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DNA Molecular Testing and Personalized Medicine – Part 2

Skin-Cancer-and-Reconstructive-Surgery-Center-SCARS-Newport-Beach-SRT-Dermatologist-MicroarrayAnother genetic molecular technology that has evolved tremendously is real time polymerase chain reaction (PCR). When accompanied by reverse transcription prior to PCR (RT-PCR), it has also allowed rapid multiple gene analysis useful for cancer staging such as OncotypeDx. This platform analyzes RNA for 21 genes with RT-PCR to stratify breast cancer patients according to risk of metastases and chemotherapy benefit.

In addition to risk assessment, PCR can guide specific therapy by identifying specific gene variations. KRAS gene analysis in metastatic colorectal and non-small cell lung cancer predicts response to epidermal growth factor receptor (EGFR) inhibitor – panitumumab (Vectibix) and cetuximab (Erbitux), both monoclonal antibodies. BRAF V600 mutation in melanoma identified by PCR supports the use of enzyme inhibitors such as vemurafenib (Zelboraf) in unresectable or metastatic melanoma. See Clarient’s website for a list of available PCR tests. The large national laboratories are offering a more limited selection of DNA microarray tests generally not focusing on oncology. The innovations in microarray cancer testing are in the early stages of adoption, typically offered initially by smaller companies and academic laboratories such as CombiMatrix and UCSF lab.

Not to be outdone by RT-PCR, expression microarrays are now making inroads into the realm of genetic expression with RNA identification on massive scale. Instead of searching for copy number variations with preset sequences as markers, these microarrays identify and quantitate specific RNAs expressed in tumors. These arrays not only approach the sensitivity of detection of RT-PCR, but also assess the entire expression profile of the tumor (termed transcriptome). Instead of ordering a few PCR tests as offered by laboratories, clinicians and researchers will be able to test for a large number of gene expression products using these expression arrays.

Here is an overview of various applications of microarrays – with gene expression profiling featured at 0:30.

Comprehensive DNA sequencing technology has also been accelerating at a rapid rate. This video explains some of these technologies.

Recently, researchers of the 1000 Genomes Project announced that they have sequenced the complete DNA of more than 1000 people from 14 populations groups around the world. This global project involved 700 scientists and was published in Nature, November 2012. Scientists identified 38 million variations in genes or 98% of all the estimated human variation in the world. Today, an entire person’s genome can be sequenced in less than a month. Further development of sequencing of tumor genomes will further guide cancer research.

The massive and growing database of genetic information about cancers has been derived, in part, from molecular microarrays. Matching that information with the cancer’s clinical behavior and response to specific therapies will define specific genes and their effect on tumor growth. ErbB-2 amplification, KRAS and HRAS variation, and BRAF V600 gene discovery are but small steps of many needed to discover the role of the 200 + genes responsible for cancer proliferation. As these genes and their gene products are revealed, multiple drugs can be developed and ultimately used to counteract their expression. Personalized medicine with improved cancer staging utilizing DNA analysis and with individualized targeted cancer therapies is upon us. In another 10 years, it is reasonable to assume that some of the cancers can become chronic conditions or can even be cured.

Additional References:

A good learning and teaching tool for understanding DNA microarrays

Microarray based comparative genomic hybridization

DNA Microarray

Copy number variation

BAC clone vs. Oligonucleotide arrays

Genetic testing and molecular diagnostics