Pharmacogenomics in the nursing literature: An integrative review

Background

Pharmacogenomics is a rapidly growing component of personalized health care, and nurses must be competent to deliver genomic-focused nursing care.

Methods

We conducted an integrative review of pharmacogenomics in the nursing literature. A comprehensive search of the nursing literature was conducted using the key words pharmacogenomics and pharmacogenetics. A total of 47 unique articles were included.

Results

Articles represented mainly narrative reviews, with limited discussions of the implications for nursing practice, education, or research. As such, they provide limited direction for advancing either clinical practice or scientific inquiry.

Conclusions

This review serves as a call to action for more systematic and empirical publications addressing pharmacogenomics in nursing practice, education, and research. Nurses must be involved in and contribute to interdisciplinary conversations and burgeoning clinical practice initiatives related to pharmacogenomics.     

Epidermal growth factor receptor and K-Ras in non-small cell lung cancer-molecular pathways involved and targeted therapies

Lung cancer is currently the leading cause of cancer death in Western nations. Non-small cell lung cancer (NSCLC) represents 80% of all lung cancers, and adenocarcinoma is the predominant histological type. Despite the intensive research carried out on this field and therapeutic advances, the overall prognosis of these patients remains unsatisfactory, with a 5-year overall survival rate of less than 15%. Nowadays, pharmacogenetics and pharmacogenomics represent the key to successful treatment. Recent studies suggest the existence of two distinct molecular pathways in the carcinogenesis of lung adenocarcinoma: one associated with smoking and activation of the K-Ras oncogene and the other not associated with smoking and activation of the epidermal growth factor receptor (EGFR). The K-ras mutation is mainly responsible for primary resistance to new molecules which inhibit tyrosine kinase EGFR (erlotinib and gefitinib) and most of the EGFR mutations are responsible for increased tumor sensitivity to these drugs. This article aims to conduct a systematic review of the literature regarding the molecular pathways involving the EGFR, K-Ras and EGFR targeted therapies in NSCLC tumor behavior.     

Gap between the US and Japan in coverage of pharmacogenomic biomarkers by health insurance programs: More coverage is needed in Japan

In this study, we aimed to understand the gap in coverage of pharmacogenomic (PGx) biomarkers between Japan and the US. PGx biomarkers (1) in the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines; (2) that are CPIC level A or B; or (3) have US Food and Drug Administration (FDA)-approved drug labels, were determined. Subsequently, their coverage by US health insurance companies and the National Health Insurance (NHI) in Japan was investigated. We identified the top six health insurance companies with the largest market shares in the US and investigated the coverage for the PGx biomarkers by these health insurers, Medicare, Medicaid, and the NHI in Japan. We found that 19.9% of these biomarkers are covered by the six companies (10.0%, the CPIC guidelines; 25.1%, the FDA-approved drug labels). The coverage of somatic and germline biomarkers was respectively 86.8% and 8.5% in the US and 56.3% and 0.6% in Japan. A few germline PGx biomarkers are covered both in Japan and the US, but the coverage of both somatic and germline biomarkers was lower in Japan. Therefore, more coverage should be considered to improve patient outcomes after prescribing medications in Japan.     

儿童华法林药动和药效相关基因型频率和通路富集研究

目的 探讨华法林药动和药效相关基因位点的人群频率差异,为华法林药物基因组学研究提供基础数据。方法 利用复旦大学附属儿科医院(我院)620例全外显子测序（WES）数据,对公共数据库中已报道的华法林药物相关位点计算等位基因频率。与千人基因组东亚人和欧洲人的等位基因频率进行比较。结果 我院620例WES数据共检测到27个药物相关的多态性位点,涉及12个基因。27个华法林药物相关位点中,3个位点在这3组人群间差异无统计学意义（P≥0.01）; 10个位点在我院WES数据与千人基因组东亚人等位基因频率差异无统计学意义（P≥0.01）、与千人基因组欧洲人等位基因频率差异有统计学意义（P<0.01）;1个位点我院WES数据与千人基因组东亚人等位基因频率差异有统计学意义(P<0.01)、与千人基因组欧洲人等位基因频率差异无统计学意义（P≥0.01）;13个位点在我院WES数据与千人基因组东亚人、欧洲人等位基因频率差异均有统计学意义（P<0.01）。结论 华法林已报道的药物相关位点存在明显种族差异性,明确其变异为制定华法林个体化给药的精准医疗提供了基础数据。     

MDR1 (ABCB1) G1199A (Ser400Asn) polymorphism alters transepithelial permeability and sensitivity to anticancer agents

Purpose  P-glycoprotein (P-gp), encoded by MDR1 (or ABCB1), is important in anticancer drug delivery and resistance. We evaluated alterations in P-gp-mediated transport of anticancer agents due to the MDR1 G1199A polymorphism. Methods  Using stable recombinant epithelial cells expressing wild-type (MDR1 _wt ) or G1199A (MDR1 _1199A ), anticancer drug sensitivity and transepithelial permeability were evaluated. Results  The recombinant cells MDR1 _wt and MDR1 _1199A displayed comparable doxorubicin resistance. However, MDR1 _1199A cells displayed greater resistance to vinblastine, vincristine, paclitaxel, and VP-16 (11-, 2.9-, 1.9-, and 2.9-fold, respectively). Alterations in transepithelial permeability paralleled these changes. Efflux of doxorubicin was similar between MDR1 _wt - and MDR1 _1199A -expressing cells, while P-gp-mediated transport was greater for vinblastine and vincristine in MDR1 _1199A cells (2.9- and 2.0-fold, respectively). Conclusions  The occurrence and magnitude of the MDR1 G1199A effect is drug specific. Overall, the MDR1 G1199A polymorphism may impact anticancer efficacy through modulation of drug distribution and delivery to target tumor cells.     

Genomic era diagnosis and management of hereditary and sporadic colon cancer

The morbidity and mortality attributable to heritable and sporadic carcinomas of the colon are substantial and affect children and adults alike. Despite current colonoscopy screening recommendations colorectal adenocarcinoma (CRC) still accounts for almost 140000 cancer cases yearly. Familial adenomatous polyposis (FAP) is a colon cancer predisposition due to alterations in the adenomatous polyposis coli gene, which is mutated in most CRC. Since the beginning of the genomic era next-generation sequencing analyses of CRC continue to improve our understanding of the genetics of tumorigenesis and promise to expand our ability to identify and treat this disease. Advances in genome sequence analysis have facilitated the molecular diagnosis of individuals with FAP, which enables initiation of appropriate monitoring and timely intervention. Genome sequencing also has potential clinical impact for individuals with sporadic forms of CRC, providing means for molecular diagnosis of CRC tumor type, data guiding selection of tumor targeted therapies, and pharmacogenomic profiles specifying patient specific drug tolerances. There is even a potential role for genomic sequencing in surveillance for recurrence, and early detection, of CRC. We review strategies for diagnostic assessment and management of FAP and sporadic CRC in the current genomic era, with emphasis on the current, and potential for future, impact of genome sequencing on the clinical care of these conditions.     

FOXO3 mutation predicting gefitinib-induced hepatotoxicity in NSCLC patients through regulation of autophagy

Hepatotoxicity is a common side effect for patients treated with gefitinib, but the related pathogenesis is unclear and lacks effective predictor and management strategies. A multi-omics approach integrating pharmacometabolomics, pharmacokinetics and pharmacogenomics was employed in non-small cell lung cancer patients to identify the effective predictor for gefitinib-induced hepatotoxicity and explore optional therapy substitution. Here, we found that patients with rs4946935 AA, located in Forkhead Box O3 (FOXO3) which is a well-known autophagic regulator, had a higher risk of hepatotoxicity than those with the GA or GG variant (OR = 18.020, 95%CI = 2.473 to 459.1784, P = 0.018) in a gefitinib-concentration dependent pattern. Furthermore, functional experiments identified that rs4946935_A impaired the expression of FOXO3 by inhibiting the promotor activity, increasing the threshold of autophagy initiation and inhibiting the autophagic activity which contributed to gefitinib-induced liver injury. In contrast, erlotinib-induced liver injury was independent on the variant and expression levels of FOXO3. This study reveals that FOXO3 mutation, leading to autophagic imbalance, plays important role in gefitinib-induced hepatotoxicity, especially for patients with high concentration of gefitinib. In conclusion, FOXO3 mutation is an effective predictor and erlotinib might be an appropriately and well-tolerated treatment option for patients carrying rs4946935 AA.     

Pharmacogenomics in allogeneic hematopoietic stem cell transplantation: Implications on supportive therapies and conditioning regimens

Allogeneic hematopoietic stem cell transplantation mortality has declined over the years, though prevention and management of treatment-related toxicities and post-transplant complications remains challenging. Applications of pharmacogenomic testing can potentially mitigate adverse drug outcomes due to interindividual variability in drug metabolism and response. This review summarizes clinical pharmacogenomic applications relevant to hematopoietic stem cell transplantation, including antifungals, immunosuppressants, and supportive care management, as well as emerging pharmacogenomic evidence with conditioning regimens.