Genetics researchers have identified a key gene that, when mutated, causes the rare multisystem disorder Cornelia deLange syndrome (CdLS). By revealing how mutations in the HDAC8 gene disrupt the biology of proteins that control both gene expression and cell division, the research sheds light on this disease, which causes intellectual disability, limb deformations and other disabilities resulting from impairments in early development.
‘As we better understand how CdLS operates at the level of cell biology, we will be better able to define strategies for devising treatments for CdLS, and possibly for related disorders,’ said study leader Matthew A. Deardorff, M.D., Ph.D., a pediatric genetics clinician and scientist at The Children’s Hospital of Philadelphia. Deardorff also is in the Perelman School of Medicine at the University of Pennsylvania.
The current findings add to previous discoveries by researchers at The Children’s Hospital of Philadelphia. A group led by Ian Krantz, M.D., and Laird Jackson, M.D., announced in 2004 that mutations in the NIPBL gene are the primary cause of CdLS, accounting for roughly 60 percent of the ‘classical’ cases of the disease. In 2007, Deardorff joined them to describe mutations in two additional genes, SMC1A and SMC3. First described in 1933, CdLS affects an estimated 1 in 10,000 children.
The CdLS research team at Children’s Hospital has focused on the cohesin complex, a group of proteins that form a bracelet-like structure that encircles pairs of chromosomes, called sister chromatids. ‘Cohesin has two roles,’ said Deardorff. ‘It keeps sister chromatids together during cell division, and it allows normal transcription—the transmission of information from DNA to RNA.’
Deardorff added that mutations that perturb normal cohesin function can interfere with normal human development. Such is the case in CdLS, which exemplifies a newly recognised class of diseases called cohesinopathies.
In the current study, the scientists investigated both acetylation—how an acetyl molecule is attached to part of the cohesin complex—and deactylation, the removal of that molecule. Normally, deactylation helps recycle cohesin to make it available during successive rounds of cell division. The study team found that mutations in the HDAC8 gene threw off normal cellular recycling of cohesin.
Mutations in the gene cause loss of HDAC8 protein activity, and consequently decrease the amount of ‘recharged’ cohesin available to properly regulate gene transcription. This, in turn, the researchers suggest, impairs normal embryonic development and gives rise to CdLS.
The researchers showed in cell cultures that mutations in HDAC8 lead to a decrease in cohesin binding to genes, similar to that seen for cells deficient in the NIPBL gene. They also identified HDAC8 mutations in approximately 5 percent of patients with CdLS.
Because mothers of children with CdLS may carry mutations in the HDAC8 gene, identifying these mutations will be very useful in accurately counseling families of their recurrence risk—the likelihood of having a subsequent child with CdLS.
Furthermore, added Deardorff, by providing biological details of the underlying defect in CdLS, the current research suggests future approaches to treating the genetic disease. ‘By concentrating downstream on the biological pathway in the cohesin cycle rather than focusing on the defective gene, we may be able to eventually screen for small-molecule drugs that could be used to intervene in CdLS.’ Children’s Hospital of Philadelphia

In the first broad genetic landscape mapped of a Burkitt lymphoma tumour, scientists at Duke Medicine and their collaborators identified 70 mutations, including several that had not previously been associated with cancer and a new one that was unique to the disease.

Findings from the genetic sequencing of Burkitt lymphoma, an aggressive form of lymphoma, could be used to develop new drugs or aim existing therapies at mutations known to be susceptible

‘This study lays out the most common genetic alterations in the disease, and allows us to understand the biology of the disease so we can design better therapies,’ said Sandeep S. Dave, M.D., MBA, MS, associate professor at Duke and senior author of the study.

Dave and colleagues sequenced the first complete Burkitt lymphoma genome, plus the genes from 59 additional Burkitt cases and 94 diffuse large B cell lymphomas, which share many of the same characteristics of Burkitt lymphoma. Similarities between the malignancies can often lead to mistaken diagnoses and failed treatments.

The researchers reported striking differences in the gene mutation patterns of Burkitt lymphomas vs. the diffuse large B cell lymphomas.

‘It’s important that doctors make the right diagnosis for Burkitt lymphoma, which can be cured with the correct therapies,’ Dave said. ‘But if misdiagnosed and given the standard chemotherapy regimes for diffuse large B cell lymphomas, Burkitt lymphoma patients invariably relapse.’

The analysis identified 70 genes that were frequently mutated in the Burkitt lymphomas, including a number of genes that were identified in cancer for the first time. One of the newly identified gene mutations, ID3, appeared in 34 percent of the Burkitt cases, but was not evident in any of the diffuse large B cell lymphomas.

The mutation has a silencing effect on a gene that suppresses cell growth, enabling cells to multiply. Dave said this alteration alone may not cause cancer, but when it occurs along with the MYC gene mutations that are common in Burkitt lymphoma and other malignancies, it works like an accelerant to fuel tumour growth.

That finding could prove helpful for developing a new drug to function like a normal ID3 gene and suppress cancer cell proliferation in lymphomas as well as numerous other cancers.

‘If we can find a way to mimic ID3, restoring the function of the gene to slow the growth of tumours, this could provide a new treatment approach,’ Dave said. ‘We have experiments that suggest this is the case, but much more research is needed. This work provides a starting point.’ Duke Medicine

A new study shows that loss of a small RNA molecule in liver cells might cause liver cancer and that restoring the molecule might slow tumour growth and offer a new way to treat the disease.

The animal study was led by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

The scientists examined what happens when liver cells lack a molecule called microRNA-122 (miR-122). They found that when the molecule is missing, the liver develops fat deposits, inflammation and tumours that resemble hepatocellular carcinoma (HCC), the most common form of liver cancer.

When the researchers artificially restored miR-122 to nearly normal levels by delivering the miR-122 gene into liver cells, it dramatically reduced the size and number of tumours, with tumours making up 8 percent on average of liver surface area in treated animals versus 40 percent in control animals.

‘These findings reveal that miR-122 has a critical tumour-suppressor role in the healthy liver, and they highlight the possible therapeutic value of miR-122 replacement for some patients with liver cancer,’ says study leader Dr. Kalpana Ghoshal, associate professor of pathology and a member of the OSUCCC – James Experimental Therapeutics Program.

More than 28,700 new cases of HCC are expected in the United States in 2012, and 20,550 Americans are expected to die of the malignancy. Major risk factors for HCC include hepatitis B and C virus infection and liver damage due to alcohol use. HCC is curable if caught early, but most cases are diagnosed at a late, incurable stage.

MiR-122 is found mainly in liver cells – it is the most abundant microRNA in those cells – and it plays a major role in regulating cholesterol in the body. This microRNA is lost in some people with HCC, however, resulting in a poor prognosis.

For this study, Ghoshal and her colleagues developed a strain of mice that lacks miR-122 and develops HCC through the progression of events that begins with fatty liver deposits followed by inflammation and liver cancer.

The researchers then used a second strain of mice that spontaneously develops liver cancer due to over-expression of a cancer-causing gene called MYC (pronounced ‘mick’). The researchers delivered miR-122 into the animals’ livers during tumour development. Three weeks later, those treated with the molecule had smaller and fewer tumours.

‘The model we developed for these studies will not only facilitate our understanding of liver biology but also be good for testing therapeutic efficacy of newly developed drugs against liver disease, including HCC,’ Ghoshal says.

Ghoshal also notes that research by others has shown that hepatitis C virus requires miR-122 for replication. ‘Because our findings demonstrate what happens when miR-122 is lost in liver cells, they might help improve the safety of new drugs that treat hepatitis C virus infection by blocking miR-122,’ she says. The Ohio State University Comprehensive Cancer Center

Blood hormone tests can predict a woman’s risk for developing postmenopausal breast cancer for up to 20 years, according to a study led by Xuehong Zhang, MD, Channing Division of Network Medicine, Brigham and Women’s Hospital (BWH) Department of Medicine.
Using data from the Nurses’ Health Study, Zhang , Susan Hankinson, ScD, Channing Division of Network Medicine, BWH Department of Medicine and colleagues analysed 796 patients with postmenopausal breast cancer who had not received hormone therapy.
They conducted blood hormone tests at two time points: between 1989 and 1990 and between 2000 and 2002. Researchers matched each patient with two controls who were not diagnosed with breast cancer.
‘We found that a single hormone level was associated with breast cancer risk for at least 16 to 20 years among postmenopausal women not using postmenopausal hormones,’ said Zhang. ‘We, and others, are now evaluating if the addition of hormone levels to current risk prediction models can substantially improve our ability to identify high-risk women who would benefit from enhanced screening or chemoprevention-if so, the current data suggest that hormone levels would not need to be measured in the clinic more than once every 10, or possibly 20, years.’
Women with hormone levels in the highest 25 percent for estradiol, testosterone and DHEAS had a 50 percent to 107 percent greater chance for developing breast cancer compared with women in the lowest 25 percent. Relative risks for developing breast cancer were similar at one to 10 years vs. 11 to 20 years (also 16 to 20 years) after blood collection.
Researchers also investigated whether these higher levels were more closely linked to hormone-receptor positive breast cancers and if they predicted risk regardless of tumour aggressiveness.
In the first case, they found that elevated levels of estradiol increase a woman’s risk for hormone receptor-positive breast cancer, specifically oestrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) tumours.
In general, increased hormone levels, except for DHEAS, tracked closely with increased risk for receptor-positive breast cancer. Data on receptor-negative cancers were inconclusive and need additional, large studies.
Significantly, elevated hormone levels were also associated with aggressive breast cancer, which the study defined as recurrent or fatal cancer.
‘The relationship was comparable or possibly stronger for recurrent and fatal breast cancer than it was for overall breast cancer risk although these results were based on relative small numbers of participants,’ said Zhang.
Researchers also confirmed the protective effect of sex hormone-binding globulin (SHBG), which seems to negate the cancer-causing effects of certain hormones. Women in the highest 25 percent of SHBG levels had a 30 percent lower risk for breast cancer compared with women in the lowest 25 percent for SHBG levels.
Zhang noted that the study had low case numbers for several cancer subgroups, including HER2, triple-negative and basal-like breast cancers. More research is necessary to determine the relationship between elevated hormone levels and these important breast cancer groups. Brigham and Women’s Hospital