The future of clinical laboratory genomics

Medical Laboratory Observer, Dec, 2004 by Paul R. Billings, Matthew P. Brown

CONTINUING EDUCATION

[ILLUSTRATION OMITTED]

To earn CEUs, see test on page 16.

LEARNING OBJECTIVES

1. Recognize the number of genes coding for proteins in the human genome.

2. Recognize nontranscriptional methods used to expand the protein repertoire in vivo.

3. Recognize types of genetic testing and the impact that sequencing of the human genome has had on genetic testing.

4. List diseases for which nucleic acid testing is cost-effective and in current use.

5. List potential uses for molecular arrays.

6. Describe a molecular array.

7. Define pharmacogenomics.

8. Discuss differences between genomic and proteomic methods.

With the announcement of the completion of the draft sequence of the human genome in 2001, three pathways of activity seemed likely to be followed. (1,2) First, there were technical issues to resolve. The sequence was not totally complete--it needed sequence error correction and selected verification--and interpretations of data then required revision. This important activity has recently led to a reduction in the estimates of the total number of genes in our genome to the surprisingly small number of approximately 25,000. (3) Now nearing completion, the full revised sequence of the human genome and its interpretation will be essential to its further use. (4,5)

Second, the information generated as part of the Human Genome Project (HGP) would need to be compared to other information known about human diversity and would form the basis of a whole new series of comparative studies essential to developmental and evolutionary biology as well as anthropology. It was clear, for instance, that the complete set of human proteins when compared to the genomic set was substantially larger. Therefore, mechanisms for amplifying genomic information including messenger RNA (mRNA) splicing, translational and post-translational variations, and epigenetic mechanisms were likely to be important. In addition, proposals for the minimum set of genes required for a functional living genome flow directly from comparative genomics and the results of HGP. (6) New insights into human diversity and our role in the biological world continue to be aided by progress in genomics.

Finally, there needed to be direct clinical applications of the work associated with producing the human genomic sequence. Methods for the isolation, manipulation, and analysis of genetic material were improved as part of HGP. Previously unknown genes and modifying deoxyribose nucleic acid (DNA) sequences were discovered. Important bioinformatic tools were created to help mine genomic information and make appropriate associations with clinical data. In some cases, these developments would supplement already applied laboratory methods and clinical information. In other situations, they appeared to be "disruptive" innovations and discoveries that were likely to create new types of clinical laboratory practice. (7) This post-project clinical activity is critical for deriving near-term benefits from the basic knowledge generated as part of HGP.

This brief framework provides understanding as to how progress in genomics will impact clinical laboratory practices by reviewing:

* tests and methods that are currently being ordered;

* some important new procedures and assays that are or will likely become prominent parts of laboratory menus in the next few years;

* the types of new equipment, skills, and ancillary services required to deliver clinical genomics in a high-quality manner; and

* some practical suggestions about how clinical laboratories, with their differing goals, sizes, and resources, might prepare for continuing innovation and application of molecular biology and genomics.

Clinical laboratory genomics: a framework

Technically, genomics and genomic testing imply the assessment of many or all elements within the genome that modify a trait or condition of interest. Therefore, genetic testing traditionally involved the assessment of a single genetic locus that was relevant. In the current clinical laboratory milieu, aside from molecular assessment of multiallelic genes (e.g., DNA testing for cystic fibrosis) and certain new oncology tests, most testing is genetic; assays include biochemical, cytogenetic, and molecular methods.

Biochemical genetic testing is the most common. Genotype is inferred from measures of protein products and clinical history, if available. It is represented by traditional assays for hormones or other analytes as part of combination assays for fetal risk assessment during pregnancy (approx 2.5 million per year) or the assessment of risk in newborns (about 4 million per year via Guthrie spots). A variety of immunohistochemistry (IHC) methods are applied to cytology and microscopic pathology samples to assess the expression of proteins that may characterize the presence or activity of clinically important genes. IHC has been most prominently utilized in detecting and subclassifying malignant cells and tissues--for example, in characterizing the presence of products of the estrogen receptor gene on breast-cancer cells.