Review of Emerging 2018 Genomic Variants – a Genomenon Research Report

2018 has been another banner year in the progression of Precision Medicine! Year over year, there has been a dramatic rise in the number of scientific studies and initiatives that resulted in meaningful published findings, and 2018 was another record-breaker. To demonstrate trends in genetics and genomics research seen through the lens of scientific publications, the Genomenon team mined the genomics data aggregated in Genomenon’s Mastermind Genomic Search Engine to reflect on these trends.

Genomenon’s Mastermind Genomic Search Engine has indexed the full text of millions of genomic articles and supplemental data to provide immediate insight into the published research for every disease, gene, and mutation found in the literature. Mastermind is used by hundreds of diagnostic labs around the world to accelerate genomic interpretation and by pharmaceutical companies in drug discovery for its comprehensive genomic landscape of every disease.

New Genomic Insights Indicate an Emergence of Drug Resistance in Cancer and Focus on Rare Disease Research

Aggregating the granular genomics data allowed us to see the bigger-picture patterns that emerged.

  • 2017 findings: Newly-emergent variants were predominantly associated with cancer and research was predominantly focused on resistance mechanisms or the development of new therapeutics.
  • 2018 findings: A continued trend of studies and new discoveries detailing drug resistance mechanisms, with several of the previously identified emerging variants re-appearing on the list of the top 300 newly discovered variants; an increasing number of emergent variants were found in non-cancer diseases. Notable results are summarized in Tables 1 and 2.

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CRISPR Base Editors: An Upgrade for Treatment of Genetic Disease

The CRISPR(Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9(CRISPR-associated system 9) technology, often touted as one of the greatest recent inventions to drive progress in biotechnology, is currently being challenged and viewed more critically as a recent flurry of articles is casting doubt on the overall safety of this rising technology which up to now has mostly seen positive press.

CRISPR gene editing recent news and controversies

CRISPR, also often referred to as CRISPR/Cas9, is a technically and scientifically fascinating biological system that promises to yield a revolution in treatment of genetic diseases. CRISPR also offers a basis for powerful and flexible tools for furthering our understanding of eukaryotic gene expression. The underlying biology – though rather obscure just a decade ago – is nowadays an enormously active area of research in both basic science and medical/technical applications.

CRISPR

CRISPR has such a promise that a cautionary article about issues with off-target genetic mutations in some CRISPR applications (Kosicki et al., 2018), also recently presented in the Wall Street Journal (WSJ) by Mohan and Marcus (2018) shook the research community. Both the study in question and the industry effects that the WSJ article touch upon are relevant when using the form of technology called CRISPR/Cas9 (Cas9 DNA nuclease paired with its targeting CRISPR RNA(s)). However, there are more advanced and specialized versions of CRISPR technology that may avoid those challenges, in this case referring to the ‘base editor’ versions of derived Cas9 (Komor et al., 2016, Nishida et al., 2016). More about the details of both will be discussed later in this post.

Image credit:  Cancer Research UK.

Recent “ruling by the European Court of Justice that gene editing equals genetic engineering”

The concerns over use of CRISPR-Cas9 in the context of therapeutic development have been further amplified with a recent ruling by the European Court of Justice that Continue reading

Long Non-coding RNAs and Their Clinical Relevance in Cancer and Cancer Therapy

Long non-coding RNAs (lncRNAs) are clinically relevant in at least two major ways: as biomarkers for cancer or carcinogenesis and as actual targets for cancer therapy.

LncRNAs as biomarkers for cancer and carcinogenesis

LncRNAs can be biomarkers for cancer or carcinogenesis, and can yield insight into possible sensitivity or resistance to potential anti-cancer therapies. A well-known example includes the FDA-approved PROGENSA PCA3 assay testing in urinary samples used as part of the screening paradigm for prostate cancer. This is one demonstration of a testable form of lncRNA that exists with sufficient stability in a non-invasive biological sample, highlighting the key attributes of stability and ability to be assayed of a viable biomarker.

LncRNAs as targets for cancer therapy

A number of lncRNA genes have been found to be expressed at elevated levels which correlate with various cancers. To investigate a possible causal connection, there are several options to reduce or knockout expression in vivo, where the technology has already been proven to be effective in in vitro or cell culture settings. These approaches include (Gutschner et al.,2018):

  • siRNAs that are complementary to lncRNA which takes advantage of the RISC/argonaute system to degrade the target molecule
  • anti-sense oligos (ASOs), refined with chemical modifications to enhance activity or stability, which have been demonstrated to function by targeting lncRNAs to the endogenous RNase H systems for destruction
  • the use of targeting ribozymes, deoxyribozymes, or CRISPR/Cas9-derived technologies which have been proposed for silencing lncRNA.

The evolving field of RNA biology and lncRNA

Image credit: Parasramka et al. (2016)

Once relegated to the ‘junk’ DNA category, large segments of the genome and their associated transcripts have long been ignored, or thought of as unimportant. Only a few Continue reading