A “winning” genomic signature

 

Glue Grant investigators have demonstrated that 16% of trauma patients die, 35% suffer from the life threatening condition of multiple organ failure (MOF), and the average time to recovery from MOF is 12 days.  The development of MOF and its often accompanying sepsis remain significant challenges to treat and cure in the intensive care unit.  A rapid prognostic to detect early changes in the patient’s blood leukocyte transcriptome associated with complicated or unfavorable clinical outcomes later in the hospital course would provide clinicians with valuable information regarding susceptibility to conditions like MOF, the major cause of late death in trauma.   The information from an “unfavorable” genomic signature obtained within hours of injury could be used to direct the patient’s clinical treatment during hospitalization and identify those patients who might benefit from early interventional therapies with biological response modifiers, creating a “winning” genomic signature compatible with clinical recovery and survival after serious injury. Read More

Genes turn on and off while re-establishing homeostasis

Severe injury is one example of an external perturbation that disturbs the homeostasis of many physiological processes. When homeostasis cannot be maintained after trauma or burns, a stress response is engaged.  If the stress response cannot defend homeostasis, an inflammatory response is induced.  Both the stress response and inflammatory response are engaged to eliminate the stressor, to promote adaptations to the stressor, and to return the system to the homeostatic, or more normal, state.  Maintaining homeostasis is a physiological imperative and the body’s natural, built-in mechanisms to maintain biological equilibrium include the regulation of genes to produce more protein (turned on or up-regulated) or less protein (turned off or down-regulated) at any given moment in time.  The patterns of certain genes being “up” versus “down” under select conditions can be used to create expression profiles or “genomic signatures” for the diagnosis and classification of human disease.

Genomic profiling in trauma and burns

The investigators are continuing their systematic analyses of the human leukocyte transcriptome, first in total blood leukocytes and subsequently in highly enriched blood leukocyte populations (neutrophils, lymphocytes, and monocytes) to assess how much information about patient prognosis might be contained in the gene expression profile.  In circulating blood leukocytes (white blood cells that are very active during inflammation), the investigators have identified post-injury changes in the expression of the entire genome or selected large portions of it, to glean important information about the inflammatory and immune response in critically ill trauma patients especially in those patients at risk for a complicated hospital course or death.

In a landmark study for the field of trauma, Glue Grant investigators examined genome-wide expression patterns following severe injury in 167 trauma patients and unearthed a “genomic storm” in which severe trauma alters the expression of more than 75% of the leukocyte genome during the first 28 days post-injury.  The investigators also wanted to learn whether the gene expression profiles could help the investigators distinguish between two different trauma patient cohorts: patients who were responding to the injury and patients who not only were responding to the injury, but also were responding to one or more medical complications like nosocomial infection or organ dysfunction.

“Genomic signatures” of innate and adaptive immune responses after critical illness and injury

Very surprisingly, the complicated and uncomplicated patient groups showed remarkable similarities in their genome profiles (as shown by the heat map), only differing by the magnitude of the early response and the time required for expression to return to control expression values. Investigators identified only 63 genes that were different between the complicated and uncomplicated patient groups over 28 days following injury (2-fold level at all time points with a false discovery rate <0.001). In examining the two genomic signatures, the investigators determined that the genomic response to trauma (1) induces (up-regulates) the activation of a large number of inflammatory mediators and genes involved in pattern recognition and antimicrobial functions and (2) suppresses (down-regulates) genes involved in antigen presentation, T-cell proliferation, and apoptosis.  Read additional details about this study.

&copy Warren et al.  Originally published in Molecular Medicine,. 15:220-7. doi: 10.2119/molmed.2009.00027

Conceptual representation of genomic DFR score. The DFR score can be visualized as the distance from the patient genomic profile (▾) to a healthy reference profile (●).

In a separate analysis using the same genome-wide expression data, investigators were able to derive a single genomic score within hours of massive injury that was associated with adverse clinical outcomes that developed later in the hospital course (infections, organ failure, and prolonged ventilation days, among others). This genomic score based on the patient’s own genomic profile uses a “distance from reference” (DFR, compared to healthy, non-injured individuals) to provide early important and useful information, above and beyond the current anatomic or physiologic scoring systems that are used over days into the patient’s hospital course.

The genomic data has been re-evaluated and confirmed in two follow-on studies.  One confirmatory study identified the same 63 genes whose gene expression was significantly different between trauma patients with complicated and uncomplicated clinical outcomes over 28 days.   The stored blood samples from the first 24 hours after injury were reassessed in a blinded fashion using NanoString™ technology and this genomic data was reduced to a single DFR score.  This rapid genomic composite score was able to retrospectively identify trauma patients at risk for a complicated clinical trajectory and organ failure.  In the second study, the genomic data were confirmatory to discriminate between the complicated and uncomplicated patient groups using the patient’s expression profile changes over 40-80 hours after injury.

Time to recovery (TTR) from multiple organ failure

&copy Minei et al. Originally published in Critical Care Medicine. 8:e1001093. doi: 10.1097/CCM.0b013e3182376e9f

Heat map of MOF scores over time after injury up to 28 days for 1,637 severely injured trauma patients

Using the genomic data, the investigators coined the term “time to recovery” or TTR from organ failure and used TTR to categorize the 167 trauma patients: 55 uncomplicated patients with TTR less than 4 days, 71 intermediate patients with TTR between 4–14 days, and 41 complicated patients with TTR more than 14 days.  In patients with an uncomplicated recovery, gene expression was returning or had returned to baseline within 7-14 days for both up- and down-regulated genes.  But, in patients with a complicated and prolonged recovery, the early changes in gene expression were greater, and the later changes had not returned to baseline, for the most part, by 28 days.  And, in burn patients, genomic changes are observed more than one year after injury.

Using genomic signatures to direct drug therapy

Glue Grant investigators have demonstrated that clinical trajectories that play out over several weeks post-injury can be identified by changes in circulating blood leukocyte expression measured in the first 12-24 hours after injury. In these genomic studies in injured patients, the investigators have identified two genomic signatures in trauma patients – one signature favorable toward an uncomplicated recovery and one associated with a prolonged and clinically challenging course.  What has sparked the interest of the investigators is the genomic finding of the suppression of the interferon genes and interferon-responsive genes that are downstream of interferon.  These interferon and related genes are highly suppressed in complicated patients compared with uncomplicated patients.

To take the next bold step in using genomic signatures to direct therapy, the investigators are designing an interventional clinical trial to prospectively predict clinical trajectories (uncomplicated and complicated patient cohorts) to identify those patients who might benefit from administration of the biological response modifier, interferon-gamma.  In these predicted to be complicated patients, the investigators will also determine whether interferon-gamma alters the unfavorable genomic signature, returning it to a more normal or favorable signature representing clinical recovery and survival after serious injury.

Relevant publications

Warren HS, Elson CM, Hayden DL, Schoenfeld DA, Cobb JP, Inflammation and Host Response to Injury Large Scale Collaborative Research Program. A genomic score prognostic of outcome in trauma patients. Mol Med. 2009 Jul-Aug;15(7-8):220-7.  PubMed PMID: 19593405; PubMed Central PMCID: PMC2707513

Xiao W, Mindrinos MN, Seok J, Cuschieri J, Cuenca AG, Inflammation and Host Response to Injury Large-Scale Collaborative Research Program. A genomic storm in critically injured humans. J Exp Med. 2011 Dec 19;208(13):2581-90. PubMed PMID: 22110166; PubMed Central PMCID: PMC3244029.  http://web.mgh.harvard.edu/TRT/

Desai KH, Tan CS, Leek JT, Maier RV, Tompkins RG, Inflammation and the Host Response to Injury Large-Scale Collaborative Research Program. Dissecting inflammatory complications in critically injured patients by within-patient gene expression changes: a longitudinal clinical genomics study.PLoS Med. 2011 Sep;8(9):e1001093. PubMed PMID: 21931541; PubMed Central PMCID:  PMC3172280

Minei JP, Cuschieri J, Sperry J, Moore EE, West MA, Harbrecht BG,  Inflammation and the Host Response to Injury Collaborative Research Program. The changing pattern and implications of multiple organ failure after blunt injury with hemorrhagic shock. Crit Care Med. 2012 Apr;40(4):1129-35. PubMed PMID: 22020243; PubMed Central PMCID: PMC3343366

Cuschieri J, Johnson JL, Sperry J, West MA, Moore EE, Inflammation and Host Response to Injury, Large Scale Collaborative Research Program. Benchmarking outcomes in the critically injured trauma patient and the effect of implementing standard operating procedures. Ann Surg. 2012 May;255(5):993-9. PubMed PMID: 22470077; PubMed Central PMCID: PMC3327791

Cuenca AG, Gentile LF, Lopez MC, Ungaro R, Liu H, Inflammation and Host Response to Injury Collaborative Research Program. Development of a genomic metric that can be rapidly used to predict clinical outcome in severely injured trauma patients. Crit Care Med. 2013 May;41(5):1175-85.  PubMed PMID: 23388514; PubMed Central PMCID: PMC3652285

Klein MB, Goverman J, Hayden DL, Fagan SP, McDonald-Smith GP, Inflammation and Host Response to Injury, and Large-Scale Collaborative Research Program. Benchmarking outcomes in the critically injured burn patient. Ann Surg. 2014 May;259(5):833-41. PubMed PMID: 24722222; PubMed Central PMCID: PMC4283803

Contact

Ronald Tompkins, MD, ScD Wenzhong Xiao, PhD Lyle Moldawer, PhD Ronald Maier, MD
rtompkins@mgh.harvard.edu wenzhong.xiao@mgh.harvard.edu moldawer@surgery.ufl.edu ronmaier@u.washington.edu
617-726-3447 617-724-7261 352-265-0494 206-744-3299

 

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sangwonleeA “winning” genomic signature