Category Archives: Genetic Medicine

SUNDAY, June 4, 2017 (HealthDay News) -- A twice-daily pill could help some advanced breast cancer patients avoid or delay follow-up sessions of chemotherapy, a new clinical trial reports.

The drug olaparib (Lynparza) reduced the chances of cancer progression by about 42 percent in women with breast cancer linked to BRCA1 and BRCA2 gene mutations, according to the study.

Olaparib delayed cancer progression by about three months. The drug also caused tumors to shrink in three out of five patients who received the medication, the researchers reported.

"Clearly the drug was more effective than traditional chemotherapy," said Dr. Len Lichtenfeld, deputy chief medical officer for the American Cancer Society.

"This is a group where a response is more difficult to obtain -- a young group with a more aggressive form of cancer -- and nonetheless we saw a close to 60 percent objective response rate," he said.

The study was funded by AstraZeneca, the maker of Lynparza.

Olaparib works by cutting off the avenues that malignant cancer cells use to stay alive, said lead researcher Dr. Mark Robson. He's a medical oncologist and clinic director of Clinical Genetics Service at Memorial Sloan Kettering Cancer Center in New York City.

The drug inhibits PARP, an enzyme that helps cells repair damaged DNA, Robson said.

Normal cells denied access to PARP will turn to the BRCA genes for help, since they also support the repair of damaged DNA, Robson said.

But that "backup capability" is not available to breast cancer cells in women with BRCA gene mutations, Robson said.

"When you inhibit PARP, the cell can't rescue itself," Robson said. "In theory, you should have a very targeted approach, one specifically directed at the cancers in people who have this particular inherited predisposition."

Olaparib already has been approved by the U.S. Food and Drug Administration for use in women with BRCA-related ovarian cancer. Robson and his colleagues figured that it also should be helpful in treating women with breast cancer linked to this genetic mutation.

The study included 302 patients who had breast cancer that had spread to other areas of their body (metastatic breast cancer). All of the women had an inherited BRCA mutation.

They were randomly assigned to either take olaparib twice a day or receive standard chemotherapy. All of the patients had received as many as two prior rounds of chemotherapy for their breast cancer. Women who had hormone receptor-positive cancer also had been given hormone therapy.

After 14 months of treatment, on average, people taking olaparib had a 42 percent lower risk of having their cancer progress compared with those who received another round of chemotherapy, Robson said.

The average time of cancer progression was about seven months with olaparib compared with 4.2 months with chemotherapy.

Tumors also shrank in about 60 percent of patients given olaparib. That compared with a 29 percent reduction for those on chemotherapy, the researchers said.

Severe side effects also were less common with olaparib. The drug's side effects bothered 37 percent of patients compared with half of those on chemo. The drug's most common side effects were nausea and anemia.

"There were fewer patients who discontinued treatment because of toxicity compared to those who received chemotherapy," Robson said. "Generally it was pretty well tolerated."

Only about 3 percent of breast cancers occur in people with BRCA1 and BRCA2 mutations, the researchers said in background notes.

Despite this, the results are "quite exciting," said Dr. Julie Fasano, an assistant professor of hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York City.

Olaparib could wind up being used early in the treatment of metastatic breast cancer as an alternative to chemotherapy, and future studies might find that the drug is effective against other forms of breast cancer, Fasano said.

"It may be a practice-changing study, in terms of being able to postpone IV chemotherapy and its associated side effects" like hair loss and low white blood cell counts, Fasano said.

Lichtenfeld noted that olaparib also places less burden on patients.

"It may be easier for women to take two pills a day rather than go in for regular chemotherapy," Lichtenfeld said. "Clearly, this is a treatment that will garner considerable interest.

The findings were scheduled to be presented Sunday at the American Society of Clinical Oncology's annual meeting, in Chicago. The study was also published June 4 in the New England Journal of Medicine.

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Drug Helps Fight Breast Tumors Tied to 'Cancer Genes' - Sioux City Journal

A genetic predisposition is a genetic characteristic which influences the possible phenotypic development of an individual organism within a species or population under the influence of environmental conditions. In medicine, genetic susceptibility to a disease refers to a genetic predisposition to a health problem,[1] which may eventually be triggered by particular environmental or lifestyle factors, such as tobacco smoking or diet. Genetic testing is able to identify individuals who are genetically predisposed to certain diseases.

Predisposition is the capacity we are born with to learn things such as language and concept of self. Negative environmental influences may block the predisposition (ability) we have to do some things. Behaviors displayed by animals can be influenced by genetic predispositions. Genetic predisposition towards certain human behaviors is scientifically investigated by attempts to identify patterns of human behavior that seem to be invariant over long periods of time and in very different cultures.

For example, philosopher Daniel Dennett has proposed that humans are genetically predisposed to have a theory of mind because there has been evolutionary selection for the human ability to adopt the intentional stance.[1] The intentional stance is a useful behavioral strategy by which humans assume that others have minds like their own. This assumption allows you to predict the behavior of others based on personal knowledge of what you would do.

E. O. Wilson's book on sociobiology and his book Consilience discuss the idea of genetic predisposition to behaviors

The field of evolutionary psychology explores the idea that certain behaviors have been selected for during the course of evolution.

The Genetic Information Nondiscrimination Act, which was signed into law by President Bush on May 21, 2008,[2] prohibits discrimination in employment and health insurance based on genetic information.

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Genetic predisposition - Wikipedia

Pacific Standard

The Future of Medicine Depends on Protections for Pre-Existing Conditions Pacific Standard Biomedical researchers can see a future where genetic tests are used to treat and prevent many diseases before major symptoms even present themselves. But that future won't be possible without strong insurance protections for pre-existing conditions.

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The Future of Medicine Depends on Protections for Pre-Existing Conditions - Pacific Standard

To aid our variant interpretation process, we created an openly-available online tool to efficiently classify variants based on the evidence categories outlined in the article: Richards, et al. Standards and guidelines for the interpretation of sequence variants. 2015. This site displays the evidence categories and descriptions from Table 3 and Table 4 with simple checkboxes for selecting appropriate criteria. The site then incorporates the algorithm in Table 5 to automatically assign the pathogenicity or benign impact based on the selected evidence categories. Since our process often requires analyzing multiple variants per patient, we have also allowed the option of aggregating each variant into an exportable table at the foot of the website for easy documentation of the variant review process for our records. Although this tool is based on the ACMG/AMP Standards and Guidelines, it is not affiliated with ACMG, AMP, or any of the authors of the publication.

_ PVS1 null variant (nonsense, frameshift, canonical 1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease

_ PS1 Same amino acid change as a previously established pathogenic variant regardless of nucleotide change _ PS2 De novo (both maternity and paternity confirmed) in a patient with the disease and no family history _ PS3 Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product _ PS4 The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls _ PP1 (Strong evidence) Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease

_ PM1 Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation _ PM2 Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium _ PM3 For recessive disorders, detected in trans with a pathogenic variant _ PM4 Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants _ PM5 Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before _ PM6 Assumed de novo, but without confirmation of paternity and maternity _ PP1 (Moderate evidence) Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease

_ PP1 Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease _ PP2 Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease _ PP3 Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) _ PP4 Patients phenotype or family history is highly specific for a disease with a single genetic etiology _ PP5 Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation

_ BP1 Missense variant in a gene for which primarily truncating variants are known to cause disease _ BP2 Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern _ BP3 In-frame deletions/insertions in a repetitive region without a known function _ BP4 Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.) _ BP5 Variant found in a case with an alternate molecular basis for disease _ BP6 Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation _ BP7 A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved

_ BS1 Allele frequency is greater than expected for disorder _ BS2 Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age _ BS3 Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing _ BS4 Lack of segregation in affected members of a family

_ BA1 Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

_ Sequencing artifact as determined by depth, quality, or other previously reviewed data

Download Table as CSV

Please note that the text of the variant evidence has been pulled directly from Richards, et al. Genet Med. 2015 May;17(5). This site does not claim authorship of any of the variant evidence descriptions.

This tool is based on the published ACMG/AMP Standards and Guidelines [Genet Med (2015)]. Anyone using this tool should be familiar with that publication. Individuals or institutions choosing to use this tool for clinical variant classification purposes assume legal responsibility for the consequences of its use. The authors make no warranty, express or implied, nor assume any legal liability or responsibility for any purpose for which the tool is used.

Please cite the following when using this tool in publications: Kleinberger J, Maloney KA, Pollin TI, Jeng LJ. An openly available online tool for implementing the ACMG/AMP standards and guidelines for the interpretation of sequence variants. Genet Med. 2016 Mar 17. doi: 10.1038/gim.2016.13. [Epub ahead of print] PubMed PMID: 26986878.

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Genetic Variant Interpretation Tool | University of ...

Imagine a world where an ambulance arrives to pick you up, not after a heart attack but before it happens, based on a signal sent from a device on your arm via your mobile phone. This sounds like the stuff of science fiction but could become a reality. It is all part of focusing healthcare more on prevention and less on cure. You dont wait for your car to break down before getting it repaired; you have it serviced and act on warning signs. Similarly, with healthcare, prevention is cheaper, more effective and less traumatic.

Another major change is a shift from a one size fits all approach to one tailored to individuals. Most medical treatments are designed for the average patient, and are successful for some but not others. Advances in what is called precision medicine will allow treatments to be tailored to characteristics, such as a persons genetic makeup or the genetic profile of a tumour.

The science that makes possible this combination of prevention and tailoring is genomics. The Human Genome Project mapped the human genome sequence in 2001, which is freely available in public databases. Less well known are the Precision Medicine Initiative in the US (which is creating a health database of a million Americans) and the 100,000 Genomes Project in the UK. These have only become viable because of huge advances in technology and data analytics.

Sequencing the first human genome cost $2.7bn and took 15 years. By 2008, the cost of sequencing had fallen to about $10m. Now sequencing can be done in a few days, with analysis in a few weeks, at cost of $1,000-$2,000.

Your genome is all the genetic information in your bodys instruction manual, encoded as DNA within the 23 chromosome pairs in cell nuclei. We are all very similar genetically: 99.9% of peoples genes are identical and it is the final tenth of a percent that determines differences like hair colour, build and predisposition to disease. Sequencing therefore has the ability to highlight a greater likelihood (or not) of developing conditions such as heart disease, lung cancer or Alzheimers.

The main aim of the 100,000 Genomes Project is to transform the use of genetics in the NHS. The project is run by Genomics England, a company owned by the Department of Health. It will sequence 100,000 whole genomes, half in people with rare genetic diseases (and close relatives who do not exhibit the disease) and half in patients with cancer. The results will be linked with patients medical records and stored securely and confidentially. By combining this information and allowing authorised researchers to access it, the project aims to provide a diagnosis for some patients with rare diseases and adapt cancer treatments. It will help to develop genomic medicine services for the NHS and support researchers to develop new medicines, therapies and diagnostic tests.

The 100,000 Genomes Project and similar ones around the world are unlikely to help the participants directly as the science of genomics is still in its infancy and there is a yawning gap between what sequencing technology enables us to discover and what doctors can do about it. However, it could provide invaluable data to help their children and grandchildren, as well as saving the NHS billions.

John Thornton is the director of e-ssential Resources and an independent adviser on business transformation, financial management and innovation.

John.Thornton@e-ssentialresources.co.uk

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Future medicine is all in the genes - Public Finance

New research published today in Genome Medicine uses large-scale DNA sequencing to identify genetic variants that cause developmental delay, a condition that currently goes undiagnosed in a large number of cases. Here to tell us more is author of the research, Dr. Greg Cooper.

Dr. Greg Cooper 30 May 2017

Developmental delay is associated with impaired cognition and failure to meet developmental milestones.

Developmental delay affects 1-2% of children worldwide. Symptoms often associated with developmental delay include impaired cognition, failure to meet developmental milestones, craniofacial and skeletal abnormalities, autism, and seizures. These disabilities can pose major medical, financial and psychological challenges.

Specific diagnoses for children with developmental delay are in many cases elusive, and the lack of a diagnosis is a major hardship for patients and their families. Inaccurate or unavailable diagnoses can result in years of expensive, invasive, and futile testing that complicates treatment decisions and may also lead to anxiety and emotional distress. Moreover, not knowing the reason for specific developmental delays slows research into improving therapeutic or educational options.

Anna Brooke Ainsworth, diagnosed with Cornelia de Lange syndrome (CDL), a rare genetic developmental disorder

In an effort to end the diagnostic odyssey for children with developmental delay, we have employed large-scale DNA sequencing to identify specific genetic variants that are causally relevant to developmental disabilities. As part of the NHGRI-funded Clinical Sequencing Exploratory Research Consortium, we began enrolling affected children into our study in 2013. Thus far, we have sequenced 371 children who present with developmental delay, and we have found the genetic cause and thus contributed to more precise and definitive clinical diagnoses in 27%.

We also enrolled biological parents when available to facilitate the identification of de novo i.e., present in a child but absent from his/her parents genetic variants, as these are known to be enriched among variants that cause developmental disabilities.

By sequencing the affected child and their parents, we were able in many cases to more efficiently identify the pathogenic variant relevant to their symptoms. In addition, by efficiently revealing relatively short lists of candidate de novo variants, trio sequencing also can greatly improve discovery of novel disease contributions.

That said, through retrospective analysis of proband genetic variants in the absence of parental sequence information, we were able to show that completing sequencing for only the child will often still yield a diagnosis, but will on average require more time and analytical effort when compared to the analysis of a trio.

Reanalysis success is driven by, and dependent upon, data sharing by clinicians and scientists who are also sequencing developmentally delayed patients.

Through our study, we observed that finding a pathogenic variant in an affected child is more challenging when close relatives have a neurological condition. This finding suggests that the underlying genetics in such multiplex families are more complex and harder to interpret than in simplex families, and that this distinction influences the success rate in terms of pathogenic variant discovery.

We also demonstrate that reanalysis over time of data from affected children with no initially identified causal genetic finding will often lead to new findings that considerably improve overall yield. Reanalysis success is driven by, and dependent upon, data sharing by clinicians and scientists who are also sequencing developmentally delayed patients.

Our data underscore the value of whole genome sequencing as an effective first-choice diagnostic tool in patients with developmental disabilities. Further, such sequencing, especially as proband-parent trios, will advance clinical and research progress and reduce the number and length of diagnostic odysseys that continue to impact numerous children and their families.

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Finding the genetic causes of developmental delay - BMC Blogs Network (blog)