Annual Review of Medicine - Volume 65, 2014

Recent advances in genetic analysis especially DNA sequencing technology open a new strategy for adult disease prevention by genetic screening. Physicians presently treat disease pathology with less emphasis on disease risk prevention/reduction. Genetic screening has reduced the incidence of untreatable childhood genetic diseases and improved the care of newborns. The opportunity exists to expand screening programs and reduce the incidence of adult onset diseases via genetic risk identification and disease intervention. This article outlines the approach, challenges, and benefits of such screening for adult genetic disease risks.

Genes causing rare heritable childhood diseases are being discovered at an accelerating pace driven by the decreasing cost and increasing accessibility of next-generation DNA sequencing combined with the maturation of strategies for successful gene identification. The findings are shedding light on the biological mechanisms of childhood disease and broadening the phenotypic spectrum of many clinical syndromes. Still, thousands of childhood disease genes remain to be identified, and given their increasing rarity, this will require large-scale collaboration that includes mechanisms for sharing phenotypic and genotypic data sets. Nonetheless, genomic technologies are poised for widespread translation to clinical practice for the benefit of children and families living with these rare diseases.

For a decade, the technologies behind DNA sequencing have improved rapidly in cost reduction and speed. Sequencing in large populations of cancer patients is leading to dramatic advances in our understanding of the cancer genome. The wide variety of cancer types sequenced and analyzed using these technologies has revealed many novel fundamental genetic mechanisms driving cancer initiation, progression, and maintenance. We have deepened our understanding of the signaling pathways, demonstrating disruption in epigenetic regulation and destabilization of the splicing machinery. The molecular mechanisms of resistance to targeted therapies are being elucidated for the first time. The translation of genome-scale variation into clinically actionable information is still in its infancy; nevertheless, insights from sequencing studies have led to the discovery of a variety of novel diagnostic biomarkers and therapeutic targets. Here, we review recent advances in cancer genomics and discuss what the new findings have taught us about cancer biology and, more importantly, how these new findings guide more effective diagnostic and treatment strategies.

Abdominal aortic aneurysm (AAA) disease is a common, morbid, and highly lethal pathology. Extraordinary efforts have been launched to determine the molecular and pathophysiological characteristics of AAAs. Although surgery is highly effective in preventing death by rupture for larger AAAs, no guidance or preventive therapy is currently available for the >90% of patients whose aneurysms are below the surgical threshold. Predictive animal models of AAA as well as human pathological samples have revealed a complex circuit of AAA formation and progression. The proteolytic destruction of matrix components of the aorta by different proteases has been extensively studied over many years. Recently, a novel class of small noncoding RNAs, called microRNAs, was identified as “fine-tuners” of the translational output of target genes; they act by promoting mRNA degradation. Their therapeutic potential in limiting AAA development appears very intriguing. Further, current studies assessing genetic and heritable associations for AAA disease have provided great insight into its pathogenesis, potentially enabling us to better clinically manage affected patients.

DNA sequencing has taught us much about the structure of cancer genomes and enabled the discovery of novel genes that drive and maintain tumorigenesis. With the advent and application of next-generation massively parallel sequencing technologies, one can rapidly generate and analyze data from the cellular “-omes”: genomes, exomes, and transcriptomes. This review highlights recent genomic discoveries in signal transduction, metabolism, epigenetic modifications, cell cycle and genome maintenance, RNA processing, and transcription. Additionally, genomic sequencing has revealed the complexity of the cancer genome and has enabled the discovery of functional rearrangements with therapeutic and diagnostic potentials.

Interindividual heterogeneity in drug response is a central feature of all drug therapies. Studies in individual patients, families, and populations over the past several decades have identified variants in genes encoding drug elimination or drug target pathways that in some cases contribute substantially to variable efficacy and toxicity. Important associations of pharmacogenomics in cardiovascular medicine include clopidogrel and risk for in-stent thrombosis, steady-state warfarin dose, myotoxicity with simvastatin, and certain drug-induced arrhythmias. This review describes methods used to accumulate and validate these findings and points to approaches—now being put in place at some centers—to implementing them in clinical care.

Tumor biomarker tests are critical to implementation of personalized medicine for patients at risk for or affected by breast cancer. A tumor biomarker test must have high analytical validity and clinical utility to be used to guide clinical care in standard practice. Few tumor biomarkers meet these high standards. These include germline DNA single-nucleotide polymorphisms in the BRCA1 and -2 genes to determine high risk in unaffected women, selected tissue-based markers to determine prognosis and predict benefit from therapy, and circulating MUC1, CEA and perhaps tumor cells to monitor patients with metastatic disease. Efforts to discover biomarkers that predict therapeutic toxicity are promising but not yet successful. Further research is needed to enhance the number of tumor biomarker tests so that patients with breast cancer can get the correct treatment at the appropriate time.

Large prospective randomized trials, such as the Prostate Cancer Prevention Trial (PCPT), Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, and Selenium and Vitamin E Cancer Prevention Trial (SELECT), have provided practitioners with considerable data regarding methods of treatment and prevention of prostate cancer. The best-studied medications for prevention are 5 alpha-reductase inhibitors. Their efficacy and side effects are well characterized. Other medications, dietary nutrients, and supplements have not been as well studied and generally do not demonstrate efficacy for disease prevention with an acceptable level of evidence.

Thyroid cancer is rapidly increasing in incidence, but the mortality rate remains flat. Debate has arisen over the need to detect or treat most thyroid cancers early, given their favorable natural history. The appropriate extent of surgery for thyroid cancer is also controversial: some researchers advocate partial and others total thyroidectomy; some advocate prophylactic central cervical lymph node dissection, whereas others only rarely recommend lymphadenectomy. Although radioactive iodine is effective, its appropriate use and dosage remain controversial. In addition, molecular analysis of thyroid cancer is frequently used for diagnostic purposes involving preoperative fine-needle biopsy specimens as well as to define targetable pathways altered in the disease to guide clinical trials of drug therapy for advanced thyroid cancers.

The past decade has witnessed tremendous advances in the discovery and development of novel small-molecule inhibitors targeting apoptosis pathways for cancer treatment, with some compounds now in clinical development. Early promising clinical data have been reported with these new classes of anticancer drugs. This review highlights the recent advancements in the development of small-molecule inhibitors targeting three major classes of antiapoptotic proteins: antiapoptotic B cell lymphoma 2 (BCL-2) proteins, inhibitor of apoptosis proteins (IAPs), and murine double-minute 2 (MDM2). Special emphasis is given to those that have been advanced into clinical trials. The challenges and future directions in the further preclinical and clinical development of these new anticancer drugs are also discussed.

Therapeutic strategies designed to target cancer metabolism are an area of intense research. Antimetabolites, first used to treat patients in the early twentieth century, served as an early proof of concept for such therapies. We highlight strategies that attempt to improve on the anti-metabolite approach as well as new metabolic drug targets. Some of these targets have the advantage of a strong genetic anchor to drive patient selection (isocitrate dehydrogenase 1/2, Enolase 2). Additional approaches described here derive from hypothesis-driven and systems biology efforts designed to exploit tumor cell metabolic dependencies (fatty acid oxidation, nicotinamide adenine dinucleotide synthesis, glutamine biology).

Retinoblastoma has gone from >95% mortality to >95% survival in the past 100 years. Once enucleation techniques were perfected, the majority of children survived, but without the eye (or vision in that eye). Over the past 100 years, progressively better techniques have been developed for salvaging vision without sacrificing patient survival. Presently, 99% of children treated at our center survive their cancer, >99% retain at least one eye, and >90% retain normal vision in at least one eye. The introduction of ophthalmic artery chemosurgery has been the most dramatic, non-radiation-based mode to maximally preserve vision.

Ipilimumab is the prototypical immunomodulatory antibody, approved by the FDA in 2011 for advanced melanoma on the basis of survival benefit. Since that time, we have made significant strides in optimizing this therapy: we have characterized the spectrum of immune-related adverse events and learned how to mitigate them with treatment algorithms, discovered potential biomarkers of activity, and identified the potential synergy between checkpoint modulation and other therapeutic modalities. Recent phase I trials have established the efficacy and safety of next-generation checkpoint agents, including PD-1 and PD-L1 inhibitors, across multiple tumor types. Much work lies ahead in developing these next-generation checkpoint agents, testing them in combination, and determining how to integrate them into the treatment paradigms of various tumor types.

Innate immune activation and inflammation have been posited to play a role in the pathophysiology of both depression and neoplastic growth. Cancer patients experience a threefold higher rate of depression than the general population within the first five years of diagnosis. Chronic depression is associated with increased cancer risk and shortened survival. Although the precise cellular and molecular mechanisms of this bidirectional relationship remain unclear, elevated concentrations of circulating plasma proinflammatory cytokines associated with depression may mediate the neuroendocrine, neural, and immune pathways that account for the relationship. Proinflammatory cytokines, in turn, are known to modulate key neurobiological correlates of depression including hypothalamic-pituitary-adrenal (HPA) axis dysregulation, monoamine neurotransmitter metabolism, and limbic system activity. Research is needed to determine whether optimal depression treatment improves cancer survival and to develop antidepressant strategies that target molecular and cellular mechanisms mediating inflammation and the neurobiological pathways influenced by the proinflammatory cytokines.

Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. Pathogenic variants in two interleukin-1 (IL-1)–regulating genes, NLRP3 and IL1RN, cause two severe and early-onset autoinflammatory syndromes, CAPS (cryopyrin associated periodic syndromes) and DIRA (deficiency of IL-1 receptor antagonist). The discovery of the mutations that cause CAPS and DIRA led to clinical and basic research that uncovered the key role of IL-1 in an extended spectrum of immune dysregulatory conditions. NLRP3 encodes cryopyrin, an intracellular “molecular sensor” that forms a multimolecular platform, the NLRP3 inflammasome, which links “danger recognition” to the activation of the proinflammatory cytokine IL-1β. The success and safety profile of drugs targeting IL -1 in the treatment of CAPS and DIRA have encouraged their wider use in other autoinflammatory syndromes including the classic hereditary periodic fever syndromes (familial Mediterranean fever, TNF receptor–associated periodic syndrome, and hyperimmunoglobulinemia D with periodic fever syndrome) and additional immune dysregulatory conditions that are not genetically well defined, including Still's, Behcet's, and Schnitzler diseases. The fact that the accumulation of metabolic substrates such as monosodium urate, ceramide, cholesterol, and glucose can trigger the NLRP3 inflammasome connects metabolic stress to IL-1β-mediated inflammation and provides a rationale for therapeutically targeting IL-1 in prevalent diseases such as gout, diabetes mellitus, and coronary artery disease.

α7-Nicotinic acetylcholine receptors have emerged as a potential therapeutic target for the treatment of neurocognitive dysfunctions in schizophrenia that are often resistant to existing antipsychotic drugs. Molecular evidence for involvement in schizophrenia of CHRNA7, the gene for the receptor subunit, in the neurobiology of deficits in attention is a critical rationale for the clinical study of α7-nicotinic receptor agonists to improve neurocognition. Initial clinical trials show enhancement of inhibitory neuron function related to sensory gating and increased attention and working memory, as well as improvement in negative symptoms such as anhedonia and alogia. Further development of this therapeutic strategy requires assessment of interactions with patients' heavy cigarette smoking and the relationship of this mechanism to the therapeutic effects of clozapine and olanzapine, both highly effective therapeutics with significant side effects.

Several monoclonal antibodies targeting B cells have been tested as therapeutics for inflammatory rheumatic diseases. We review important observations from randomized clinical trials regarding the efficacy and safety of anti–B cell antibody-based therapies for rheumatoid arthritis, systemic lupus erythematosus, antineutrophil cytoplasmic antibody-associated vasculitis, polymyositis/dermatomyositis, and primary Sjögren's syndrome. For some anti–B cell agents, clinical benefits have been convincingly demonstrated, while other B cell–targeted therapies failed to improve outcomes when added to standard-of-care treatment or were associated with increased rates of adverse events. Although the risk-benefit balance seems to be acceptable for currently licensed anti–B cell agents, additional studies are required to fully assess the safety of treatment regimens involving prolonged interference with B cell counts and functions in rheumatic disorders. Future studies should also evaluate how to maintain disease control by means of conventional and/or biologic immunosuppressants after remission-induction with anti–B cell antibodies.

Transcriptional coregulators (coactivators and corepressors) have emerged as the principal modulators of the functions of nuclear receptors and other transcription factors. During the decade since the discovery of steroid receptor coactivator-1 (SRC-1), the first authentic coregulator, more than 400 coregulators have been identified and characterized, and deciphering their function has contributed significantly to our understanding of their role in human physiology. Deregulated expression of coregulators has been implicated in diverse disease states and related pathologies. The advancement of molecular technologies has enabled us to better characterize the molecular associations of the SRC family of coactivators with other protein complexes in the context of gene regulation. These continuing discoveries not only expand our knowledge of the roles of coactivators in various human diseases but allow us to discover novel coactivator-targeting strategies for therapeutic intervention in these diseases.

Randomized trials have demonstrated that male circumcision (MC) reduces heterosexual acquisition of HIV, herpes simplex virus type 2, human papillomavirus (HPV), and genital ulcer disease among men, and it reduces HPV, genital ulcer disease, bacterial vaginosis, and trichomoniasis among female partners. The pathophysiology behind these effects is multifactorial, relying on anatomic and cellular changes. MC is cost effective and potentially cost saving in both the United States and Africa. The World Health Organization and Joint United Nations Program on HIV/AIDS proposed reaching 80% MC coverage in HIV endemic countries, but current rates fall far behind targets. Barriers to scale-up include supply-side and demand-side challenges. In the United States, neonatal MC rates are decreasing, but the American Academy of Pediatrics now recognizes the medical benefits of MC and supports insurance coverage. Although MC is a globally valuable tool to prevent HIV and other sexually transmitted infections, it is underutilized. Further research is needed to address barriers to MC uptake.

Patient-reported outcomes (PROs) are data elements directly reported by patients or their surrogates about experiences with care, including symptoms, functional status, or quality of life. PROs have commonly been evaluated in clinical trials for drug and medical device development. Interest is growing in the ability to integrate PROs into additional contexts, particularly product safety evaluation, comparative effectiveness research, and measurement of care quality. This interest reflects a growing focus on patient-centeredness in health care broadly and on provisions of the US Patient Protection and Affordable Care Act of 2010. Multiple initiatives demonstrate the feasibility and value of patient reporting in these areas. Inclusion of PROs in electronic health records and hospital patient portals, as well as longitudinal registries, can facilitate use of these data for multiple analytic purposes as well as enhance delivery of care and patient-provider communication. Challenges include the logistics and cost of implementing PRO programs; missing data, particularly from hard-to-reach and ill patients; and the need for standardization of outcome measures and electronic data representation. These challenges have been surmounted in limited initiatives and now must be translated to larger implementations.