Clinical drug response constitutes a complex phenotype emerging from the interplay of demographic, clinical, environmental, and genomic factors, among others. This complexity results in a marked interindividual variation in cardiovascular drug response, affecting both efficacy and toxicity, which can result in patient harm and the inefficient utilization of limited healthcare resources. Pharmacogenomics is the study and clinical application of the genetic determinants of drug response variation and aims to optimize drug efficacy and minimize adverse drug reactions through genotype-informed prescribing and monitoring recommendations. Pharmacogenomic associations have been established for several licensed cardiovascular drugs, including clopidogrel (CYP2C19), warfarin (VKORC1, CYP2C9, CYP4F2), and simvastatin (SLCO1B1). However, no cardiovascular pharmacogenomic association has yet been translated into routine clinical practice, which is attributable to a variety of reasons including logistical, financial, and knowledge barriers. Polygenic risk scores, multiomics approaches, and quantitative modeling are expected to become increasingly important in the effort to realize cardiovascular personalized medicine.
Human diseases reflect a spectrum of pathologies and mechanisms of disease pathogenesis. Despite the grouping of diseases according to their common features, the pathogenesis of various diseases is unique, and in some cases, multiple distinct mechanisms can give rise to a similar pathology (disease manifestation). Disease causation may be related to intrinsic factors or extrinsic factors, but many/most diseases are multifactorial, involving a combination of intrinsic (genetic) and extrinsic factors (exposures). It is now well recognized that most major diseases are ultimately the result of aberrant gene expression, and that susceptibility to disease is significantly influenced by patterns of gene expression in target cells or tissues for a particular type of pathology. It follows that gene mutations and other genetic (or epigenetic) alterations are important in the pathogenesis of many human diseases. Hence, molecular diagnostic testing for genetic alterations may (1) facilitate disease detection, (2) aid in disease classification (diagnosis), (3) predict disease outcomes (prognostication), and/or (4) guide therapy.
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with high mortality. Patients with a disease limited to the pancreas have a chance for a cure, but the likelihood of remission decreases if the cancer involves adjacent vessels or lymph nodes. Eventually the disease progresses to a terminal stage when the cancer is locally advanced and unresectable or when there are distant metastases. To prevent progression, the current goal is to detect PDAC in its earliest stages. Diagnostic biomarkers for pancreatic cancer must fulfill this criterion with a high sensitivity, specificity, and accuracy, but also be able to distinguish PDAC from other pancreatic conditions. Some of these conditions are associated with an increased risk of PDAC, but do not have the invasive disease at the time of identification. Although genetic alterations are well described in chronic pancreatitis, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms, the natural progression of these lesions to PDAC is not well understood. Over the last three decades the search for adequate diagnostic biomarkers for PDAC has closely followed the establishment of new biotechnological methods. Early methods detected protein biomarkers using enzyme-linked immunosorbent assay and Western blots. Subsequently the PCR was developed and found to have utility for the detection of genetic alterations. The latest chromatographic methods, gene-chips, and protein-chips enable a very broad search for diagnostic biomarkers including genome-wide screening. Most recently, epigenetic changes were found to be significantly altered in PDAC. Several studies have shown that panels of biomarkers increase sensitivity, specificity, and diagnostic accuracy in the diagnosis of PDAC, reflecting the fact that PDAC exhibits significant heterogeneity. Despite similar anatomic location cancers can have different biological backgrounds reflecting distinct molecular pathways to tumorigenesis, and therefore require different diagnostic biomarkers.
Glioblastoma (GBM) is the most common primary malignant brain tumor (WHO grade 4) with an overall survival following diagnosis of 1–2 years. GBM makes up approximately 12%–15% of all intracranial tumors and the great majority (60%–75%) of astrocytic tumors. Given the dismal prognosis for this malignancy, there has been an emphasis on characterizing the molecular alterations in these tumors for both prognosis and therapy. GBM development occurs due to alterations in several distinct pathways involving a combination of overexpression of growth factors and loss of apoptosis activators. With the explosion of molecular testing, particularly The Cancer Genome Atlas, GBM, as well as other types of gliomas, such as astrocytomas and oligodendrogliomas, are now characterized by distinct mutations in genes such as IDH and the presence or absence of chromosomal abnormalities such as the loss of 1p and 19q. This wealth of data has raised the possibility of better and more accurate characterization of this tumor for diagnostic, prognostic, and predictive purposes.
Fetuses with trisomy 21, or Down syndrome, can be identified in the first or second trimester of pregnancy using a combination of serum markers in maternal serum and ultrasound findings. The sensitivity and specificity of these modalities are quite good, being in the range of 95%. Recently, several groups have begun to exploit the power of massively parallel sequencing (MPS) to identify prenatal aneuploidies in cell-free fetal DNA that is found in the maternal circulation. Although court rulings regarding the patent positions surrounding this technology have led to other entities being able to offer this form of testing, including academic institutions, four major companies were originally founded with prenatal detection of fetal chromosome abnormalities as their primary focus and most testing in the United States is performed through these companies. The sensitivity and specificity of detection for Down syndrome using MPS are markedly superior to serum and ultrasound markers, being greater than 99%. However, it is important to stress to women seeking testing that the specificity of the MPS approach, while very high, is not perfect. This is a screening test and positive results need confirmation with invasive testing (amniocentesis). In this chapter, we review the techniques that each of these major, currently active U.S. companies are using for noninvasive prenatal screening.
