Sunday, January 1, 2012

What types of treatment decisions are based on KRAS status

Trial data showed that no colorectal carcinoma patient with an activating KRAS mutation has responded to treatment with anti-EGFR antibodies. Carcinomas from patients unresponsive to first-line therapy can be screened retrospectively for the presence of the activating KRAS point mutations in codons 12, 13, and 61 by use of DNA template extracted from paraffin blocks.

Wild-type KRAS is necessary but not sufficient for response to EGFR inhibitors in patients with metastatic colorectal cancer. In addition, it has been shown that mutated KRAS [and BRAF (v-raf murine sarcoma viral oncogene homolog B1)] is associated with poorer overall survival. Since approximately 40% of tumor specimens in patients with colorectal cancer will exhibit KRAS mutations, KRAS mutation analysis is critical when considering anti-EGFR therapy. Patients with tumors exhibiting KRAS mutations should be considered for other treatments. Unfortunately, this does limit therapeutic options, but clinical trials are now open that specifically address patients with KRAS-mutated tumors.
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Bioelectronic DNA detection involves forming an electronic circuit mediated by nucleic acid hybridization and it serves as the basis for a DNA detection system called eSensor™ [1-4]. This system uses low-density DNA chips containing electrodes coated with DNA capture probes. Target DNA present in the sample hybridizes specifically both to capture probes and ferrocene labeled signal probes in solution thereby generating an electric current. Currente Sensor DNA chips contain as many as 36 electrodes for simultaneous detection of multiple pathogens from a single sample.

Many pathogens cause both acute and chronic disease at relatively low copy number and may be difficult or impossible to propagate in culture. Thus, most pathogen detection systems rely on nucleic acid amplification by using polymerase chain reaction (PCR). One highly effective amplification strategy targets conserved sequences among the family of organisms of interest. Such broad-range PCR strategies have been used to identify and characterize several known and previously uncharacterized bacteria [5,6] and viruses [7,8]. In order to maximize the utility of these effective pathogen nucleic acid amplification systems, amplification needs to be coupled with rapid, sensitive, and specific detection. Bioelectronic DNA detection by use of the eSensor chip might fulfill this need.

Human papillomaviruses (HPV) serve as an ideal model system for determining the efficiency and feasibility of eSensor DNA detection technology since there are at least 30 distinct genital HPV types that can be effectively amplified with broad-range consensus PCR primers. We designed two eSensor chips, each containing 14 probes specific for the conserved L1 region of the HPV genome. We evaluated clinical cervical cytology samples known to contain one or more HPV types. The eSensor DNA detection platform successfully detected the correct HPV type in most of these clinical samples, demonstrating that the system provides a rapid, sensitive, specific, and economical approach for multiple-pathogen detection and identification from a single sample.Background We used human papillomaviruses (HPV) as a model system to evaluate the utility of a nucleic acid, hybridization-based bioelectronic DNA detection platform (eSensor) in identifying multiple pathogens.