Genetic studies in humans, zebrafish and mice have revealed how two different types of genetic variations team up to cause a rare condition called Hirschsprung’s disease. The findings add to an increasingly clear picture of how flaws in early nerve development lead to poor colon function, which must often be surgically corrected. The study also provides a window into normal nerve development and the genes that direct it.

About one in every 5,000 babies is born with Hirschsprung’s disease, which causes bowel obstruction and can be fatal if not treated. The disease arises early in development when nerves that should control the colon fail to grow properly. Those nerves are part of the enteric nervous system, which is separate from the central nervous system that enables our brains to sense the world.

The genetic causes of Hirschsprung’s disease are complex, making it an interesting case study for researchers like Aravinda Chakravarti, Ph.D., a professor in the Johns Hopkins University School of Medicine’s McKusick-Nathans Institute of Genetic Medicine. His research group took on the condition in 1990, and in 2002, it performed the first-ever genomewide association study to identify common variants linked to the disease.

But while Chakravarti’s and other groups have identified several genetic variants associated with Hirschsprung’s, those variants do not explain most cases of the disease. So Chakravarti and colleagues conducted a new genomewide association study of the disease, comparing the genetic markers of more than 650 people with Hirschsprung’s disease, their parents and healthy controls. One of their findings was a variant in a gene called Ret that had not been previously associated with the disease, although other variations in Ret had been fingered as culprits.

The other finding was of a variant near genes for several so-called semaphorins, proteins that guide developing nerve cells as they grow toward their final targets. Through studies in mice and zebrafish, the researchers found that the semaphorins are indeed active in the developing enteric nervous system, and that they interact with Ret in a system of signals called a pathway.

‘It looks like the semaphorin variant doesn’t by itself lead to Hirschsprung’s, but when there’s a variant in Ret too, it causes the pathway to malfunction and can cause disease,’ Chakravarti says. ‘We’ve found a new pathway that guides development of the enteric nervous system, one that nobody suspected had this role.’

Chakravarti notes that the genetic puzzle of Hirschsprung’s is still missing some pieces, and no clinical genetic test yet exists to assess risk for the disease. Most of the genetic variants that have so far been connected to this rare disease are themselves relatively common and are associated with less severe forms of the disease. The hunt continues for rare variants that can explain more severe cases. EurekAlert

There is the Addams Family. And then there is the ADAMTS family. While one is mindless entertainment, the latter may prove to be a new genetic avenue for designing ovarian cancer treatment.

Scientists at The University of Texas MD Anderson Cancer Center have identified a new class of gene mutations in the ADAMTS gene family that may contribute to outcomes in ovarian cancer without BRCA1 or BRCA2 mutations. BRCA1/BRCA2 are tumour-suppressing genes involved in DNA repair that are well known for increasing risk for ovarian and breast cancer when mutated.

Patients with BRCA1/BRCA2 mutations generally respond better to chemotherapy with longer survival. However, these mutations are found in only 20 percent of ovarian cancer patients. This doesn’t account for the 70 percent of patients who respond well to platinum-based chemotherapy.

“This suggests that events other than BRCA1 or BRCA2 mutations exist that predict chemotherapy response,” said Zhang, who has previously published on the significance of BRCA2 mutations in ovarian tumours. “In this study, we examined data from The Cancer Genome Atlas to determine the association between novel gene mutations in ovarian cancer and patient overall survival, progression-free survival and chemotherapy response.”

Zhang’s team looked at data for the years 2009 to 2014 and identified mutations from eight members of the ADAMTS family among the 512 cases studied. The data revealed a significantly higher rate of chemotherapy sensitivity within this group.

“We concluded that ADAMTS mutations may contribute to outcomes in ovarian cancer cases without BRCA1 or BRCA2 mutations and this may have important clinical implications,” said Yuexin Liu, Ph.D., assistant professor of Pathology, the first author of the study. “We found no statistical correlation between ADAMTS and BRCA1 or BRCA2 mutations.”

Ovarian cancer remains the leading cause of mortality from gynaecological cancer. Despite aggressive surgery and chemotherapy, most patients eventually experience relapse with generally incurable disease mainly due to chemotherapy resistance, said Zhang. M.D. Anderson Cancer Center

A new study from Lund University in Sweden shows that women with low levels of an anti-stress hormone have an increased risk of getting breast cancer. The study is the first of its kind on humans and confirms previous similar observations from animal experiments.
The recent findings on a potential new marker for the risk of developing breast cancer. The study focused on a hormone which circulates freely in the blood, enkephalin, with pain- and anxiety-reducing properties. Enkephalin also reinforces the immune system by directly affecting immune cells.

“This is the first time the role of enkephalin in breast cancer has been studied in humans, and the results were surprisingly clear. Among women with the lowest levels of the hormone, the risk of breast cancer was more than three times that of the women with the highest levels of the hormone. This is one of the strongest correlations between cancer risk and a freely circulating biomarker ever described”, said Olle Melander and Mattias Belting, both professors at Lund University and consultant physicians at Skåne University Hospital.

The findings were possible thanks to a broad approach combining the latest knowledge within cancer and cardiovascular research at Lund University; the study was based on blood samples taken from just over 1 900 women in Malmö.  The women were followed up with regard to breast cancer for an average period of 15 years.

The results were adjusted for age, menopause, hormonal treatment, smoking and other factors which can affect the risk of getting breast cancer.

The current study confirms a statistical correlation between low enkephalin concentrations in the blood and increased risk of breast cancer, and it remains to be seen whether there is a causal relation showing that a low level of the hormone directly affects tumour development. The researchers also point out that geographical location and age, in spite of the adjustments in the study, may be significant. The average age of the women studied was 57.

On the other hand, the study’s results are backed up by a subsequent control study of a group of 1 500 women with a marginally higher average age. In this group, the link between low levels of the hormone and breast cancer was even stronger. Animal studies by other researchers also gave similar indications. These studies established that enkephalin can reinforce the activity of the immune system against cancer cells, as well as having a direct tumour-inhibiting effect.

The researchers at Lund University hope that, after further studies, the results will facilitate prevention and early detection of breast cancer.  For those with an increased risk of breast cancer, potential preventive treatments could take the form of lifestyle interventions to reduce stress and new drugs. The findings fit well with the development towards individualised risk assessment and treatment, on the basis of each woman’s needs. Lund University

In a recent study, Virginia Commonwealth University School of Medicine researchers predicted which cirrhosis patients would suffer inflammations and require hospitalization by analysing their saliva, revealing a new target for research into a disease that accounts for more than 30,000 deaths in the United States each year.

The findings could trigger a change in the way researchers study chronic liver disease and associated microbiota, the network of tiny organisms in the human body such as bacteria and fungi that can either bolster an immune system or weaken it.

The breakdown of defences in the mucosa of the gut has long been a signal of inflammation in those with cirrhosis, which sees healthy liver tissue replaced by scar tissue.

The recent findings suggest that another part of the body also can produce warning signs.

“It has been believed that most of the pathogenesis of cirrhosis starts in the gut, which is what makes this discovery so fascinating,” said Jasmohan S. Bajaj, M.D., associate professor of hepatology in the VCU School of Medicine and Hunter Holmes McGuire Veterans Affairs Medical Center.“The fact that saliva, along with fluid in the gut, can be an indicator of inflammation tells us that we need to further explore the oral cavity and its connections to liver disease.”

The paper describes a study of more than 100 cirrhosis patients from VCU and VA Medical Center, 38 of which had to be hospitalized within 90 days because of flare-ups. Researchers found that the ratio of good-to-bad microbes was similar in the saliva as in the stool of these patients who required hospitalization.

Another part of the same study looked at an additional group of more than 80 people with and without cirrhosis. Those with cirrhosis had impaired salivary defenses, mirroring the immune deficiencies that take place in the gut.

“The data suggest that there may be a change in the overall mucosal-immune interface in cirrhosis patients, allowing a more toxic microbiota to emerge in both the gut and oral cavity,” said Phillip B. Hylemon, Ph.D., professor of microbiology and immunology in the VCU School of Medicine and co-author of the paper.

In addition to using oral microbiota to predict the disease status of cirrhosis patients, Hylemon said the new evidence could provide a useful tool for testing treatment protocols for patients with cirrhosis or other diseases driven by inflammation. Virginia Commonwealth University Scool of Medicine

The gene and hormone soup that enables women to breastfeed their newborns also can be a recipe for breast cancer, particularly when the first pregnancy is after age 30.

Researchers have now found that the gene DNMT1 is essential to maintaining breast, or mammary,  stem cells, that enable normal rapid growth of the breasts during pregnancy, as well as the cancer stem cells that may enable breast cancer. They’ve learned that the DNMT1 gene also is highly expressed in the most common types of breast cancer.

Conversely, ISL1 gene, a tumour suppressor and natural control mechanism for stem cells, is nearly silent in the breasts during pregnancy as well as cancer, said Dr. Muthusamy Thangaraju, biochemist at the Medical College of Georgia at Georgia Regents University.

“DNMT1 directly regulates ISL1,” Thangaraju said. “If the DNMT1 expression is high, this ISL1 gene is low.” They first made the connection when they knocked out DNMT1 in a mouse and noted the increase in ISL1. Then they got busy looking at what happened in human breast cancer cells.

They found ISL1 is silent in most human breast cancers and that restoring higher levels to the human breast cancer cells dramatically reduces the stem cell populations and the resulting cell growth and spread that are hallmarks of cancer.

When they eliminated the DNMT1 gene in a breast-cancer mouse model, “The breast won’t develop as well,” Thangaraju said, but neither would about 80 percent of breast tumours. The deletion even impacted super-aggressive, triple-negative breast cancer.

The findings point toward new therapeutic targets for breast cancer and potentially using blood levels of ISL1 as a way to diagnose early breast cancer, the researchers report. In fact, they’ve found that the anti-seizure medication valproic acid, already used in combination with chemotherapy to treat breast cancer, appears to increase ISL1 expression, which may help explain why the drug works for these patients, he said. The scientists are screening other small molecules that might work as well or better. Georgia Regents University and Health System