Race and Ethnicity Linked to Risk of Relapse and Treatment Response in Young Leukemia Patients
Genome-wide study demonstrates the PDE4B gene predisposes patients with Native American ancestry to an increased risk of cancer relapse and decreased sensitivity to treatment.
“To overcome racial disparity you have to understand the reasons behind it”, Dr Jun Yang, assistant member of the St Jude Department of Pharmaceutical Sciences (TN, USA) and first author of the recent genome-wide study states. “While genetic ancestry may not completely explain the racial differences in relapse risk or response to treatment, this study clearly shows for the first time that it is a very important contributing factor”.
The study was a collaborative effort between researchers at the St Jude Children‘s Research Hospital and the worldwide Children‘s Oncology Group (COG) and comprised 2534 children and adolescents suffering from acute lymphoblastic leukemia (ALL). Hispanic patients, who have a high percentage of Native American ancestry, were found to be more likely to carry variants of the PDE4B gene which was strongly linked with relapse and reduced sensitivity to glucocorticoids; key medication in ALL treatment. In addition, the findings demonstrated that cancer was 59% more likely to return in patients whose genetic makeup reflected at least 10% Native American ancestry.
“This is just one example of how ancestry could affect relapse risk”, highlights the study‘s senior author Mary Relling, Pharmaceutical Sciences chair at St Jude Children‘s Research Hospital. “It is likely that many other genes are involved”.
Asked why the results of this study are so significant, Yang replied: “Childhood ALL has been a prototype for a cancer curable with drugs thanks to sophisticated chemotherapy individualization. However, racial disparities in ALL outcome have persisted and the underlying causes are largely unknown. Our study is the first to establish a pharmacogenetic basis of racial differences in ALL relapse. Further, we demonstrated that this genetic ancestry-related increase in relapse risk can be effectively reduced by a simple phase of additional chemotherapy. Collectively, our results convey a very positive message: disparities exist, some are genomically based, but they can be obviated by changing therapy”.
On how the results of the study should be carried forward, Yang speculated: “Building upon findings in this study, we are moving forward in two aspects. First, the prognostic value of ancestry-related genetic variations needs to be carefully examined in the context of different ALL therapy to determine potential applications of these genetic markers in treatment individualization in ALL. Secondly, we are focusing on specific genetic variations identified from this study to (1) characterize the mechanisms by which they affect response to antileukemic agents and (2) evaluate them as potential therapeutic targets for overcoming drug resistance in ALL using experimental model systems”.
The study, which would not have been possible without continued NIH and public support of large Phase III clinical trials – trials that enroll all patients, regardless of their race or ethnicity – marks an important step in the community, as Relling highlights: “The application of extensive genome-wide genotyping to large, unselected groups of patients in publicly supported clinical trials are necessary to discover the full spectrum of gene variations that may affect anticancer drug response in the racially and ethnically diverse group of individuals that constitute the American population”.
Source: Yang JJ, Cheng C, Devidas M et al.: Ancestry and pharmacogenomics of relapse in acute lymphoblastic leukemia. Nat. Genet. 43(3), 237–241 (2011).
Link Between Biomarkers and Risk of Cardiovascular Events in Kidney Disease Patients Not as Strong as First Suspected
Despite clinical practice guidelines for the disease recommending targeted treatment of specific biomarkers, a group of researchers from New Zealand have found inconclusive evidence for a positive association. With the exception of higher serum phosphorus levels, the meta-analysis of data from previous studies, failed to find an association between parathyroid hormone and calcium levels and the risk of death and cardiovascular events in kidney disease patients. The findings are published in the 16 March 2011 issue of the journal JAMA.
Remarking on the background of the findings, one of the authors of the study, Dr Suetonia Palmer, who joined the Christchurch Kidney Research Group (University of Otago, Christchurch, New Zealand) in early 2010, commented: “Nephrology guidelines recommend targets and treatment strategies to correct serum levels of phosphorus, calcium and parathyroid hormone because observational data suggest there is an association between these potential risk biomarkers and vascular disease and death. However, to date, randomized controlled trials have not shown that treating mineral levels with existing treatment options reduces cardiovascular events or mortality”. Palmer went on to stress that existing guidelines, which are predominantly based on observational studies, may subsequently be unsuitably promoting treatment for abnormal mineral metabolism in chronic kidney disease patients.
The meta-analysis comprised 47 studies (n = 327,644 patients) published between 1995 and 2010, derived from a database search. With this dataset, the Otago researchers were able to assess the quality of evidence linking the levels of the three biomarkers with the risk of death, cardiovascular death and nonfatal cardiovascular events in chronic kidney disease patients.
The evidence suggested that for every 1 mg/dl increase in serum phosphorus, the risk of death increased by 18%. “There was no significant association between all-cause mortality and serum level of parathyroid hormone or serum level of calcium. Data for the association between serum level of phosphorus, parathyroid hormone and calcium and cardiovascular death were each available in only one adequately adjusted cohort study”, the authors commented.
The implications of these results are wide-reaching, as the authors highlighted: “Broad adoption of healthcare practices that have insufficient evidence for safety or efficacy (in this case targeting serum mineral levels in individuals with chronic kidney disease) may lead to considerable unintended harm”.
In an accompanying JAMA editorial, Dr Bryan Kestenbaum from the University of Washington (WA, USA) commented: “Placebo-controlled clinical trials are the necessary next step to determine the risks and benefits of treatments that target mineral metabolism disturbances in patients with chronic kidney disease as a means to improve their health”.
Source: Palmer SC, Hayen A, Macaskill P et al.: Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA 305(11), 1119–1127 (2011); Kestenbaum B: Mineral metabolism disorders in chronic kidney disease. JAMA 305(11), 1138–1139 (2011).
Potential Biomarker for Amyloid Clearance in Alzheimer’s Disease May Enable Personalized Therapy
A new genetic biomarker that can be investigated using peripheral blood cells may have the potential to predict the prognosis of Alzheimer‘s disease (AD) patients and, furthermore, predict whether patients will react to immune-based amyloid-clearing treatment. It is hoped that the new findings, published in the Journal of Alzheimer‘s Disease, may lead to more accurate predictions of AD prognosis and the creation of patient groups within which personalized therapies can be targeted.
Biomarkers for AD diagnosis are currently needed to predict disease progression and severity. In addition, neuroprotective therapies are required to slow disease progression and prevent the loss of neurons; however, these need to be targeted to those patients for whom it will be of the most benefit. The team from the Greater Los Angeles VA Medical Center (CA, USA) and the UCLA School of Medicine (CA, USA) aimed to develop a biomarker based on the immune system‘s response to amyloid-β (Aβ) 1–42, a peptide that constitutes most of the amyloid plaques that are so damaging to those individuals with AD.
The Californian researchers found that the expression of MGAT3, a gene essential for Aβ phagocytosis, has an altered expression in peripheral blood macrophages in those patients with AD. Following Aβ stimulation of macrophages, response, in the form of MGAT3 transcription, differentiated cells into three groups. Type 0 cells exhibited very low MGAT3 transcription and were found to be representative of 45% of AD patients, compared with 10% of controls (p = 0.009).
Including the cellular response to bisdemethoxycurcumin, a synthetic curcuminoid believed to help the immune system boost the clearance of amyloids, allowed the team to further differentiate two more cell groups: Type I, which had low MGAT3 transcription and was upregulated by bisdemethoxycurcumin; and Type II, which had high MGAT3 transcription and was downregulated by bisdemethoxycurcumin. AD patients with Type 0 cells were demonstrated to have a more severe 2-year prognosis regarding loss of independence in comparison to Type I and Type II patients (p = 0.013).
In vivo vitamin D therapy has been suggested to improve AD symptoms in models, and in vitro has been demonstrated to improve the phagocytosis of Aβ. Incubation of the cells with a specific inhibitor of the vitamin D nuclear receptor demonstrated that Aβ phagocytosis in Type I and II patients was dependent on 1,25-dihydroxyvitamin D3, the active form of vitamin D, indicating that vitamin D therapy in some patients may improve the clearance of Aβ and reduce plaque formation.
The first author of the study Milan Fiala (David Geffen School of Medicine at UCLA, CA, USA) commented that while vitamin D3 appears to be beneficial to most people, the benefits of synthetic curcumin appeared to be more individualized. In addition, a commercially available test may become available in the future to check for MGAT3 immunity as a biomarker for AD.
However, it was noted that this is early research and that no dosage of vitamin D nor curcumin can be recommended for patients at this time. Larger studies with more patients are planned and should clarify some more details of the potential for treatment of AD.
Source: Fiala M, Mahanian M, Rosenthal M et al.: MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer‘s disease by vitamin D and curcuminoids. J. Alzheimers Dis. (2011) (Epub ahead of print).
Transferrin Crowned as New Biomarker for Sporadic Creutzfeldt–Jakob Disease
Researchers at Case Western Reserve University School of Medicine (OH, USA) have identified the first disease-specific premortem biomarker for sporadic Creutzfeldt–Jakob disease in cerebrospinal fluid (CSF) samples.
The study, which was led by Dr Neena Singh, associate professor of pathology at the School of Medicine, provides a springboard for developing a test to diagnose the universally fatal, degenerative brain disease in living patients. Currently, the only definitive diagnostic test for sporadic Creutzfeldt–Jakob disease (sCJD) requires brain tissue derived from biopsy or after death. The findings are published in the 9 March 2011 issue of the journal PLoS ONE.
By estimating levels of the iron-transport protein transferrin (Tf) in the CSF collected up to 24 months before death from patients with confirmed cases of sCJD, and those with dementia of non-CJD origin, the Case Western Researchers found that levels of Tf were significantly lower in the CSF of patients with sCJD compared with that of patients with dementia of non-CJD origin.
Commenting on the results, Dr Singh speculated: “The decrease in Tf is significant enough to distinguish sCJD from dementia of non-CJD origin with an accuracy of 80%. When combined with the currently used nondisease-specific biomarker T-tau, the diagnostic accuracy increases to 86%. This suggests that the two biomarkers represent separate disease processes, and complement each other as diagnostic biomarkers”.
Dr Singh went on to explain how the decrease in CSF Tf levels reflects the imbalance of the brain‘s iron metabolism that is associated with sCJD: “Being a part of the sCJD disease process, CSF Tf is likely to be a more precise indicator of sCJD than the current tests”.
One of the current methods of sCJD diagnosis to which Dr Singh refers is the detection of elevated levels of the proteins 14-3-3 and T-tau in the CSF of patients suspected of having the disease. This method results in a high incidence of false positive results owing to the fact that the elevated levels of these biomarkers are not specific to sCJD.
As outlined by Dr Singh, with the new biomarker comes the promise of accurately diagnosing patients while they are still alive. This is crucial in preventing the inadvertent spread of sCJD to healthy individuals, reducing the misdiagnosis of potentially treatable causes of dementia and eventually in the development of potential therapies.
In addition to providing improved diagnostic accuracy, Dr Singh notes: “CSF Tf has several other advantages: it is resistant to degradation by enzymes, ensuring consistent results even in poorly preserved CSF samples; Tf-β2, the brain specific isoform of Tf is equally efficient in identifying sCJD and is likely to provide accurate results even from samples that are accidentally contaminated with blood during the collection process; and, Tf is abundant in the CSF relative to the currently used biomarkers 14-3-3 and T-tau, allowing accurate diagnosis from a small sample volume”.
The next step for the researchers is establishing a user-friendly, quantitative test for Tf which allows quick and uniform sCJD diagnosis. Singh‘s group will also continue testing CSF samples from sCJD and other forms of human and animal prion disorders in order to determine the earliest time point in the disease course when this test becomes positive.
Source: Singh A, Beveridge AJ, Singh N: Decreased CSF Transferrin in sCJD: a potential pre-mortem diagnostic test for prion disorders. PLoS ONE 6(3), e16804 (2011).