Pigment Epithelium-Derived Factor (PEDF) is a Determinant of Stem Cell Fate: Lessons from an Ultra-Rare Disease.

J Dev Biol. 2015 Dec;3(4):112-128

Authors: Sagheer U, Gong J, Chung C

Abstract
PEDF is a secreted glycoprotein that is widely expressed by multiple organs. Numerous functional contributions have been attributed to PEDF with antiangiogenic, antitumor, anti-inflammatory, and neurotrophic properties among the most prominent. The discovery that null mutations in the PEDF gene results in Osteogenesis Imperfecta Type VI, a rare autosomal recessive bone disease characterized by multiple fractures, highlights a critical developmental function for this protein. This ultra-rare orphan disease has provided biological insights into previous studies that noted PEDF's effects on various stem cell populations. In addition to bone development, PEDF modulates resident stem cell populations in the brain, muscle, and eye. Functional effects on human embryonic stem cells have also been demonstrated. An overview of recent advances in our understanding by which PEDF regulates stem cells and their potential clinical applications will be evaluated in this review.

PMID: 27239449 [PubMed - as supplied by publisher]

Validation of the Korean Genome Epidemiology Study Risk Score to Predict Incident Hypertension in a Large Nationwide Korean Cohort.

Circ J. 2016 May 25;

Authors: Lim NK, Lee JW, Park HY

Abstract
BACKGROUND: This study aimed to validate the Korean Genome Epidemiology Study (KoGES) risk score to predict the 4-year risk of hypertension (HT) in a large nationwide sample, and compare its discrimination and calibration with the Framingham and blood pressure (BP)-only models.Methods and Results:This study analyzed 69,918 subjects without HT at baseline from the National Sample Cohort in the National Health Insurance Service database. We compared the Framingham, KoGES, and BP-only models for discrimination using area under the receiver-operating characteristic curves (AROC), calibration using goodness-of-fit tests, and reclassification ability using the continuous net reclassification improvement (NRI) and integrated discrimination improvement. Of 69,918 subjects, 18.6% developed HT during the follow-up. AROC was significantly higher for the KoGES (0.733) than for the Framingham (0.729) or BP-only (0.707) model. Recalibrated Framingham model underestimated HT incidence in all deciles (P<0.001). BP-only model overestimated risk in the lower deciles (P<0.001). KoGES model accurately predicted risk in all except the highest decile (χ(2)=14.85, P=0.062). The KoGES model led to a significant improvement in risk reclassification compared with the Framingham and BP-only models (NRI, 0.354; 95% confidence interval [CI], 0.343-0.365 and 0.542; 95% CI, 0.523-0.561, respectively).
CONCLUSIONS: In this validation study, the KoGES model demonstrated better discrimination, calibration, and reclassification ability than either the Framingham or BP-only model. The KoGES model may help identify Korean individuals at high risk for HT.

PMID: 27238835 [PubMed - as supplied by publisher]

Primary actinomycosis of breast-A diagnosis on cytology.

Diagn Cytopathol. 2016 May 30;

Authors: Gosavi AV, Anvikar AR, Sulhyan KR, Manek DD

Abstract
Primary actinomycosis of breast is a rare disease with only a few cases reported in the literature. We present a case of a 25-year-old lactating woman with primary actinomycosis of breast which was diagnosed on cytology. The patient presented with lump in left breast with dull aching pain. Fine-needle aspiration cytology smears showed acute suppurative inflammation with presence of fluffy basophilic colonies on Hematoxylin and Eosin staining and branched, Gram positive filamentous bacilli on Gram staining. The bacilli were non-acid fast with 1% Zeihl Neelsen stain. A diagnosis of actinomycosis was suggested on cytology. Histopathological examination revealed an abscess with few Gram positive basophilic granules surrounded by eosinophilic Splendore-Hoeppli material thus confirming the diagnosis of actinomycosis. Meticulous search for microorganisms with the aid of special stains should be done on cytology smears before labeling an inflammatory lesion as nonspecific. Diagn. Cytopathol. 2016. © 2016 Wiley Periodicals, Inc.

PMID: 27238823 [PubMed - as supplied by publisher]

Association of first-trimester angiogenic factors with placental histological findings in late-onset preeclampsia.

Placenta. 2016 Jun;42:44-50

Authors: Triunfo S, Crovetto F, Crispi F, Rodriguez-Sureda V, Dominguez C, Nadal A, Peguero A, Gratacos E, Figueras F

Abstract
OBJECTIVE: To explore in women with late-onset preeclampsia (PE) the association between maternal levels of angiogenic/antiangiogenic factors in the first trimester of pregnancy and histological findings attributable to placental underperfusion (PUP).
METHODS: A nested case-control cohort study was conducted in 73 women with pregnancies complicated by late-onset PE (>34 weeks at delivery) matched with controls. First trimester uterine artery Doppler (UtA); maternal levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) were retrieved. Placentas were histologically evaluated using a hierarchical and standardized classification system. One-way ANOVA with linear polynomial contrast or linear-by-linear association test was performed to test the hypothesis of a linear association across study groups (controls, PE without PUP and PE with PUP).
RESULTS: In 54 (74%) placentas, 89 placental histological findings qualifying for PUP were found. Across study groups, significant values were observed in maternal levels of decreased PlGF (MoM values: 1.53, 1.41 and 1.37; p < 0.001), increased sFlt-1 (MoM values: 3.11, 3.11 and 3.22; p = 0.002), increased sFlt-1/PlGF ratio (MoM values: 2.3, 2.3 and 2.44; p < 0.001), abnormal UtA Doppler (MoM values: 1, 1.26 and 1.32; p < 0.001), and worse perinatal outcomes in terms of gestational age at delivery, cesarean section for not reassuring fetal status, birth weight and neonatal acidosis.
DISCUSSION: In late-onset PE an imbalance of circulating angiogenic and anti-angiogenic factors already present at 8-10 weeks of pregnancy was associated with histological findings reflecting placental insufficiency. An early first trimester screening by angiogenic factors might help to identify patients with placental involvement among late-onset PE cases.
CONCLUSION: In late-onset preeclampsia, first-trimester uterine Doppler and circulating levels of angiogenic/antiangiogenic factors are associated with placental underperfusion.

PMID: 27238713 [PubMed - in process]

A case of DIPNECH presenting as usual interstitial pneumonia.

Pneumonol Alergol Pol. 2016;84(3):174-7

Authors: Chatterjee K, Kamimoto JJ, Dunn A, Mittadodla E, Joshi M

Abstract
Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare disease that is classically described as presenting with cough, dyspnea, and wheezing in non-smoker middle aged females. Pulmonary function tests commonly demonstrate an obstructive pattern and CT of chest usually reveals diffuse air trapping with mosaic pattern. We present a case of patient with DIPNECH manifesting with restrictive pattern and as usual interstitial pneumonia on imaging.

PMID: 27238180 [PubMed - in process]

Discovery of a gamma heavy chain disease in a patient followed-up for a lymphoplasma cell proliferative disorder.

Ann Biol Clin (Paris). 2016 Jun 1;74(3):338-340

Authors: Humeau C, Monjanel H, Schellenberg F

Abstract
Gamma-heavy chains disease is a rare disease, with very few cases described in the literature. It is characterized by the presence of a monoclonal gamma-heavy chain without associated light chain. Its prevalence and prognosis are unknown. We report here the accidental discovery of a case of gamma-heavy chain disease during a pancytopenia exploration, performed in the hospital, in a patient known since 2002 for a lymphoplasmacytic type lymphoma first localized in bone marrow.

PMID: 27237805 [PubMed - as supplied by publisher]

The First Reported Case of Erdheim-Chester Disease in Egypt with Bilateral Exophthalmos, Loss of Vision, and Multi-Organ Involvement in a Young Woman.

Am J Case Rep. 2016;17:360-370

Authors: Abdellateef EE, Abdelhai AR, Gawish HH, Abdulmonaem GA, Abdelbary EH, Ahmed AI

Abstract
BACKGROUND Erdheim-Chester disease is a rare non-Langerhans-cell histiocytosis of unknown etiology with multi-organ involvement. CASE REPORT A 19-year-old woman presented with orthopnea, severe fatigue, bilateral exophthalmos, and gradual loss of vision. She had anemia and mild leucocytosis related to chronic illness. Marked left side pleural effusion and massive pericardial effusion with bilateral hydronephrosis were detected by plain X-ray, echocardiography, and computed tomography, respectively. Retro-orbital tissue and bone marrow biopsy revealed histiocytic infiltration, which was CD68-positive and CD1a-negative. CONCLUSIONS This report describes the first case presentation of Erdheim-Chester disease in our country. This case report may advance our understanding of an orphan disease. Our patient's young age and stable clinical status may allow long-term follow-up of treatment results.

PMID: 27237445 [PubMed - as supplied by publisher]

Comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells.

J Proteomics. 2015 Aug 3;126:163-71

Authors: Núñez de Villavicencio-Díaz T, Ramos Gómez Y, Oliva Argüelles B, Fernández Masso JR, Rodríguez-Ulloa A, Cruz García Y, Guirola-Cruz O, Perez-Riverol Y, Javier González L, Tiscornia I, Victoria S, Bollati-Fogolín M, Besada Pérez V, Guerra Vallespi M

Abstract
The second generation peptide CIGB-552 has a pro-apoptotic effect on H460 non-small cell lung cancer cells and displays a potent cytotoxic effect in HT-29 colon adenocarcinoma cells though its action mechanism is ill defined. Here, we present the first proteomic study of peptide effect in HT-29 cells using subcellular fractionation, protein and peptide fractionation by DF-PAGE and LC-MS/MS peptide identification. In particular, we explored the nuclear proteome of HT-29 cells at a 5h treatment identifying a total of 68 differentially modulated proteins, 49 of which localize to the nucleus. The differentially modulated proteins were analyzed following a system biology approach. Results pointed to a modulation of apoptosis, oxidative damage removal, NF-κB activation, inflammatory signaling and of cell adhesion and motility. Further Western blot and flow-cytometry experiments confirmed both pro-apoptotic and anti-inflammatory effects of CIGB-552 peptide in HT-29 cells.

PMID: 26013411 [PubMed - indexed for MEDLINE]

Role of frameshift ubiquitin B protein in Alzheimer's disease.

Wiley Interdiscip Rev Syst Biol Med. 2016 May 30;

Authors: Chen X, Petranovic D

Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by accumulation of misfolded and aggregated proteins. Since the ubiquitin-proteasome system (UPS) is the major intracellular protein quality control (PQC) system in eukaryotic cells, it is likely involved in the etiology of AD. The frameshift form of ubiquitin (Ubb(+1) ) accumulates in the neuritic plaques and neurofibrillary tangles in patients with AD. Ubb(+1) accumulates in an age-dependent manner as a result of RNA-polymerase mediated molecular misreading during transcription, which allows the formation of mutant proteins in the absence of gene mutations. The accumulation of the Ubb(+1) protein may act as an endogenous reporter for proteasome dysfunction and a growing number of studies have shown that Ubb(+1) may play more important pathogenic roles in AD etiology than previously hypothesized. The yeast Saccharomyces cerevisiae shares many conserved biological processes with all eukaryotic cells, including human neurons. This organism has been regarded as a model system for investigating the fundamental intracellular mechanisms, including those underlying neurodegeneration. We propose here that yeast systems biology approaches, combined with cell and molecular biology approaches will increase the relevant knowledge needed for advancement and elucidation of mechanisms and complex traits, which could provide new targets for therapeutic intervention in AD. For further resources related to this article, please visit the WIREs website.

PMID: 27240056 [PubMed - as supplied by publisher]

Clearing and Labeling Techniques for Large-Scale Biological Tissues.

Mol Cells. 2016 May 30;

Authors: Seo J, Choe M, Kim SY

Abstract
Clearing and labeling techniques for large-scale biological tissues enable simultaneous extraction of molecular and structural information with minimal disassembly of the sample, facilitating the integration of molecular, cellular and systems biology across different scales. Recent years have witnessed an explosive increase in the number of such methods and their applications, reflecting heightened interest in organ-wide clearing and labeling across many fields of biology and medicine. In this review, we provide an overview and comparison of existing clearing and labeling techniques and discuss challenges and opportunities in the investigations of large-scale biological systems.

PMID: 27239813 [PubMed - as supplied by publisher]

From big data to smart data in Alzheimer's disease. The brain health modeling initiative to foster actionable knowledge.

Alzheimers Dement. 2016 May 26;

Authors: Geerts H, Dacks PA, Devanarayan V, Haas M, Khatchaturian Z, Gordon MF, Maudsley S, Romero K, Stephenson D, Brain Health Modeling Initiative (BHMI)

Abstract
Massive investment and technological advances in the collection of extensive and longitudinal information on thousands of Alzheimer patients results in large amounts of data. These "big-data" databases can potentially advance CNS research and drug development. However, although necessary, they are not sufficient, and we posit that they must be matched with analytical methods that go beyond retrospective data-driven associations with various clinical phenotypes. Although these empirically derived associations can generate novel and useful hypotheses, they need to be organically integrated in a quantitative understanding of the pathology that can be actionable for drug discovery and development. We argue that mechanism-based modeling and simulation approaches, where existing domain knowledge is formally integrated using complexity science and quantitative systems pharmacology can be combined with data-driven analytics to generate predictive actionable knowledge for drug discovery programs, target validation, and optimization of clinical development.

PMID: 27238630 [PubMed - as supplied by publisher]

Comparison and Optimization of Methods for the Simultaneous Extraction of DNA, RNA, Proteins, and Metabolites.

Anal Biochem. 2016 May 26;

Authors: Vorreiter F, Richter S, Peter M, Baumann S, von Bergen M, Tomm JM

Abstract
The challenge of performing a time-resolved comprehensive analysis of molecular systems has led to the quest to optimize extraction methods. When the size of a biological sample is limited, there is demand for the simultaneous extraction of molecules representing the four areas of 'omics,' genomics, transcriptomics, proteomics, and metabolomics. Here,we optimized a protocol for the simultaneous extraction of RNA, proteins, and metabolites and a compared it to tow existing protocols.second for the concurrent recovery of DNA, RNA, and proteins and compared it to two existing protconducted a previouslty described method. Our optimisation comprised the addition of a methanol/chloroform metabolite purification before the separation of DNA/RNA and proteins. Extracted DNA, RNA, proteins, and metabolites were quantitatively and/or qualitatively analyzed. Of the three methods, only the newly developed protocol yielded all biomolecule classes of adequate quantity and quality.

PMID: 27237373 [PubMed - as supplied by publisher]

Characteristics of 419 patients with acquired middle ear cholesteatoma.

Braz J Otorhinolaryngol. 2016 May 3;

Authors: Rosito LP, da Silva MN, Selaimen FA, Jung YP, Pauletti MG, Jung LP, Freitas LA, da Costa SS

Abstract
INTRODUCTION: Cholesteatoma is a destructive lesion that can result in life-threatening complications. Typically, it presents with hypoacusis and continuous otorrhea as symptoms. Because it is a rare disease, there are few studies in Brazil describing the characteristics of patients with the disease.
OBJECTIVE: This study aimed to determine the prevalence of cholesteatoma in patients with chronic otitis media and describe clinical, audiological and surgical characteristics of patients with acquired middle ear cholesteatoma treated at a referral hospital in the public health system.
METHODS: Cross-sectional and prospective cohort study, including 1710 patients with chronic otitis media, treated between August 2000 and June 2015, without prior surgery. Detailed clinical history, videotoscopy, and audiometry were performed, in addition to review of medical records to search for surgical data. Cholesteatomas were classified according to their route of formation.
RESULTS: Of the patients with chronic otitis media, 419 (24.5%) had cholesteatoma; mean age of 34.49 years; 53.5% female and 63.8% adults. Bilateral cholesteatoma was observed in 17.1%. Anterior epitympanic cholesteatoma corresponded to 1.9%; posterior epitympanic, 32.9%; posterior mesotympanic, 33.7%; two routes, 14.8%; and indeterminate, 16.7%. The mean air-bone gap was 29.84dB and did not differ between routes of formation. There were no correlations between gap size and patient age or duration of symptoms. Of the surgical cases, 16.8% underwent closed tympanomastoidectomy and 75.2% open tympanomastoidectomy.
CONCLUSION: The prevalence of cholesteatoma in patients with chronic otitis media was 24.5% and it was more common in adults than in children. Posterior mesotympanic cholesteatoma was more frequent, with no difference in mean air-bone gap between the different routes of formation. In patients undergoing surgery, open tympanomastoidectomy was the procedure most frequently chosen.

PMID: 27236633 [PubMed - as supplied by publisher]

Metastatic malignant pleural mesothelioma masquerading as a case of acute abdomen secondary to small bowel perforation.

Ann Saudi Med. 2016 May-Jun;36(3):229-231

Authors: Alkhayal K

Abstract
Metastatic pleural mesothelioma is a rare disease. The present study aimed to report a rare presentation of metastatic malignant mesothelioma (MM). The patient was an elderly man who presented with small bowel (jejunal) perforation secondary to metastatic pleural mesothelioma deposits. This was a rare presentation of a rare disease and the first reported case in the published studies in which MM masqueraded as bowel perforation prior to the primary diagnosis.
SIMILAR CASES PUBLISHED: 1.

PMID: 27236396 [PubMed - as supplied by publisher]

Non-diabetic clinical applications of insulin.

J Basic Clin Physiol Pharmacol. 2016 May 28;

Authors: Benni JM, Patil PA

Abstract
BACKGROUND: Introducing a new drug to the market is a time-consuming process, is complex, and involves consumption of a lot of resources. Therefore, discovering new uses for the old drugs (i.e. drug repurposing) benefits the patients by providing them time-tested drugs. With developments in insulin therapy still happening, it is worth keeping up to date on trends in the use of this powerful glucose-lowering agent. The aim of this article is to explore the potential non-diabetic clinical applications of insulin.
METHODS: Literature survey was carried out through the various scientific journals publishing experimental and clinical research papers regarding the diverse applications of insulin other than in diabetes mellitus. These applications include both therapeutic as well as diagnostic uses of insulin. The relevant information collected from these publications was paraphrased in the present paper.
RESULTS: On studying the literature, the non-diabetic uses of insulin include the following: wound healing, parenteral nutrition, antiaging, body building, cardioprotection in acute coronary syndromes, insulin tolerance test to test the hypothalamo-pituitary-adrenal axis functioning, cell culture, cancer treatment, organ preservation, and management of septic shock, calcium channel, β blocker overdose and other critical illnesses in intensive care units.
CONCLUSIONS: This review attempts to survey some interesting new applications of insulin other than in diabetes mellitus.

PMID: 27235672 [PubMed - as supplied by publisher]

Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery.

BMC Genomics. 2016;17(1):414

Authors: Jia Z, Liu Y, Guan N, Bo X, Luo Z, Barnes MR

Abstract
BACKGROUND: Drug repositioning, finding new indications for existing drugs, has gained much recent attention as a potentially efficient and economical strategy for accelerating new therapies into the clinic. Although improvement in the sensitivity of computational drug repositioning methods has identified numerous credible repositioning opportunities, few have been progressed. Arguably the "black box" nature of drug action in a new indication is one of the main blocks to progression, highlighting the need for methods that inform on the broader target mechanism in the disease context.
RESULTS: We demonstrate that the analysis of co-expressed genes may be a critical first step towards illumination of both disease pathology and mode of drug action. We achieve this using a novel framework, co-expressed gene-set enrichment analysis (cogena) for co-expression analysis of gene expression signatures and gene set enrichment analysis of co-expressed genes. The cogena framework enables simultaneous, pathway driven, disease and drug repositioning analysis. Cogena can be used to illuminate coordinated changes within disease transcriptomes and identify drugs acting mechanistically within this framework. We illustrate this using a psoriatic skin transcriptome, as an exemplar, and recover two widely used Psoriasis drugs (Methotrexate and Ciclosporin) with distinct modes of action. Cogena out-performs the results of Connectivity Map and NFFinder webservers in similar disease transcriptome analyses. Furthermore, we investigated the literature support for the other top-ranked compounds to treat psoriasis and showed how the outputs of cogena analysis can contribute new insight to support the progression of drugs into the clinic. We have made cogena freely available within Bioconductor or https://github.com/zhilongjia/cogena .
CONCLUSIONS: In conclusion, by targeting co-expressed genes within disease transcriptomes, cogena offers novel biological insight, which can be effectively harnessed for drug discovery and repositioning, allowing the grouping and prioritisation of drug repositioning candidates on the basis of putative mode of action.

PMID: 27234029 [PubMed - as supplied by publisher]

The importance of review articles in making the voice of rare diseases heard: OJRD's 10th anniversary.

Orphanet J Rare Dis. 2016;11(1):71

Authors: Aymé S

PMID: 27234175 [PubMed - as supplied by publisher]

Perirenal Involvement of Mantle Cell Lymphoma: Imaging Features.

Urology. 2016 May 24;

Authors: Ufuk F, Karaman E, Karabulut N

Abstract
Perirenal lymphoma is a rare disease and accouning for less than 10% of all malignant lymphomas. Mantle cell lymphoma (MCL) is the rarest but one of the most aggressive non-Hodgkin's lymphoma (NHL) subtype. The perirenal involvement of MCL has not been reported previously. A 69-year-old male, who had been diagnosed as having mantle cell lymphoma (MCL) one year ago, presented with recent-onset right back pain. Herein we present the key imaging findings of perirenal soft tissue manifestation of MCL.

PMID: 27233934 [PubMed - as supplied by publisher]

From frames to OWL2: Converting the Foundational Model of Anatomy.

Artif Intell Med. 2016 May;69:12-21

Authors: Detwiler LT, Mejino JL, Brinkley JF

Abstract
OBJECTIVE: The Foundational Model of Anatomy (FMA) [Rosse C, Mejino JLV. A reference ontology for bioinformatics: the Foundational Model of Anatomy. J. Biomed. Inform. 2003;36:478-500] is an ontology that represents canonical anatomy at levels ranging from the entire body to biological macromolecules, and has rapidly become the primary reference ontology for human anatomy, and a template for model organisms. Prior to this work, the FMA was developed in a knowledge modeling language known as Protégé Frames. Frames is an intuitive representational language, but is no longer the industry standard. Recognizing the need for an official version of the FMA in the more modern semantic web language OWL2 (hereafter referred to as OWL), the objective of this work was to create a generalizable Frames-to-OWL conversion tool, to use the tool to convert the FMA to OWL, to "clean up" the converted FMA so that it classifies under an EL reasoner, and then to do all further development in OWL.
METHODS: The conversion tool is a Java application that uses the Protégé knowledge representation API for interacting with the initial Frames ontology, and uses the OWL-API for producing new statements (axioms, etc.) in OWL. The converter is relation centric. The conversion is configurable, on a property-by-property basis, via user-specifiable XML configuration files. The best conversion, for each property, was determined in conjunction with the FMA knowledge author. The convertor is potentially generalizable, which we partially demonstrate by using it to convert our Ontology of Craniofacial Development and Malformation as well as the FMA. Post-conversion cleanup involved using the Explain feature of Protégé to trace classification errors under the ELK reasoner in Protégé, fixing the errors, then re-running the reasoner.
RESULTS: We are currently doing all our development in the converted and cleaned-up version of the FMA. The FMA (updated every 3 months) is available via our FMA web page http://si.washington.edu/projects/fma, which also provides access to mailing lists, an issue tracker, a SPARQL endpoint (updated every week), and an online browser. The converted OCDM is available at http://www.si.washington.edu/projects/ocdm. The conversion code is open source, and available at http://purl.org/sig/software/frames2owl. Prior to the post-conversion cleanup 73% of the more than 100,000 classes were unsatisfiable. After correction of six types of errors no classes remained unsatisfiable.
CONCLUSION: Because our FMA conversion captures all or most of the information in the Frames version, is the only complete OWL version that classifies under an EL reasoner, and is maintained by the FMA authors themselves, we propose that this version should be the only official release version of the FMA in OWL, supplanting all other versions. Although several issues remain to be resolved post-conversion, release of a single, standardized version of the FMA in OWL will greatly facilitate its use in informatics research and in the development of a global knowledge base within the semantic web. Because of the fundamental nature of anatomy in both understanding and organizing biomedical information, and because of the importance of the FMA in particular in representing human anatomy, the FMA in OWL should greatly accelerate the development of an anatomically based structural information framework for organizing and linking a large amount of biomedical information.

PMID: 27235801 [PubMed - as supplied by publisher]

SLCO1B1*5 polymorphism (rs4149056) is associated with chemotherapy-induced amenorrhea in premenopausal women with breast cancer: a prospective cohort study.

BMC Cancer. 2016;16(1):337

Authors: Reimer T, Kempert S, Gerber B, Thiesen HJ, Hartmann S, Koczan D

Abstract
BACKGROUND: Because inheritance is recognized as playing a role in age at menarche and natural menopause, the development of chemotherapy-induced amenorrhea (CIA) might depend on inherited genetic factors; however, studies that explore such a correlation are few and have received scant attention. Given the importance of this topic we conducted a comprehensive genotype study in young women (≤45 years) with early-stage breast cancer.
METHODS: Our approach tested the effect of variant polymorphisms in drug metabolism enzymes (DMEs) using a predesigned pharmacogenomics panel (TaqMan® OpenArray®, Life Technologies GmbH, Darmstadt, Germany) in premenopausal women (n = 50). Patients received contemporary chemotherapy; in all cases a cyclophosphamide-based regimen with a dose of at least 500 mg/m(2) for six cycles. CIA was considered to be present in women with no resumption of menstrual bleeding within 12 months after completion of chemotherapy or goserelin.
RESULTS: Twenty-six patients (52 %) showed CIA during follow-up whereas 24 women (48 %) remained premenopausal. Of all the DMEs studied, only the SLCO1B1*5 (rs4149056) genotype was associated with the development of CIA (P = 0.017). Of the 26 patients who were homozygous for the T/T allele SLCO1B1*5, 18 (69.2 %) developed CIA compared with 8 (30.8 %) of the 22 patients who were heterozygous (C/T allele). The association of heterozygous SLCO1B1*5 allele (OR 0.038; 95%CI: 0.05-0.92) with a lower risk of developing CIA remained significant in a binary logistic regression analysis that include age, SLCO1B1*5 allele variants, and goserelin therapy.
CONCLUSIONS: Patient age and SLCO1B1*5 allele variants predict the likelihood of young women with breast cancer developing CIA.

PMID: 27234217 [PubMed - as supplied by publisher]