Earlier this month at the 58th Annual Meeting of the American Society of Human Genetics in Philadelphia, researchers reported the results of two genome-wide genetic analyses, identifying five significant loci that contribute to autism susceptibility, three of which have not been reported previously [1], as well as a novel association of genetic variation on chromosome 5 with autism [2].

Today, one in 150 children is diagnosed with autism. In fact, more children will be diagnosed with autism this year than with cancer, diabetes and AIDS combined [3]. Autism is a brain development disorder that impairs a person’s ability to communicate or interact socially. The disorder is associated with restricted and repetitive behavior. While there is no cure for autism, with appropriate treatment and education, many children can learn and develop. The genetics of autism are the focus of much study, as it is unclear whether the disorder is due to rare mutation(s) or multigene interactions.

In 2007, the Autism Genome Project Consortium evaluated 10,000 single nucleotide polymorphisms or SNPs in 1,181 families that had at least two autistic individuals [4]. SNPs (pronounced “snips”) are DNA sequence variations that occur when a single nucleotide — A, T, C or G — in the genome is changed, producing different alleles (meaning sequences that code for the same gene). These small variations in DNA sequence make up almost 90% of all human genetic variation.

The consortium study, using genetic linkage and copy number variation analysis, highlighted a region of chromosome 11 tightly linked to a gene called neurexin 1 (NRXN1), which encodes a cell surface protein found in neurons that contributes to glutamate synapses. Although the result was intriguing, it failed to meet genome-wide significance, scoring just below the threshold (4.03 versus 4.1).

Now, researchers at Johns Hopkins University, the Broad Institute of Harvard and MIT and the Institute for Juvenile Research at the University of Illinois at Chicago, have used more recent SNP technologies to profile 500,000 SNPs in 802 affected sibling pairs; 50x the number of SNPs as the 2007 consortium study. They performed family-based linkage analysis [1] and an association analysis to examine the role of common variants [2].

The scientists identified five genomic loci of significant linkage, three of which have not been previously identified; two at the end of the long arm of chromosome 6 (6q25.2 and 6q27) and one near the centromere (meaning the region of DNA typically found near the middle of a chromosome) of chromosome 17 (17p12).

Image generated from the Ensemble Karyotype Genome Browser

The SNP data set was also combined with a smaller National Institue of Mental Health (NIMH) autism sample to perform familial association mapping in 864 complete families [2]. Utilizing additional SNP microarray follow-up data and genotyping top hits revealed an array SNP on chromosome 5p15 that was transmitted less often than expected from parent to autistic offspring. The researchers argue that the allele likely confers some protection against autism [5]. A likely candidate for the allele is the gene semaphorin 5A (SEMA5A), which is in the genomic region and is involved in axonal (i.e. nerve fiber) guidance during neural development.

The scientists assayed brain slices from 20 autistic individuals (compared to 10 controls) and found reduced SEMA5A expression, further implicating a role in autism [5]. SEMA5A has been suggested by others to be a candidate gene in the etiology of autism. A 2006 gene expression study of six subjects with autistic disorder compared to healthy controls identified SEMA5A downregulation in blood samples [6].

For additional information on autism, visit Autism Speaks, an advocacy group that promotes autism research and improved public awareness about autism.

The familial association mapping study is compelling because it utilized genomic data, focused in on a target gene and validated the difference between autistic and control samples biochemically. Even more striking is the involvement of SEMA5A during neural development. These are the types of studies that will identify the molecular basis for autism and help us to better diagnose and treat the disorder.

References

1. Arking et al. A large-scale high-density linkage study of autism identifies multiple genome-wide significant loci. American Society of Human Genetics. 2008 Nov 15.
2. Weiss et al. Genome-wide association mapping in multiplex autism families. American Society of Human Genetics. 2008 Nov 15.
3. Facts about Autism. Autism Speaks. Accessed 2008 Nov 22.
4. Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007 Mar;39(3):319-28. Epub 2007 Feb 18.
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5. New autism loci discovered. The Scientist. 2008 Nov 12.
6. Melin et al. Constitutional downregulation of SEMA5A expression in autism. Neuropsychobiology. 2006;54(1):64-9. Epub 2006 Oct 5.
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Traditional media (i.e. television, print) are the principal sources of science information for the public. This is changing however; adult home broadband users under the age of 30 report that the internet is the most popular source for science news and information [1]. Unfortunately, while the public is consuming science reporting today more than ever before, the media is doing a poorer job covering the field. This is particularly troublesome for genomic medicine and personal genetics, since many physicians who lack training in genomics and genetics frequently get their information from the same mainstream media sources as the public.

Moving knowledge from the world of scientists into the public arena, where there are limitations on both space and reader interest, can be a challenging task. Reporting on medical genomics and personal genetics requires a translation in both language and phrasing. A 2004 study addressed popular media’s coverage of genomics, tracing reports from their original source in a scientific journal through to media publication [2]. The researchers found a significant difference in content between the original research paper and the news report, demonstrating the failure of mainstream media to accurately translate and report genomics for the public. However, until today, no standards existed to hold journalists accountable for accurate reporting of genomic medicine.

The HelixGene Foundation for Genomics was created to address the issue of reporting accuracy in medical genomics. Developed in response to significant misinformation published in a recent New York Times article discussing Google co-founder Sergey Brin and risk of Parkinson Disease, the Foundation organizes the distributed efforts of academics. The HelixGene Foundation grades publications to hold the media accountable for honest and accurate reporting of medical genomics, acting as a liaison between researchers, doctors and journalists. Additionally, the HelixGene Foundation will publish press releases about mutations to help journalists better report medical genomics and produce media about medical genomics to educate others.

Genomic medicine is believed to be the future of healthcare. Indeed, it is poised to improve disease diagnosis, therapy and prevention. All physicians will soon need to have a fundamental grasp of genomic medicine; to understand the concept of genetic variability, its interactions with the environment and its implications for patient care [3]. For both public and physician education, medical genomics and personal genetics must be accurately reported by media. The HelixGene Foundation for Better Genomic Medicine will review media reports on genomic medicine, in essence providing a peer review for accuracy and honesty.

Additional information on Genetics and Genomics for patients and the public, as well as health professionals, can be found at the National Human Genome Research Institute website. A publicly accessible New England Journal of Medicine article from 2002, Genomic Medicine — A Primer, is also recommended [3].

Additional resources on genome-based medicine or personalized medicine can be found in the Personalized Medicine category of the Highlight HEALTH Web Directory.

The media isn’t doing its job educating the public about genomic medicine and personalized genetics. The HelixGene Foundation will thus provide a valuable resource to verify media reports and hold journalists accountable for the accurate reporting of genomic medicine.

References

1. The Internet as a Resource for News and Information about Science. Pew Internet & American Life Project. 2006 Nov 20.
2. Kua et al. Science in the news: a study of reporting genomics. Public Understand. Sci. 13: 309-322. 2004.
3. Guttmacher and Collins. Genomic medicine–a primer. N Engl J Med. 2002 Nov 7;347(19):1512-20.
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A large-scale, multi-dimensional analysis of the genomic characteristics of glioblastoma, the most common primary brain tumor in adults, provides new insights into the roles of several genes and defines core biological pathways altered in tumor development [1]. The new Cancer Genome Atlas study, published in the September 4th advanced online edition of the journal Nature, also reveals a link between the DNA repair enzyme MGMT and a hypermutation phenotype, and has potential implications for the diagnosis and treatment of glioblastoma.

Glioblastoma is the most common and aggressive type of brain cancer. Patients newly diagnosed with glioblastoma have a median survival of approximately one year with generally poor response to therapy [2]. Gene expression profiling studies suggest multiple subtypes of glioblastoma that, when fully defined, may allow for more personalized therapeutic approaches [3-4].

The Cancer Genome Atlas (TCGA) is an integrated network of clinical sites, core resources and specialized genome characterization and genome sequencing centers that work together to accelerate our understanding of the molecular basis of cancer. The TCGA was launched in December 2005 as a pilot program to determine the feasibility of a large-scale effort to systematically explore genomic changes in all types of human cancer [5]. TCGA utilizes genome analysis technologies to catalog and discover major cancer causing genome alterations in large groups of human tumors through integrated multi-dimensional analyses. Glioblastoma is the first type of cancer to be studied in the TCGA pilot.

Investigators from seven cancer centers and research institutions across the U.S. integrated multiple types of data, including genetic mutations, gene expression, large-scale changes in chromosome number (amplification or deletion), epigenomics and clinical treatment. The scientists evaluated 206 biospecimens for DNA copy number, gene expression and DNA methylation (a chemical modification of DNA that reduces gene expression). Of these, 143 samples had matched normal peripheral blood DNA; 91 were selected for detection of somatic (meaning cells that differentiate into various tissues and organs, as opposed to germline cells (e.g. sperm and ova)) mutation in 601 selected genes. Eight genes were identified as significantly mutated, three of which were not previously reported for glioblastoma:

• Neurofibromatosis type 1 (NF1), the tumor suppressor responsible for the peripheral nerve disorder neurofibromatosis type 1.
• Avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2), a gene that functions as a co-receptor for connective tissue-derived growth factors and is frequently amplified in breast cancer.
• Phosphatidylinositol 3-kinase, regulatory subunit 1 (PIK3R1), a gene that influences the activity of an enzyme called PI3 kinase, which regulates cell proliferation and survival.

Researchers then mapped the sequencing data with additional genome characterization information onto major biological pathways and identified a highly interconnected network of alterations. By copy number data alone, three critical biological signaling pathways were identified: the Receptor Tyrosine Kinase/Ras/Phosphatidylinositol 3-Kinase pathway (a.k.a. RTK/Ras/PI3K pathway), which controls cell proliferation, cell survival and RNA translation; the p53 signaling pathway, which controls senescence (aging) and apoptosis (cell death); and the Retinoblastoma (RB) signaling pathway, which controls cell cycle progression and cell division. In a given tumor sample, it was likely that there was at least one aberrant gene from each of the three pathways. In fact, 74% of the samples had mutations in all three pathways, suggesting that deregulation of the three pathways is a requirement for glioblastoma pathogenesis.

Oncologists already know glioblastomas that have a methylated MGMT gene (DNA methylation reduces gene expression) respond better to temozolomide, an alkylating chemotherapy drug that is the current standard of care for glioblastoma patients. By integrating methylation data, somatic mutation data and clinical treatment data, scientists identified a relationship between MGMT methylation and a hypermutator phenotype described previously [6]. In patients with MGMT methylation, temozolomide treatment introduces a strong selective pressure to mutate genes that are essential for DNA repair. Thus, patients who initially respond to temozolomide may evolve not only treatment resistance but also a hypermutator phenotype (since DNA repair genes have been mutated). Future selective therapies may therefore require targeting both DNA-repair-deficient cells and an alkylating agent.

National Institutes of Health (NIH) Director Elias A. Zerhouni, M.D. said [7]:

These impressive results from TCGA provide the most comprehensive view to date of the complicated genomic landscape of this deadly cancer. The more we learn about the molecular basis of glioblastoma, the more swiftly we can develop better ways of helping patients with this terrible disease. Clearly, it is time to move ahead and apply the power of large-scale, genomic research to many other types of cancer.

The power of this study lies in the statistically robust number of samples evaluated, allowing for the identification of molecular subtypes that may otherwise be undetectable. Additionally, multiple technologies were employed to identify genomic copy number alterations, which were used to validate the results from any one platform. These approaches highlight the power of comprehensive integrative analyses.

This is an excellent example of how current genome characterization technologies can systematically explore the universe of genomic changes involved in cancer. The TCGA is also studying lung and ovarian cancer.

References

1. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Sep 4. [Epub ahead of print] DOI: 10.1038/nature07385
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2. Mischel and Cloughesy. Targeted molecular therapy of GBM. Brain Pathol. 2003 Jan;13(1):52-61.
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3. Mischel et al. Molecular analysis of glioblastoma: pathway profiling and its implications for patient therapy. Cancer Biol Ther. 2003 May-Jun;2(3):242-7.
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4. Liang et al. Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proc Natl Acad Sci U S A. 2005 Apr 19;102(16):5814-9. Epub 2005 Apr 12.
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5. NIH Launches Comprehensive Effort to Explore Cancer Genomics. National Cancer Institute Office of Media Relations press release. 2005 Dec 13.
6. Cahill et al. Loss of the mismatch repair protein MSH6 in human glioblastomas is associated with tumor progression during temozolomide treatment. Clin Cancer Res. 2007 Apr 1;13(7):2038-45.
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7. The Cancer Genome Atlas Reports First Results of Comprehensive Study of Brain Tumors: Large-Scale Effort Identifies New Genetic Mutations, Core Pathways. National Cancer Institute Office of Media Relations press release. 2008 Sept 4.