A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression.

The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type.

There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that the majority of triple-negative tumours are of the basal-like subtype.

Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer.

The team looked at breast cancers from almost 3000 patients. Their search had a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A.

‘Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong,’ says Dr Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. ‘BCL11A activity stood out because it is so active in triple-negative cancers.

‘It had all the hallmarks of a novel breast cancer gene.’

Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished.

‘Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers,’ says Dr Walid Khaled, joint first author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. ‘We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells. Wellcome Trust Sanger Institute

Despite a strong suspected link between genetics and asthma, commonly found genetic mutations account for only a small part of the risk for developing the disease — a problem known as missing heritability.

Rare and low frequency genetic mutations have been thought to explain missing heritability, but it appears they are unlikely to play a major role, according to a new study led by scientists from the University of Chicago. Analysing the coding regions of genomes of more than 11,000 individuals, they identified mutations in just three genes that were associated with asthma risk. Each was associated with risk in specific ethnicities.

‘Previous studies have likely overestimated the heritability of asthma,’ said study senior author Carole Ober, PhD, Blum-Riese Professor and chair of the Department of Human Genetics at the University of Chicago. ‘This could be because those estimates are based on correlations between family members that share environment as well as genes, which could inflate the heritability. Gene-environment interactions are not considered in these large scale association studies, and we know that these are particularly important in establishing individual risks for asthma.’

Asthma affects more than 25 million adults and children of all ages and ethnicities in the US. Due to the widespread nature of the disease, most studies of its genetic underpinnings have focused on commonly occurring mutations, referred to as genetic variants. However, while numerous such variants have been identified, they are able to account for only a small proportion of the risk for inheriting or developing asthma. Rare mutations, found in less than five percent of the population, have been hypothesized to explain this disparity.

Graduate student Catherine Igartua led the analysis under the supervision of co-senior author Dan Nicolae, PhD, Professor in the Departments of Medicine, Statistics and Human Genetics. She evaluated nearly 33,000 rare or low frequency mutations in more than 11,000 individuals of a variety of ethnicities representing European, African and Latino backgrounds. She analysed mutations jointly across subjects, using a technique that allowed them to study mutations common in one ethnicity, but rare in others.

Only mutations in the genes GRASP, GSDMB and MTHFR showed a statistical link to asthma risk. Mutations in the first two genes were found primarily in Latino individuals, and mutations in the last gene in those with African ancestry. These genes, involved in protein scaffolding, apoptosis regulation and vitamin B9 metabolism respectively, have as yet unknown roles in asthma. The rarity and ethnic-specificity of these genes is insufficient to account for the widespread prevalence of asthma.

Although rare mutations might not contribute much to population asthma risk, these genes still have the potential to serve as targets for therapeutic development. Ober points to the discovery of rare mutations in the LDL receptor that eventually led to the development of statins to treat high cholesterol. She also notes that it is possible, but unlikely, that there are mutations with large effects on asthma risk outside of their screen as it looked at approximate 60 percent of mutations in coding regions of the genome.

‘It was assumed that there would be rare mutations with larger effect sizes than the common variants we have been studying,’ Ober said. ‘Surprisingly, we found that low frequency mutations explain only a very small amount of asthma risk.’ The University of Chicago Medicine

The largest genome-wide association study to date of the malaria parasite Plasmodium falciparum unveils a complex genetic architecture that enables the parasite to develop resistance to our most effective antimalarial drug, artemisinin. The results could help to improve early detection of emerging artemisinin resistance.

The global research collaboration analysed 1612 samples from 15 locations in Southeast Asia and Africa finding 20 mutations in the kelch13 gene, a known artemisinin resistance marker, that appear to work in concert with a set of background mutations in four other genes to support artemisinin resistance.

‘Our findings suggest that these background mutations emerged with limited impact on artemisinin resistance – until mutations occurred in the kelch13 gene,’ explains Dr Roberto Amato, a first author and Research Associate in Statistical Genomics at the Wellcome Trust Sanger Institute and Oxford University’s Wellcome Trust Centre for Human Genetics. ‘It’s similar to what we see with pre-cancerous cells which accumulate genetic changes but only become malignant when they acquire critical driver mutations that kick-off growth.’

The variety of kelch13 mutations associated with artemisinin resistance, with new variants continually emerging, makes it difficult to use this gene alone as a marker for genetic surveillance.

Monitoring parasite populations for a specific genetic background – in this case, a fixed set of four well-defined mutations in the fd, arps10, mdr2, and crt genes – could allow researchers to assess the likelihood of new resistance-causing mutations emerging in different locations, helping to target high-risk regions even before resistant parasites take hold.

‘We are at a pivotal point for malaria control. While malaria deaths have been halved, this progress is at risk if artemisinin ceases to be effective,’ says Nick Day, Director of the Mahidol-Oxford Tropical Medicine Research Unit (MORU) in Bangkok, Thailand. ‘We need to use every tool at our disposal to protect this drug. Monitoring parasites for background mutations could provide an early warning system to identify areas at risk for artemisinin resistance.’

Researchers also uncovered new clues about how artemisinin resistance has evolved in Southeast Asia. By comparing parasites from Cambodia, Vietnam, Laos, Thailand, Myanmar and Bangladesh, scientists found that the distribution of different kelch13 mutations are localised within relatively well-defined geographical areas.

Whilst artemisinin resistant parasites do appear to have migrated across national borders, this only happened on a limited scale and, in fact, the most widespread kelch13 mutation, C580Y, appeared to have emerged independently on several occasions. Notably parasites along the Thailand-Myanmar border appear to have acquired this mutation separately from those in Cambodia and Vietnam. Crucially, parasite populations in both regions possess the genetic background mutations, even though they are clearly genetically distinct.

There remain many unanswered questions. ‘We don’t yet know the role of these background mutations,’ says Dr Olivo Miotto, a first author and Senior Informatics Fellow at MORU and the Centre for Genomics and Global Health. ‘Some may not affect drug resistance directly, but rather provide an environment where drug resistance mutations are tolerated. Since kelch13 has hardly changed in 50 million years of Plasmodium evolution, we can assume that this gene is essential to parasite survival. Therefore, kelch13 mutations may severely handicap mutant parasites, compromising their survival unless some other change can counteract this negative effect.’

Mutations in the kelch13 gene were present, yet rare, in Africa but weren’t associated with artemisinin resistance and lacked the genetic background present in artemisinin-resistant parasites in Southeast Asia. This provides some reassurance for public health authorities working to prevent the spread of artemisinin resistance to Africa where most malaria deaths occur. Wellcome Trust Sanger Institute  

Copy number variations (deletions or duplications of large chunks of the genome) are a major cause of birth defects, intellectual disability, autism spectrum disorder and other developmental disorders. Still, geneticists can definitively say how a CNV, once discovered in someone’s DNA, leads to one of these conditions in just a fraction of cases.

To aid in the interpretation of CNVs, researchers at Emory University School of Medicine have completed detailed maps of 184 duplications found in the genomes of individuals referred for genetic testing.

‘Ours is the first study to investigate a large cohort of clinically relevant duplications throughout the genome,’ says senior author Katie Rudd, PhD, assistant professor of human genetics at Emory University School of Medicine. ‘These new data could help geneticists explain CNV test results to referring doctors and parents, and also reveal mechanisms of how duplications form in the first place.’

Despite advances in ‘next generation’ DNA sequencing, the first step for patients who are referred to a clinical geneticist is currently a microarray. This is a scan using many probes across the genome, testing if someone’s DNA has one, two, three or more copies of the DNA corresponding to the probe. (Two is the baseline.) From this scan, geneticists will have a ballpark estimate of where a deletion or duplication starts and ends, but won’t know the breakpoints exactly.

‘In a few years, advances in sequencing will make it possible to routinely capture data on copy number variation and breakpoints at the same time,’ Rudd says. ‘But for now, we have to do this extra step.’

In addition, in comparison with deletions, duplications are more complicated. The extra DNA has to land somewhere, sometimes resulting in the disruption or warped regulation of nearby genes, which make it more difficult to pinpoint particular genes responsible for the individual’s medical condition.

Most healthy people have a deletion or duplication of at least 100 kilobases in size. The individuals in the study were referred for clinical microarray testing with indications including intellectual disability, developmental delay, autism spectrum disorders, congenital anomalies, and dysmorphic features. Their CNVs were larger, with an average size of more than 500 kilobases.

Rudd’s team examined 184 duplications, and found that most are in tandem (head-to-tail) orientation and adjacent to the duplicated area. Most of the CNVs in the study were inherited from a parent. The researchers also found examples where a duplicated gene inserted into and disrupted another gene on a different chromosome.

In a few cases, a duplicated gene was fused together with another gene. This is a phenomenon often seen in cancer cells, where a DNA rearrangement leads to an abnormal activation of a growth- or survival-promoting gene. In these cases, the fusions were present in all cells in the body and not related to cancer, but could be responsible for the patient’s condition.

‘These fusion genes are intriguing but we don’t know, just from looking at the DNA, if the gene is expressed,’ Rudd says. ‘These findings could be the starting point for follow-up investigation.’ Emory University School of Medicine

Moffitt Cancer Center researchers have found that breast and lung cancer patients who have low levels of a protein called tristetraprolin (TTP) have more aggressive tumours and a poorer prognosis than those with high levels of the protein. 

Cancer arises through the increased activity of oncogenes, proteins that drive cancer growth, and the decreased activity of tumour suppressors, proteins that block malignant growth and progression. TTP is a recently discovered tumour suppressor protein, and scientists at Moffitt have found that this protein can prevent lymphoma growth in mice.

Researchers wanted to further investigate the importance of TTP in cancer patients and what other genes it is associated with in cancer. Using a detailed catalogue of genetic changes in cancer developed by the National Institutes of Health, called The Cancer Genome Atlas, Moffitt scientists compared patients who had low levels of TTP to those with high levels of the protein.

These researchers found a network of 50 different genes associated with low levels of TTP in breast, lung and colon tumours. This genetic network was also present in other tumour types, including prostate, pancreatic and bladder cancer.  This demonstrates that TTP is involved in a variety of mechanisms important for tumour development and growth, and suggests that developing agents that target this network may be an effective therapeutic strategy across a wide spectrum of tumours.

They also reported that low levels of TTP were associated with poor prognosis in certain cancers, including a higher rate of relapse in breast cancer patients and lower rates of survival in lung adenocarcinoma patients.  Additionally, breast and lung cancer patients with low levels of TTP tended to have more aggressive types of tumors.

“Identifying this network allows us to set up future research projects focused on understanding how TTP functions as a tumor suppressor with the ultimate goal of developing treatments specific for patients that have low levels of TTP,” explained Robert Rounbehler, Ph.D., research scientist at Moffitt. Moffitt Cancer Center