A deadly form of T cell lymphoma is caused by an unusually large number gene deletions, making it distinct among cancers, a new Yale School of Medicine study shows.

Researchers conducted a genomic analysis of normal and cancer cells from patients with cutaneous T-cell lymphoma, a cancer of T-cells of the immune system that normally reside in the skin.

Most cancers are driven by point mutations — or single DNA nucleotides that change the function of an encoded protein — rather than deletions that remove a segment of a chromosome. However, in this form of lymphoma, gene deletions that drive cancer pathogenesis outnumbered point mutations by more than 10 to 1.

“This cancer has a very distinctive biology,” said Jaehyuk Choi, assistant professor of dermatology at Yale and lead author of the paper.

Many of the deletions occurred in genes that have been known to play a role in driving the proliferation of T-cells and are potential targets for new therapies, said Choi, a researcher with the Yale Cancer Center.

It is unclear why this cancer has such a high ratio of gene deletions compared to other cancers, said Richard Lifton, Sterling Professor of Genetics, chair of the Department of Genetics, investigator for the Howard Hughes Medical Institute, and senior author of the paper. He noted, however, that during early development DNA rearrangements can produce highly diverse T cell receptors, which enables them to recognize cells bearing viruses or other abnormal proteins. These lymphomas may arise from loss of the normal regulation of these genetic rearrangements, he explained. Yale University

Smokers with a specific genetic variation are more likely to keep smoking longer than those who don’t have the gene variant, new research indicates. They’re also more likely to be diagnosed with lung cancer at a younger age.

Researchers at Washington University School of Medicine in St. Louis led an analysis of 24 studies involving more than 29,000 smokers of European ancestry and found that smokers with a particular variation in a nicotine receptor gene were more likely to continue smoking for four years after those without the variant had quit. Those with the genetic variant also were more likely to be diagnosed with lung cancer four years earlier than those without the variation in the CHRNA5 gene.

The findings may result in changes to efforts to screen patients for lung cancer.

“People with the risk variant average a four-year delay in the age at which they quit smoking,” said first author Li-Shiun Chen, MD. “Instead of quitting at age 52, which was the average age when study participants with a normal gene stopped smoking, people with the genetic variant quit at age 56.”

Chen said those with the gene variant also tend to inhale more deeply when they smoke. That combination of genes and behaviour contributes to the development of lung cancer earlier in life.

“They are likely to be diagnosed four years earlier,” she said. “In those with lung cancer, the average smoker without the gene variant is diagnosed at age 65. Those with the greater genetic risk tend to be diagnosed at 61.”

Chen said the presence of the gene variation has important clinical implications. Smokers who have the gene variant could undergo lung cancer screening at a younger age, she said. In addition, previous work from Chen and senior investigator Laura Jean Bierut, MD, shows that those with the gene variant are more likely to respond to medications that help people quit smoking, so knowing more about a smoker’s genetic makeup could help guide that individual’s therapy.

“The same people with this high-risk gene are more likely to respond to smoking-cessation medications, such as nicotine-replacement patches, lozenges or gum,” Chen said. “Although it’s clear the gene increases the chances a person will develop lung cancer at a younger age, it also is clear that the risk can be reversed with treatment.” Washington University in St Louis

UCLA researchers have discovered that for women with a relatively common inherited genetic mutation, known as the KRAS-variant, an abrupt lowering of oestrogen in the body may increase the risk for breast cancer and impact the biology of their breast cancer. Scientists also found that women with the KRAS-variant are more likely to develop a second primary breast cancer, independent of a first breast cancer.

The two-year study, led by Dr. Joanne Weidhaas, a professor of radiation oncology at the UCLA Jonsson Comprehensive Cancer Center and director of translational research at the David Geffen School of Medicine, analysed data from more than 1,700 women with breast cancer who submitted DNA samples to be tested for the inherited KRAS-variant. The study also included a group of women with the KRAS-variant who were cancer-free, as well as biological models to scientifically confirm the clinical findings.

Weidhaas’ team found that acute oestrogen withdrawal, as experienced after removal of the ovaries or when hormone replacement therapy was discontinued, and/or a low oestrogen state were associated with breast cancer in women with the KRAS-variant. Acute oestrogen withdrawal also triggered breast cancer formation in KRAS-variant biological models used in the study. In addition, up to 45 percent of breast cancer patients with the KRAS-variant eventually developed a second independent breast cancer — representing a 12-fold greater risk than women with breast cancer who did not have the KRAS-variant.

“Although we had evidence that the KRAS-variant was a stronger predictor of cancer risk for women than men, we did not previously have a scientific explanation for this observation,” Weidhaas said. “This study’s findings, showing that oestrogen withdrawal can influence cancer risk for women with the KRAS-variant, begins to provide some answers.”

The findings are contrary to some past research suggesting that women on combination hormone replacement therapy are more likely to develop breast cancer, but the study is in agreement with follow-up studies which found that oestrogen alone might actually protect women from breast cancer.

“The KRAS-variant may be a genetic difference that could actually help identify women who could benefit from continuing oestrogen, or at a minimum, at least tapering it appropriately,” Weidhaas said. “We hope that there are real opportunities to personalize risk-reducing strategies for these women, through further defining the most protective oestrogen management approaches, as well as by understanding the impact of different treatment alternatives at the time of a woman’s first breast cancer diagnosis.” University of California – Los Angeles

Cerebral palsy (CP) is the most common cause of physical disability in children. Every year 140 children are diagnosed with cerebral palsy in Quebec.

It has historically been considered to be caused by factors such as birth asphyxia, stroke and infections in the developing brain of babies. In a new game-changing Canadian study, a research team from The Hospital for Sick Children (SickKids) and the Research Institute of the McGill University Health Centre (RI-MUHC) has uncovered strong evidence for genetic causes of cerebral palsy that turns experts’ understanding of the condition on its head.

The study could have major implications on the future of counselling, prevention and treatment of children with cerebral palsy.

“Our research suggests that there is a much stronger genetic component to cerebral palsy than previously suspected,” says the lead study author Dr. Maryam Oskoui, Paediatric neurologist at The Montreal Children’s Hospital (MCH) of the MUHC, co-director of the Canadian Cerebral Palsy Registry and an Assistant Professor in the Department of Paediatrics and Department of Neurology and Neurosurgery at McGill University. “How these genetic factors interplay with other established risk factors remains to be fully understood. For example, two newborns exposed to the same environmental stressors will often have very different outcomes. Our research suggests that our genes impart resilience, or conversely a susceptibility to injury.”

Children with cerebral palsy have difficulties in their motor development early on, and often have epilepsy and learning, speech, hearing and visual impairments. Two out of every thousand births are affected by cerebral palsy with a very diverse profile; some children are mildly affected while others are unable to walk on their own or communicate. Genetic testing is not routinely done or recommended, and genetic causes are searched for only in rare occasions when other causes cannot be found.

The research team performed genetic testing on 115 children with cerebral palsy and their parents from the Canadian Cerebral Palsy Registry, many of which had other identified risk factors. They found that 10 per cent of these children have copy number variations (CNVs) affecting genes deemed clinically relevant. In the general population such CNVs are found in less than one per cent of people. CNVs are structural alterations to the DNA of a genome that can be present as deletions, additions, or as reorganized parts of the gene that can result in disease.

“When I showed the results to our clinical geneticists, initially they were floored,” says Dr. Stephen Scherer, Principal Investigator of the study and Director of The Centre for Applied Genomics (TCAG) at SickKids. “In light of the findings, we suggest that genomic analyses be integrated into the standard of practice for diagnostic assessment of cerebral palsy.”

The study also demonstrates that there are many different genes involved in cerebral palsy. “It’s a lot like autism, in that many different CNVs affecting different genes are involved which could possibly explain why the clinical presentations of both these conditions are so diverse,” says Scherer, who is also Director of the University of Toronto McLaughlin Centre. “Interestingly, the frequency of de novo, or new, CNVs identified in these patients with cerebral palsy is even more significant than some of the major CNV autism research from the last 10 years. We’ve opened many doors for new research into cerebral palsy.” 

“Finding an underlying cause for a child’s disability is an important undertaking in management,” says Dr. Michael Shevell, co-director of the Canadian Cerebral Palsy Registry and Chair of the Department of Paediatrics at the MCH-MUHC. “Parents want to know why their child has particular challenges. Finding a precise reason opens up multiple vistas related to understanding, specific treatment, prevention and rehabilitation. This study will provide the impetus to make genetic testing a standard part of the comprehensive assessment of the child with cerebral palsy.” Research Institute of the McGill University Health Centre

Scientists don’t know the exact molecular nature of the epigenetic information that one generation transmits to the next. The list of candidate carriers includes proteins, noncoding RNA and the histones around which DNA winds itself. Or it could be modifications to the DNA itself that somehow get replicated when cells divide.

Now, a Harvard Medical School team has written a new chapter in the epigenetics story, with their discovery of a new position for an epigenetic modification to DNA that potentially carries heritable epigenetic information.

Over the past 20 years, a growing body of evidence has implicated chemical marks that are added to the DNA.  The best studied modifications scientists have found occur when a methyl group marks the C. More ancient organisms have other modifications, including methylation of the A.

Yang Shi, HMS professor of cell biology, overturned dogma in the field in 2004 when he showed that methylation of histones is not static. Adding a methyl group to histones—the spool around which the DNA double helix wraps to form chromosomes—can help turn a gene on or off; so does removing a methyl group. The discovery of enzymes that specifically remove methyl groups highlights the dynamic nature of histone methylation regulation, a process that is critical for stem cell biology, development and differentiation, and when it goes awry, can lead to many human diseases. Their surprising discovery was made in C. elegans, a transparent roundworm that is a widely studied model organism.

Scientists previously thought that C. elegans simply had no DNA methylation because their C letters showed no signs of the methyl modification that other animals have. It is also unknown how they can transmit epigenetic modifications across generations.

Shi’s team reports that C. elegans does in fact carry DNA methylation, but not on the C position. They found epigenetic modifications to adenine at the same location previously thought to exist only in more primitive organisms.

They also identified the enzymes that act to methylate and demethylate the A. Further bolstering their case, they showed that a transgenerational epigenetic inheritance system in C. elegans, which displays a generationally progressive reduced fertility, also progressively accumulates A methylations.

“We have identified what we think is a fundamental new layer of regulation that occurs in animals,” said Eric Greer, formerly a postdoctoral fellow in the Shi lab and now HMS assistant professor of pediatrics at Boston Children’s Hospital. “We’re excited about this because this is a modification that hasn’t previously been shown to occur in Metazoa, of which humans and worms are members.”

The more common C modification may overshadow the A modification in more recently evolved animals, said co-lead author Andres Blanco, an HMS postdoctoral fellow in pediatrics in the Shi lab.

“Maybe it’s not the dominant form of DNA methylation, but maybe it has a smaller role that is nonetheless extremely important,” he said. Harvard Medical School