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Genomic Biomarkers in Predictive Medicine. an Interim Analysis

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Genomic Biomarkers in Predictive Medicine. an Interim Analysis Perspective Genomic biomarkers in predictive medicine Genomic biomarkers in predictive medicine. An interim analysis Keywords: biomarkers; early detection; genomics; personalized medicine; translational research Current genomics and biotechnology markers and the limited use of such denotes the prevalence of the high-risk promise the development of biomarkers markers outside research. Failure to allele and RR denotes the relative risk of to predict individual disease risk, enable focus also results in misleading claims disease for a subject with high-risk versus early detection of disease, and improve for early detection biomarkers based on standard risk allele. Most diseases have diagnostic classification to better inform studies with inappropriate controls. Here, sufficiently low prevalences that the OR individualized treatment. I discuss these I shall discuss separately several broad and RR are essentially equal. From this objectives, commenting on progress to categories of intended use as illustrated in formula one can show that the PPV is no date and obstacles to future success. The Fig 1 (summarized in Box 1). greater than RRÃp. So if the RR is 1.22 and discussion mainly uses examples from the disease prevalence is 5% (p ¼ 0.05), oncology where the nature of the disease then the absolute risk of developing the has expedited genomic approaches for Biomarkers of Disease Risk disease for a subject with a high-risk developing biomarkers. Many of the allele is no greater than 6.1%. If the lessons being learned in oncology, how- The development of genetic biomarkers RR were 5, then the absolute risk of ever, should be applicable to other for predicting risk of disease in indivi- developing disease for a subject with a chronic diseases. duals has had limited success to date. high-risk allele could be as large as 10% Biomarkers are biological measure- Numerous large whole-genome associa- for a disease with 5% prevalence in the ments that can be used to predict risk tion studies (Ioannidis et al, 2010) population. of disease, to enable early detection of involving thousands of patients have There are several possible explana- disease, to improve treatment selection been conducted for many chronic dis- tions for the ‘low penetrance’ (low PPV) and to monitor the outcome of therapeu- eases. These studies have genotyped of the identified genetic loci. For oncol- tic interventions. One major motivation cases and controls in order to identify ogy, a major reason is the genetic of the Human Genome Project was the germ-line polymorphisms that put indi- heterogeneity of most cancers. For exam- identification and development of such viduals at higher risk for developing a ple, estrogen receptor negative and biomarkers for ‘personalized, preventive specific disease. Many genetic loci have estrogen receptor positive breast cancer and predictive medicine’. Although the been identified as statistically significant are different in terms of the somatic sequencing of the human genome has and, in some cases, are providing valu- mutations that characterize them, as well had profound impacts on biomedical able leads for understanding the biologi- as with regard to natural history and research in many other fields, and while cal basis of the diseases. However, the responsiveness to treatment. From most it is still too early to fully assess its impact strength of the associations is often far perspectives they appear to be different on biomarker development (Lander, too weak to provide much value for diseases and lumping them together in 2011), I will provide an interim analysis counselling individuals (Bloss et al, searching for polymorphisms of disease and identify some of the roadblocks to 2011). Ioannidis et al reviewed 56 GWAS susceptibility is problematic (Kraft and progress. reporting 92 statistically significant asso- Halman, 2010) Indeed, the success of One of the greatest problems in the ciations between cancer phenotypes and early genetic linkage studies that identi- development and validation of biomar- genetic variants and found a median per- fied the highly penetrant BRCA1 locus kers is the ambiguity of the term and the allele odds ratio (OR) of 1.22 with an owed, in large part, to restricting the failure to recognize that biomarker valid- interquartile range of 1.15–1.36. The studies to cases with early onset breast ity means fitness for intended use. An absolute risk of disease for a subject cancer. Many other chronic diseases are enormous amount of resources is simply with a high-risk allele can be considered phenotypically and molecularly hetero- wasted because researchers do not focus the ‘positive predictive value’ of the geneous. They are also probably geneti- clearly on an intended use. This is seen, genetic test and can be expressed cally heterogeneous and thus very diffi- for example, in the gap between the PPV ¼ RRÃp/(1 þ gÃ(RR À 1)), where p cult to study with broad genome-wide enormous literature on prognostic bio- denotes the prevalence of the disease, g association studies. www.embomolmed.org EMBO Mol Med 3, 1–7 ß 2011 EMBO Molecular Medicine 1 Perspective Genomic biomarkers in predictive medicine BOX 1: Progress in genomic biomarker development Biomarkers are biological measure- mentioned. In this paper, I provide a short life-threatening is very challenging ments that can be used for a variety and personal assessment of the progress and the validation of such biomarkers of purposes, including identifying achieved in these areas of genomic requires very large randomized individuals who are at high risk of biomarker development. screening trials. The development of developing a disease, detecting dis- It is indicated that (i) progress has biomarkers for personalizing treat- ease early at a stage when it is been slow in personalized risk prediction ment selection, particularly in oncol- treatable and diagnostic classification and in early detection; (ii) genome-wide ogy, has seen greater progress. Key for personalized treatment based on a association studies are more likely to bottlenecks that limit progress in the biological characterization of the provide leads for understanding the translation of discoveries in genomics disease of each individual patient. pathogenesis of diseases than useful to biomarkers and treatments The sequencing of the human genome information on personalized risk assess- that reduce mortality and morbidity has provided an important body of ment; and (iii) development of bio- from chronic diseases are also information for the development of markers sufficiently sensitive and specific discussed. biomarkers for all of the purposes for early detection of diseases that will be Other possible explanations for the listic to expect that individual poly- Early Detection Biomarkers failure of finding highly penetrant sus- morphisms will have substantial expla- ceptibility genes is the fact that chronic natory or predictive power in elucidating Many diseases can be more effectively diseases are caused by the combined these relationships. For other chronic treated at an early stage. Most solid effects of multiple genetic polymorph- diseases, however, GWAS may be more tumours have a long sub-clinical course isms and/or that chronic diseases are essential for generating leads concerning prior to diagnosis and hence, there caused by a combination of genetic and the biology of the disease. In most should be substantial opportunity for environmental causes. The greatest cases, however, these leads must be early detection. There has been little potential value of genome-wide associa- followed by fine mapping of the regions success to date, however, in developing tion studies is to shed light on the of the detected polymorphisms and and validating early detection biomar- biological basis of the disease. For then years of biological investigations kers with medical utility. Early detection oncology, this may be less essential since to understand the relevance of the research has been severely hindered by cancers are in large part diseases of DNA disease alleles. It is probably too early the use of poor study methodology. Many modification and the tumour genomes to evaluate the impact of GWAS on cancer biomarkers are ‘discovered’ by can be directly evaluated. Of course medical utility. It is clear, however, that comparing levels of candidate proteins in interpreting tumour genomes to find the initial expectations of easy and direct tumour tissue, collected at diagnosis, to the mutations, which are key to oncogen- translation of GWAS findings to patient normal tissue. Numerous ‘discoveries’ esis, is difficult (Ledford, 2010) and benefit were unrealistic. GWAS studies have been published and publicized GWAS could provide additional useful in heterogeneous diseases such as cancer based on such evidence. Finding such a information. Most cancers, however, could be improved by evaluating difference, however, is very weak evi- result from complex sequences of associations with biologically meaning- dence that the marker will be useful for somatic mutations, which interact with ful subsets of patients with central early detection. A recent publication each other to influence tumour evolution review of cases to ensure accuracy of evaluated 28 candidate biomarkers using (Ashworth et al, 2011). It seems unrea- classification. serum samples obtained from subjects in Figure 1. Broad categories of intended use of biomarkers. 2 ß 2011 EMBO Molecular Medicine EMBO Mol Med 3, 1–7 www.embomolmed.org Perspective Richard Simon a randomized screening trial. None of the 28 showed early detection performance BOX 2: Statistics of early detection either individually or in combination as Sens ¼ probability marker is positive at screening T years before diagnosis of good as or better than the traditional lethal tumour. CA-125 (Mai et al, 2011). This prompted Spec ¼ probability marker is negative at screening in absence of lethal tumour. a commentary in Nature titled ‘Missing p ¼ prevalence of lethal tumours in population (0.01 means 1/100 patients the Mark’. (Bucher, 2011) One way to screened). improve early detection research would DCure ¼ improvement in cure proportion of lethal tumours detected T years be to perform genome-wide or proteome- before diagnosis.
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