Over the past decade, mutations in more than 60 different genes have been linked with autism spectrum disorder, including de novo mutations, which occur spontaneously and aren’t inherited. But much of autism still remains unexplained.
A new study of nearly 6,000 families implicates a hard-to-find category of de novo mutations: those that occur after conception and therefore affect only a subset of cells.
De novo mutations can occur in a parent’s sperm or egg. Alternately, they can occur after egg and sperm meet, arising in an embryonic cell. These are known as somatic mutations or post-zygotic mutations (PZMs).
If a PZM happens very early, when the embryo has just a handful of cells, the mutation will show up in most of the mature organism’s cells. But the later PZMs occur during embryonic development, the fewer cells will carry them, making them harder to detect.
“If the mutation is in a very small fraction of all cells, it will be missed by whole-exome sequencing,” said Elaine Lim, a postdoctoral fellow in the lab of Christopher A. Walsh, the Bullard Professor of Pediatrics and Neurology at Harvard Medical School and Boston Children’s Hospital. Lim is first author of the study; Walsh is the senior investigator.
To identify PZMs, Lim, Walsh and colleagues obtained whole-exome sequencing data previously gathered from 5,947 families, usually through blood tests, courtesy of the Simons Foundation Autism Research Initiative Simplex Collection, the Autism Sequencing Consortium and Autism Speaks. They then re-sequenced some of the DNA from these children using three independent sequencing technologies in parallel.
Based on their findings, they classified 7.5 percent of autism spectrum disorder subjects’ de novo mutations as PZMs. Of these, 83 percent had not been picked up in the original analysis of their genome sequence.
Some PZMs affected genes already known to be linked to autism or other neurodevelopmental disorders (such as SCN2A, HNRNPU and SMARCA4) but sometimes affected these genes in different ways. Many other PZMs occurred in genes known to be active in brain development (such as KLF16 and MSANTD2) but not previously associated with autism spectrum disorder.
The connection of these genes to autism may have been missed because the earlier studies focused on mutations that knocked down gene function, the authors said.
“Some of the postzygotic mutations we found represented a gain of function, not a loss of function,” said Lim, who is also affiliated with the Wyss Institute for Biologically Inspired Engineering.
Lim, Walsh and colleagues then brought in another huge data set: gene expression data from the BrainSpan project. These publicly available data came from autopsies of brain samples from deceased patients of different ages, from prenatal through adult.
Comparing these with the genomic sequencing data, based mostly on blood DNA samples, allowed the researchers to estimate the timing of the PZMs and the brain regions they affected.
“By overlapping the data, we can start to map where in the brain these genes are expressed and when the mutations occurred during development,” said Lim. These analyses showed that PZMs in the subjects with autism spectrum disorder occur disproportionately in genes expressed in the amygdala.
“This was exciting to us, in that the amygdala has been proposed as an important region of the brain in autism,” said Lim.
Overall, the work adds to the evidence that complex brain disorders, such as epilepsy, intellectual disability, schizophrenia and brain malformations, can arise from non-inherited mutations that occur at some point during prenatal development.
Harvard Medical Schoolhttp://tinyurl.com/yb2lpxd7

Tens of thousands of cancer patients each year may benefit from an immunotherapy regimen called PD-1 blockade, based on results from a new clinical study. The findings establish genetic markers that help physicians identify which patients might respond to the therapy, which had been approved previously for a select few classes of cancer.
"What we describe in this paper applies to about 4% of patients with advanced cancer, regardless of the tumour type," said Bert Vogelstein of Johns Hopkins University, a senior author on the paper.
In an 86-patient clinical trial encompassing 12 different kinds of cancers, Dung Le and colleagues at Johns Hopkins University demonstrated that the immunotherapy drug pembrolizumab (an anti-PD-1 antibody) was effective against multiple types of tumours. All of the patients had cancers with defects in a genome maintenance pathway called mismatch repair (MMR).
"One patient, a young graduate student, was scheduled to go into hospice for terminal care two days prior to receiving the test result that showed he had an MMR-deficient tumour," said Vogelstein. "Shortly after beginning treatment, he went into remission. Since then he’s been able to finish his Ph.D., get married and live a happy and productive life."
PD-1 blockade doesn’t directly destroy tumours, but instead aids the immune system in targeting cancer cells — which can suppress the body’s defences in order to thrive.
Until recently, PD-1 blockade therapies were approved for only a select few classes of cancers, such as melanoma and lung cancer. Yet in a historic May 2017 decision , the United States Food and Drug Administration ruled that tumour genetics, rather than tissue of origin, could be used as a clinical indicator for pembrolizumab therapy.
"This is the first approval for a treatment that is tissue agnostic, which means clinicians can use pembrolizumab for any tumour with mismatch repair deficiency," said Le.
As many as 60,000 cancers every year might harbour MMR mutations that would render them susceptible to PD-1 blockade, according to Le and colleagues’ analysis of genome sequencing data from 12,019 cancers representing 32 distinct tumor types.
PD-1 blockade takes advantage of the fact that MMR defects make cancer genomes inherently unstable, giving them a potential Achilles’ heel.
"Tumours that have more chaotic genomes produce more proteins that are recognized by the immune system," said Geoff Lindeman, a breast cancer researcher at Walter and Eliza Hall Institute of Medical Research, who was not involved in the study.
Different types of cancers experience various levels of genomic chaos. Most tumors harbor roughly 50 genetic alterations whereas skin and lung cancers tend to have mutation counts well in the hundreds, arising from exposure to environmental DNA-damaging agents like UV light or cigarette smoke. Problems with MMR can push tumors towards thousands of mutations per cell.
Yet even with such high mutational loads, cancer can still escape from the immune system.
"Tumors find ways to switch off the immune cells," said Vogelstein. "Checkpoint inhibitors like anti-PD-1 can re-awaken these immune cells for an extra weapon in the ongoing war between cancer and the immune system."
Though the trial is still ongoing, 11 patients were able to stop taking the therapy; they have remained disease-free with no evidence of recurrence for an average of 8.3 months.

AAAS
www.aaas.org/news/studies-open-possibility-immunotherapy-more-cancer-patients

Mayo Clinic researchers have identified a new cause of treatment resistance in prostate cancer. Their discovery also suggests ways to improve prostate cancer therapy.
In the publication, the authors explain the role of mutations within the SPOP gene on the development of resistance to one class of drugs. SPOP mutations are the most frequent genetic changes seen in primary prostate cancer. These mutations play a central role in the development of resistance to drugs called BET-inhibitors.
BET, bromodomain and extra-terminal domain, inhibitors are drugs that prevent the action of BET proteins. These proteins help guide the abnormal growth of cancer cells.
As a therapy, BET-inhibitors are promising, but drug resistance often develops, says Haojie Huang, Ph.D., senior author and a molecular biologist within Mayo Clinic’s Center for Biomedical Discovery. Prostate cancer is among the most diagnosed malignancies in the United States. It is also the third leading cause of cancer death in American men, according to the American Cancer Society. Because of this, says Dr. Huang, improving treatments for prostate cancer is an important public health goal.
In the publication, the authors report SPOP mutations stabilize BET proteins against the action of BET-inhibitors. By this action, the mutations also promote cancer cell proliferation, invasion and survival.
“These findings have important implications for prostate cancer treatment, because SPOP mutation or elevated BET protein expression can now be used as biomarkers to improve outcome of BET inhibitor-oriented therapy of prostate cancer with SPOP mutation or BET protein overexpression,” says Dr. Huang.
The publication presents four major discoveries:
BET proteins (BRD2, BRD3 and BRD4) are true degradation substrates of SPOP.
SPOP mutations cause elevation of BET proteins in prostate cancer patient specimens.
Expression of SPOP mutants leads to BET-inhibitor resistance and activation of the AKT-mTORC1 pathway that promotes cancerous cell growth and survival.
Co-administration of AKT inhibitors overcomes BET inhibitor resistance in SPOP-mutated prostate cancer.

Mayo Clinichttp://tinyurl.com/y8phuv4s

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A subgroup of patients with osteosarcoma – a form of bone cancer – could be helped by an existing drug, suggest scientists from the Wellcome Trust Sanger Institute and their collaborators at University College London Cancer Institute and the Royal National Orthopaedic Hospital NHS Trust. In the largest genetic sequencing study of osteosarcoma to date, scientists discovered that 10 per cent of patients with a genetic mutation in particular growth factor signalling genes may benefit from existing drugs, known as IGF1R inhibitors.
The results suggest a re-trial of IGF1R inhibitors for the subset of patients with osteosarcoma who are likely to respond based on their genetic profile.
Osteosarcoma is the most common form of primary bone cancer in children and young adults, usually affecting people aged 10 to 24 years. 160 new patients are diagnosed with osteosarcoma in the UK each year, of which around one third cannot be cured.
The current treatment for osteosarcoma is chemotherapy followed by surgery, where the bone tumours are removed. There has not been a new treatment for osteosarcoma in almost 40 years, in spite of extensive research.
In the study, scientists analysed the genome of 112 childhood and adult tumours – double the number of tumours studied previously. In 10 per cent of cases, the team discovered cancer-driving mutations in insulin-like growth factor (IGF) signalling genes.
IGF signalling plays a major role in bone growth and development during puberty. Researchers believe that IGF signalling is also implicated in the uncontrollable growth of bone that is characteristic of osteosarcoma.
IGF signalling genes are the target of existing drugs, known as IGF1R inhibitors. Past clinical trials of IGF1R inhibitors as a treatment for osteosarcoma yielded mixed results although occasional patients responded to the treatment. In spite of this, IGF1R inhibitors have not been further tested in osteosarcoma, as it had been unclear who would benefit from the treatment.
In the study, scientists looked for mutations in the tumours to understand the mechanism of osteosarcoma development. The genetic information revealed a specific process for rearranging the chromosomes that results in several cancer-driving mutations at once.
“By sequencing the whole genome of the tumours, we have unpicked the mechanism behind osteosarcoma for the first time. We discovered a new process – chromothripsis amplification – in which the chromosome is shattered, multiplied and rejigged to generate multiple cancer-driving mutations at the same time. We believe this is why we see very similar osteosarcoma tumours in children and adults, which are not the result of ageing.”
Professor Adrienne Flanagan, senior author from the Royal National Orthopaedic Hospital NHS Trust and University College London Cancer Institute
“Currently, there are no new osteosarcoma treatments on the horizon. Genomic sequencing has provided the evidence needed to revisit clinical trials of IGF1R inhibitors for the subset of patients that responded in the past. The mutations of patients’ tumours may enable clinicians to predict who will, and will not respond to these drugs, resulting in more efficient clinical trials. The drugs could be effective for 10 per cent of osteosarcoma patients.”

Wellcome Sanger Institute
www.sanger.ac.uk/news/view/existing-drugs-could-benefit-patients-bone-cancer-genetic-study-suggests