Unravelling the genetic sequences of cancer that has spread to the brain could offer unexpected targets for effective treatment, according to new research.

Researchers say that they found that the original, or primary, cancer in a patient’s body may have important differences at a genetic level from cancer that has spread to the patient’s brain (brain metastases). This insight could suggest new lines of treatment.

Dr Priscilla Brastianos, MD, a neuro-oncologist and Director of the Brain Metastasis Program at Massachusetts General Hospital, Boston, USA, said: “Brain metastases are a devastating complication of cancer. Approximately eight to ten percent of cancer patients will develop brain metastases, and treatment options are limited. Even where treatment is successfully controlling cancer elsewhere in the body, brain metastases often grow rapidly.”

Dr Brastianos and her colleagues studied tissue samples from 104 adults with cancer. In collaboration with Dr Scott Carter and Dr Gad Getz at the Broad Institute, Cambridge, USA, they analysed the genetics of biopsies taken from the primary tumour, brain metastases and normal tissues in each adult. For 20 patients, they also had access to metastases elsewhere in the body.

Brain metastases often manifest years after the primary tumour. Before this study was carried out, the extent to which the genetic profiles of brain metastases differ from that of the primary was unknown.

The researchers found that, in every patient, the brain metastasis and primary tumour shared some of their genetics, but there were also key differences. In 56% of patients, genetic alterations that potentially could be targeted with drugs were found in the brain metastasis but not in the primary tumour.

“We found genetic alterations in brain metastases that could affect treatment decisions in more than half of the patients in our study,” Dr Brastianos will say. “We could not detect these genetic alterations in the biopsy of the primary tumour. This means that when we rely on analysis of a primary tumour we may miss mutations in the brain metastases that we could potentially target and treat effectively with drugs.”

This study also found that if a patient had more than one brain metastasis, each was genetically similar.

To date, scientists have had limited understanding of how cancers change genetically, or evolve, as they spread from the primary tumour. The researchers used their findings to map the evolution of a cancer through a patient’s body, and draw up a so-called phylogenetic tree for each patient to demonstrate how the cancer had spread and where each metastasis had come from.

They concluded that brain metastases and the primary tumour share a common genetic ancestor. Once a cancer cell, or clone, has moved from the primary site to the brain, it continues to develop and amass genetic mutations. The genetic similarity of the brain metastases in individual patients suggests that each brain metastasis has developed from a single clone entering the brain.

The genetic changes in brain metastases are independent of any occurring at the same time in the primary tumour, and in metastases elsewhere in the body, the researchers said.

Characterisation of the genetics of a patient’s primary cancer can be used to optimise treatment decisions, so that drugs that target specific mutations in the cancer can be chosen. However, brain metastases are not routinely biopsied and analysed. ECC 2015

Fragments of cancer DNA circulating in a patient’s bloodstream could help doctors deliver more personalized treatment for liver cancer, Japanese researchers report.

The new research may help address a particular challenge posed by liver cancers, which can be difficult to analyse safely. One serious risk of existing biopsy methods is that doctors who want to obtain a tumour sample for analysis might cause the cancer to spread into the space around organs.

‘Doctors need non-invasive methods that will allow them to safely study cancer progression and characterize the genomic features of a patient’s tumour,’ said Professor Kazuaki Chayama, a principal investigator in this study. ‘Testing for these circulating DNA fragments may be a much easier and safer way of doing this than conventional liver biopsy.’

The researchers showed that detecting DNA released by damaged cancer cells, called circulating tumour DNA (ctDNA), in serum before surgery could predict the recurrence of cancer and its spread through the body (metastasis) in patients with an advanced form of the most common type of liver cancer. They also demonstrated that the level of serum ctDNA reflected the treatment effect and the progression of hepatocellular carcinoma (HCC).

Recent studies have suggested that ctDNA might be a useful biomarker in various cancers. The new study brings this technique closer to clinical reality in patients with advanced HCC by showing that ctDNA provided valuable clinical information about the patient’s disease progression.

Professor Chayama and colleagues in Hiroshima University including Dr. Atsushi Ono, together with researchers at RIKEN and the University of Tokyo, investigated whether they could detect ctDNA in serum of 46 HCC patients. They found ctDNA in seven patients. These patients were more likely than the others to experience recurrence and metastasis of their cancer. ‘Furthermore, we found that the level of ctDNA correlated with progression of HCC and the treatment,’ said Professor Chayama.

The Japanese team also says that ctDNA has the potential to be a non-invasive way of studying the genetic rearrangements that a cancer has undergone. This information could help doctors provide targeted therapy specific to a patient’s cancer, they note.

Recently, detection of cancer-specific mutations by genome sequencing has attracted attention as a way to help select appropriate therapy selection, Professor Chayama said. The researchers were able to identify 25 common mutations in samples of cell-free DNA, which includes DNA from both normal cells and cancer cells, and DNA from tumours themselves. Furthermore, 83% of mutations identified in the tumour tissues could be detected in the cell-free DNA.

Although further study is necessary to develop more effective methods, the new study adds to growing evidence about the usefulness of ctDNA in cancer treatment, and shows that it is a promising biomarker that provides a new way to treat liver cancer. EurekAlert

New light has been shed on the genetic relationship between autistic spectrum disorders (ASD) and ASD-related traits in the wider population, by a team of international researchers including academics from the University of Bristol, the Broad Institute of Harvard and MIT, and Massachusetts General Hospital (MGH).

The researchers studied whether there is a genetic relationship between ASD and the expression of ASD-related traits in populations not considered to have ASD. Their findings suggest that genetic risk underlying ASD, including both inherited variants and de novo influences (not seen in an individual’s parents), affects a range of behavioural and developmental traits across the population, with those diagnosed with ASD representing a severe presentation of those traits.

Autism spectrum disorders (ASD) are a class of neurodevelopmental conditions affecting about 1 in 100 children. They are characterised by social interaction difficulties, communication and language impairments, as well as stereotyped and repetitive behaviour. These core symptoms are central to the definition of an ASD diagnosis but also occur, to varying degrees, in unaffected individuals and form an underlying behavioural continuum.

With recent advances in genome sequencing and analysis, a picture of ASD’s genetic landscape has started to take shape. Research has shown that most ASD risk is polygenic (stemming from the combined small effects of thousands of genetic differences, distributed across the genome). Some cases are also associated with rare genetic variants of large effect, which are usually de novo.

 “There has been a lot of strong but indirect evidence that has suggested these findings,” said Dr Mark Daly, co-director of the Broad Institute’s Medical and Population Genetics (MPG) Program and senior author of the study.

“Once we had measurable genetic signals in hand – both polygenic risk and specific de novo mutations known to contribute to ASD – we were able to make an incontrovertible case that the genetic risk contributing to autism is genetic risk that exists in all of us, and influences our behaviour and social communication.”

Study co-first author Dr Elise Robinson, from MGH, said: “We can use behavioural and cognitive data in the general population to untangle the mechanisms through which different types of genetic risk are operating. We now have a better path forward in terms of expecting what types of disorders and traits are going to be associated with certain types of genetic risk.”

“Our study shows that collecting and using phenotypic and genetic data in typically developing children can be useful in terms of the design and interpretation of studies targeting complex neurodevelopmental and psychiatric disorders,’ said study co-first author Dr Beate St Pourcain, from the Medical Research Council Integrative Epidemiology Unit at the University of Bristol and the Max Planck Institute for Psycholinguistics.

“Based on the genetic link between population-based social-communication difficulties and clinical ASD, we may now gain further phenotypic insight into a defined set of genetically-influenced ASD symptoms. This may help us to identify and investigate biological processes in typically-developing children, which are disturbed in children with ASD.” University of Bristol

Testicular cancer used to be a brutal killer. If you were diagnosed with non-seminoma (a type of testicular germ cell tumour) which had spread to the abdominal lymph nodes – surgical removal of these nodes was the only thing that could possibly cure you. If you had more advanced late-stage testicular cancer, little could be done.

In the 1970s, The Institute of Cancer Research, London, drove the development of the platinum-based chemotherapy cisplatin which, when used in combination with other chemotherapy drugs, was highly effective. The 1980s saw the arrival of carboplatin – also developed at the ICR – providing a much less toxic alternative to cisplatin.

Death rates from testicular cancer – even in cases where the cancer has spread to other parts of the body – came tumbling down, falling by around 80%. Since the early 1970s survival for testicular cancer has risen continuously, and current cure rates are a remarkable 96%.

With the survival rates being so high, research attention now needs to be focused on the minority of cases where patients do not survive. These are men who have disease that is inherently resistant to platinum. Finding out what is genetically different in the tumours of men who do not respond to chemotherapy will be another critical clue.

Dr Clare Turnbull, a senior researcher in the Division of Genetics and Epidemiology, and an honorary consultant at The Royal Marsden NHS Foundation Trust, is at the forefront of pinpointing the inherited genetic variants which increase a man’s risk of developing testicular cancer, and those mutations in the tumour that convey treatment resistance.

In January, Dr Turnbull and her team uncovered new genetic mutations in testicular germ cell tumours, which make up the vast majority of testicular cancers. They found new chromosome duplications and other abnormalities that could contribute to the development of this cancer, as well as confirming a previous association with a gene called KIT. Their study also found defective copies of a DNA repair gene called XRCC2 in a patient who had become resistant to platinum-based chemotherapy. They were able to support the link between XRCC2 and platinum resistance by sequencing an additional platinum-resistant tumour.

“Although generally testicular cancer responds well to treatment, resistance to platinum-based chemotherapy is associated with a poor long-term survival rate,” explains Dr Turnbull. “The repercussions of these findings could be significant for men suffering with this disease. In the future, men who are destined to fail platinum treatment – currently around 3% of cases – could be identified before they endure courses of chemotherapy and be offered different treatments, more suited to their particular type of tumour.”

Scientists are also looking for clues in the genes of men who have developed testicular cancer so these can be used to identify men who are at high risk of the disease before they develop the cancer. Dr Turnbull’s research in this area over the last 10 years has been highly successful. With the recent discovery of ten new genetic loci associated with testicular cancer development, the total number of loci for testicular cancer identified is now 19 – and all of these have been found in studies led by or involving Dr Turnbull.

“Discovering genetic factors involved in testicular cancer potentially allows us to identify those at high risk before they develop cancer,” explains Dr Turnbull. “These men might benefit from screening, so we can catch the disease very early or even put in place preventative measures to stop them developing it at all.” Institute of Cancer Research