Department of Pharmacology at Ohio State’s College of Medicine.

His team has also recently developed a blood test that can simultaneously measure the quantities of three different types of statins and their metabolites, which indicates how much of a medication the body has metabolized. This type of tool is essential to help scientists establish connections between genetic profiles and the variation in how statins are absorbed, transported, distributed and excreted. Kitzmiller is in the process of developing a multigene test that could tell clinicians if their patients have any of the genetic culprits that are likely to lead to muscle problems or other side effects from statins. He hopes to bring this test to clinical trials later this year. Science Daily

A distinct pattern in the changing length of blood telomeres, the protective end caps on our DNA strands, can predict cancer many years before actual diagnosis, according to a new study from Northwestern Medicine in collaboration with Harvard University.

The pattern – a rapid shortening followed by a stabilization three or four years before cancer is diagnosed – could ultimately yield a new biomarker to predict cancer development with a blood test. This is the first reported trajectory of telomere changes over the years in people developing cancer.

Scientists have been trying to understand how blood cell telomeres, considered a marker of biological age, are affected in people who are developing cancer. But the results have been inconsistent: some studies find they are shorter, some longer and some show no correlation at all.

The Northwestern and Harvard study shows why previous results were confusing.

In the new study, scientists took multiple measurements of telomeres over a 13-year period in 792 persons, 135 of whom were eventually diagnosed with different types of cancer, including prostate, skin, lung, leukaemia and others.

Initially, scientists discovered telomeres aged much faster (indicated by a more rapid loss of length) in individuals who were developing but not yet diagnosed with cancer. Telomeres in persons developing cancer looked as much as 15 years chronologically older than those of people who were not developing the disease.

But then scientists found the accelerated aging process stopped three to four years before the cancer diagnosis.  

“Understanding this pattern of telomere growth may mean it can be a predictive biomarker for cancer,” said Lifang Hou, MD, PhD, the lead study author and associate professor in Preventive Medicine-Cancer Epidemiology and Prevention. “Because we saw a strong relationship in the pattern across a wide variety of cancers, with the right testing these procedures could be used to eventually diagnose a wide variety of cancers.” Hou also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The Northwestern and Harvard study is believed to be the first to look at telomere length at more than one time point before diagnosis. That’s significant because cancer treatment can shorten telomeres. Post treatment, it’s uncertain whether their length has been affected by the cancer or the treatment.

“This likely explains why the previous studies have been so inconsistent,” Dr. Hou said. “We saw the inflection point at which rapid telomere shortening stabilizes. We found cancer has hijacked the telomere shortening in order to flourish in the body.”

Telomeres shorten every time a cell divides. The older you are, the more times each cell in your body has divided and the shorter your telomeres. Because cancer cells divide and grow rapidly, scientists would expect the cell would get so short it would self-destruct. But that’s not what happens, scientists discovered. Somehow, cancer finds a way to halt that process. Feinberg School of Medicine

Researchers at The University of Texas Health Science Center at Houston (UTHealth) are helping to make precision medicine a reality by sequencing entire exomes of people to assess chronic disease risk and drug efficacy.

For years, scientists have been using a method called “knockout mice,” which allows them to study gene functions by inactivating a gene in mice and then observing how it affects the mice. Now, UTHealth researchers are using new methods to study naturally occurring “knockout humans.”

Rather than genetically engineer human gene mutations in the lab, UTHealth researchers scanned 8,554 exomes, the protein-encoding portion of the genome, of African Americans and European Americans in the United States for naturally occurring mutations that inactivate a certain gene. A typical human exome has dozens of these loss-of-function gene variants.

“Years ago, we found a mutation that knocks out a gene that lowers your cholesterol. That turned into drugs that can help with cholesterol. That was with one gene. We are now sequencing lots of people and looking at where people are losing function from every gene in their body,” said Eric Boerwinkle, Ph.D., senior author, professor and chair of the Human Genetics Center and the Department of Epidemiology, Human Genetics and Environmental Sciences at UTHealth School of Public Health.

The study participants were part of Atherosclerosis Risk in Communities (ARIC), a study conducted by the National Heart, Lung and Blood Institute (NHLBI). The group was measured for 20 phenotypes related to chronic diseases, such as serum magnesium levels, triglyceride levels, blood pressure and cholesterol.

By observing how certain mutations affect health, researchers were able to identify eight new relationships between genes and diseases and confirm the already established relationship between gene variant PCSK9 and lower blood cholesterol and lower heart disease risk.

A heterozygous form of gene TXNDC5 was found to be related to Type 1 Diabetes progression and elevated fasting glucose levels. A recessive form of C1QTNF8 was related to elevated serum magnesium levels and participants who had a mutation of SEPT10 had significantly reduced lung function.

“Loss-of-function variation in certain genes, such as TXNDC5, may predispose individuals to develop disease. More research is needed to determine the exact mechanisms of these newly discovered relationships,” said Boerwinkle, who is also the Kozmetsky Family Chair in Human Genetics at UTHealth. University of Texas at Houston Health Science Center

Huntington’s disease is caused by a mutation in the Huntington’s disease gene, but it has long been a mystery why some people with the exact same mutation get the disease more severely and earlier than others. A closer look at the DNA around the Huntington’s disease (HD) gene offers researchers a new understanding of how the gene is controlled and how this affects the disease. These findings set the stage for new treatments to delay or prevent the onset of this devastating brain disease.

Huntington’s disease is a genetic disorder that gets passed down in families, but symptoms generally don’t appear until later in life. It affects the brain and gradually worsens, causing problems with coordination and movement, mental decline and psychiatric issues. While every person has two copies of each gene – one on each chromosome – a single mutation in one copy of the HD gene means the person will suffer from the disease.

The HD gene is controlled by surrounding regions of DNA that function to turn the gene on and off. Dr. Blair Leavitt, professor in UBC’s Department of Medical Genetics, and his colleagues took a closer look at this part of the genetic code. They identified critical regions where proteins, called transcription factors, can bind to the DNA and control the function of the HD gene. Changes in these DNA regions can play both good and bad roles in the disease. In some cases, the DNA changes increase the severity of the disease and speed up the onset and in other cases it protects the person by delaying the onset of the disease.

“The gene for Huntington’s was discovered over twenty years ago but there is very little known about how the expression of this important gene is controlled,” said Leavitt, who is also a scientist with the Centre for Molecular Medicine and Therapeutics. “This study helps us understand how small genetic differences in the DNA surrounding the HD gene can both delay and accelerate the disease.”

Researchers found that when the DNA change is found on a normal chromosome with no HD mutation, it turns off the expression of the good gene and allows the mutant gene on the other chromosome to predominate, speeding up the onset of the disease. If the DNA change is found on a chromosome with the HD mutation, it turns off the bad gene and offers individuals some protection from the disease.

According to Leavitt, these findings provide critical evidence to support the development of new drugs that decrease the expression of the mutant HD gene, an approach called gene silencing. Leavitt is already involved in the testing of one gene silencing treatment that shows great promise, and will begin the first human trial of this therapy for HD later this year. University of British Columbia