To the list of oncogenic drivers of lung cancer that includes ALK, EGFR, ROS1 and RET, results of a University of Colorado Cancer Center study presented at ASCO 2013 show that mutations in the gene NTRK1 cause a subset of lung cancers.

‘We’re reconceptualising lung cancer as many, related diseases. And we need to learn to identify and treat each individually. We can treat the forms of the disease that depend on ALK and EGFR mutations. We’re getting very close to treating lung cancers that depend on ROS1 and RET. And now we show another oncogenic driver of the disease that begs its own targeted treatment,’ says Robert C. Doebele, MD, PhD, investigator at the CU Cancer Center and assistant professor of medical oncology at the CU School of Medicine.

The group, in collaboration with Pasi A. Jänne, MD, PhD from the Dana-Farber Cancer Institute, started with lung cancer tumour samples from 36 ‘pan-negative’ patients, meaning that no other driver oncogene had been identified. So if not EGFR, ALK and the like, what was driving the cancer? Doebele and colleagues took the question to Foundation Medicine (Cambridge, MA), which used targeted, next-gen sequencing to analyse the samples for possible mutations in a couple hundred potential oncogenes identified as drivers of other cancers. NTRK1 had been identified as a driver of thyroid cancer and so was included in the panel (though drug development had stalled due in part to the relative rarity of the thyroid disease). Sure enough, next-gen sequencing identified NTRK1 gene fusions as the potential driver in two of these samples.

Doebele and colleagues took the lead back to the CU labs, where Marileila Varella Garcia, PhD, developed a specific test for NTRK1 fusions based on fluorescence in situ hybridisation (FISH), similar to what is used for ALK, ROS1 and RET fusions. This allowed the group to validate the finding of NRTK1 as a novel oncogene in these patient samples.

But the study went a step beyond identifying the oncogene. Doebele describes the relative ease with which genes that are improperly activated can be silenced – ‘whether a drug is already is in clinical trials, or already approved for another cancer, or just sitting on the pharma shelf somewhere, many drugs exist that turn off these candidate genes,’ Doebele says.

In this case, Doebele describes ‘walking up the street to Array BioPharma (Boulder, CO), who happened to have several compounds specific for this gene.’

The group showed that mutated NRTK1 genes in cells treated with drug candidates ARRY-772, -523, and -470 and others was effectively turned off.

‘This is still preclinical work,’ Doebele says, ‘but it’s the first – and maybe even second and third! – important steps toward picking off another subset of lung cancer with a treatment targeted to the disease’s specific genetic weaknesses.’ University of Colorado Cancer Center

A pair of studies tells the tale of how a neuroscientist at Mayo Clinic in Florida helped to discover the first African-American family to have inherited the rare movement disorder dystonia, which causes repetitive muscle contractions and twisting, resulting in abnormal posture. The research may improve diagnosis of this neurological condition in a population not known to suffer from it.
In the first study, Mayo Clinic’s Zbigniew Wszolek, M.D., and a team of neuroscientists from other institutions in the U.S. described three generations of an African-American family in Georgia who had dystonia. The team excluded mutations in genes previously associated with dystonia. The study was the first description of an African-American family with late-onset primary dystonia.
In the second study, Dr. Wszolek was part of an international team of researchers led by Mark LeDoux, M.D., Ph.D., a neurologist and neurogeneticist from the University of Tennessee Health Science Center in Memphis. The investigators identified the specific genetic abnormality seen in the African-American family and in several other white families. In the African-American family, the mutation produced a protein in which one amino acid was substituted for another.
While this isn’t the only gene anomaly linked to dystonia, it is the first found in an African-American family. All other genes found to be linked to this disorder were discovered in families of other ethnic origins.
The findings may improve diagnosis and treatment of dystonia in African-Americans, says Dr. Wszolek, who has been a driving force behind international research efforts to uncover genes that play a role in neurological disorders. Mayo Clinic

Researchers from the RIKEN Center for Integrative Medical Sciences in Japan have identified the first gene to be associated with adolescent idiopathic scoliosis (also called AIS) across Asian and Caucasian populations. The gene is involved in the growth and development of the spine during childhood.
AIS is the most common pediatric skeletal disease, affecting approximately 2% of school-age children. The causes of scoliosis remain largely unknown and brace treatment and surgery are the only treatment options. However, many clinical and genetic studies suggest a contribution of genetic factors.
To understand the causes and development of scoliosis, Dr Ikuyo Kou, Dr Shiro Ikegawa and their team have tried to identify genes that are associated with a susceptibility to develop the condition.
By studying the genome of 1,819 Japanese individuals suffering from scoliosis and comparing it to 25,939 Japanese individuals, the team identified a gene associated with a susceptibility to develop scoliosis on chromosome 6. The association was replicated in Han Chinese and Caucasian populations.
The researchers show that the susceptibility gene, GPR126, is highly expressed in cartilage and that suppression of this gene leads to delayed growth and bone tissue formation in the developing spine. GPR126 is also known to play a role in human height and trunk length.
‘Our finding suggest the interesting possibility that GPR126 may affect both AIS susceptibility and height through abnormal spinal development and growth,’ explain the authors.
‘Further functional studies are necessary to elucidate how alterations in GPR126 increase the risk of AIS in humans,’ they conclude. Medical News Today

New findings by Columbia researchers suggest that along with amyloid deposits, white matter hyperintensities (WMHs) may be a second necessary factor for the development of Alzheimer’s disease.

Most current approaches to Alzheimer’s disease focus on the accumulation of amyloid plaque in the brain. The researchers at the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, led by Adam M. Brickman, PhD, assistant professor of neuropsychology, examined the additional contribution of small-vessel cerebrovascular disease, which they visualised as white matter hyperintensities (WMHs).

The study included 20 subjects with clinically defined Alzheimer’s disease, 59 subjects with mild cognitive impairment, and 21 normal control subjects. Using data from the Alzheimer’s Disease Neuro-imaging Initiative public database, the researchers found that amyloid and WHMs were equally associated with an Alzheimer’s diagnosis. Amyloid and WMHs were also equally predictive of which subjects with mild-cognitive impairment would go on to develop Alzheimer’s. Among those with significant amyloid, WMHs were more prevalent in those with Alzheimer’s than in normal control subjects.
Because the risk factors for WMHs—which are mainly vascular—can be controlled, the findings suggest potential ways to prevent the development of Alzheimer’s in those with amyloid deposits. Columbia University Medical Center

A new study led by University of Pennsylvania researchers involves a classic case of evolution’s fickle nature: a genetic mutation that protects against a potentially fatal infectious disease also appears to increase the risk of developing a chronic, debilitating condition.

Such a relationship exists between malaria and sickle cell anaemia. Individuals who carry a gene to resist the former are carriers for the latter. And recently scientific evidence has suggested that individuals who are resistant to human African trypanosomiasis, or sleeping sickness, are predisposed to developing chronic kidney disease. That could explain why African-Americans, who derive much of their ancestry from regions where sleeping sickness is endemic, suffer from kidney disease at high rates.

In a study Penn researchers and colleagues offer further insights into the unfinished story of the sleeping sickness-kidney disease connection by looking at a variety of African populations which had not been included in prior studies. Sequencing a portion of a gene believed to play a role in both diseases, the scientists discovered new candidate variants that are targeted by recent natural selection. Their findings lend support to the idea that the advantages of resistance to sleeping sickness, a disease which continues to affect tens of thousands of sub-Saharan Africans each year, may have played a role in the evolution of populations across Africa.

The research was led by Wen-Ya Ko and Sarah Tishkoff of the Department of Genetics in Penn’s Perelman School of Medicine. Tishkoff, a Penn Integrates Knowledge professor, also has an appointment in the School of Arts and Sciences’ Department of Biology. Ko now holds a research position at the Universidade do Porto in Portugal.

Earlier research had shown that African-Americans with kidney disease frequently had one of two mutations in the gene that codes for the ApoL1 protein, endowing it with the ability to kill the parasite species that causes the form of sleeping sickness found in eastern Africa. But, puzzlingly, these variants were found at high frequencies in the Yoruba, who live in western Africa’s Nigeria.

‘That was an interesting finding, but nobody had ever done a sequencing analysis of this gene across other African populations,’ Tishkoff said. ‘We wanted to know if we would find the same variants and would they be as common.’

Using the earlier findings as a starting point, the Penn-led study expanded the sequencing effort to look at a region of the ApoL1 gene in 10 different African populations, encompassing groups from both eastern and western Africa.

They found the G1 and G2 haplotypes in some of the other populations but only at low frequencies, suggesting there may be other variants playing a similar role. Sure enough, the researchers also turned up another variant shared across groups, which they called G3.

‘This novel G3 was quite common in some of the populations but surprisingly absent in the Yoruba,’ Tishkoff said.

Not only was this variant present in the other nine groups studied, but the Ko-Tishkoff team found signs that it had been positively selected, or ferried through generations at a rate above chance, perhaps because it exerted a protective effect against sleeping sickness.

And interestingly, G3 was most common in the Fulani, a pastoralist group which lives in western and central Africa. The authors note that human African sleeping sickness, which is typically transmitted by tse tse flies, might have been an important factor driving the migration patterns of the Fulani throughout history.

Because the Fulani ‘practice cattle herding, tse tse flies and the parasites they carry may have been more of a problem … than for some other groups,’ Ko said. ‘It may have been particularly advantageous for them to be able to resist the disease.’

The different variants, therefore, may reflect a variety of selective pressures, including population movements around Africa and the historical and ongoing evolutionary arms race between the sleeping sickness parasite and the human immune system. The fact that the Yoruba can resist a form of the disease that is no longer present in the area in which they live might be the result of changes either in the parasite or in the movement patterns of the Yoruba themselves. Kidney disease might thus be considered an evolutionary trade-off, the unintended consequence of a battle to resist a powerful and prevalent infectious disease. University of Pennsylvania