Gene Summary

Gene:LIPA; lipase A, lysosomal acid type
Aliases: LAL, CESD
Summary:This gene encodes lipase A, the lysosomal acid lipase (also known as cholesterol ester hydrolase). This enzyme functions in the lysosome to catalyze the hydrolysis of cholesteryl esters and triglycerides. Mutations in this gene can result in Wolman disease and cholesteryl ester storage disease. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2014]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:lysosomal acid lipase/cholesteryl ester hydrolase
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (15)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Young Adult
  • Human papillomavirus 18
  • Precancerous Conditions
  • Squamous Cell Carcinoma
  • Messenger RNA
  • Papillomavirus Infections
  • Case-Control Studies
  • Cervix Uteri
  • Penile Cancer
  • Transfection
  • Mutation
  • TOR Serine-Threonine Kinases
  • Genotype
  • Prevalence
  • Alphapapillomavirus
  • Papillomaviridae
  • Tumor Virus Infections
  • Chromosome 10
  • Survival Rate
  • Oligonucleotide Array Sequence Analysis
  • China
  • Cancer Vaccines
  • Neoplasm Invasiveness
  • Genotyping Techniques
  • Breast Cancer
  • Staging
  • Papillomavirus Vaccines
  • Cervical Cancer
  • Tumor Suppressor Proteins
  • Immunohistochemistry
  • DNA, Viral
  • Polymerase Chain Reaction
  • CDKN2A Protein
  • Vaginal Smears
  • Human papillomavirus 16
  • Cervical Intraepithelial Neoplasia
  • Adolescents
  • Liver Cancer
  • Follow-Up Studies
  • Signal Transduction
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: LIPA (cancer-related)

Kazim Z, Wahabi K, Perwez A, et al.
PTEN Genetic and Epigenetic Alterations Define Distinct Subgroups in North Indian Breast Cancer Patients
Asian Pac J Cancer Prev. 2019; 20(1):269-276 [PubMed] Free Access to Full Article Related Publications
Background: Breast cancer is a heterogeneous disease that can be subdivided on the basis of histopathological features, genetic alterations, and gene-expression profiles. PTEN gene is considered an established tumor suppressor gene in different types of cancer including breast cancer. However, the role of PTEN alterations in north Indian breast cancer has not been explored especially in defining a group with distinct histological factors. Methodology: 181 sporadic breast cancer and their adjacent normal tissues were included in the present study. We analyzed methylation and LOH through MS-PCR and microsatellite markers respectively. While, for PTEN protein expression, we used immunohistochemistry. All the molecular findings were correlated with the clinicopathological parameters of the patients to underline clinical relevance. Results: We found that LOH and methylation of the PTEN promoter were significantly associated with loss of PTEN protein expression, while, PTEN mutation was a rare event. Furthermore, out of 46 double hit cases (i.e., having both methylation and LOH), 70% (32/46) cases showed complete loss of PTEN expression (P= 0.0249). Both LOH and PTEN promoter methylation were associated significantly with age and clinical stage, while, methylation and loss of PTEN expression were associated with high grade and Her-2 negativity. In addition, a quadruple (ER/PR/ Her-2 and PTEN) negative group with distinct features was found. Conclusion: The pattern of PTEN expression and its correlation with the clinical parameters indicates that loss of PTEN expression defines a clinical group with distinct features. Hence, PTEN expression provides differential therapeutic strategies for north Indian breast cancer.

Jadaliha M, Gholamalamdari O, Tang W, et al.
A natural antisense lncRNA controls breast cancer progression by promoting tumor suppressor gene mRNA stability.
PLoS Genet. 2018; 14(11):e1007802 [PubMed] Free Access to Full Article Related Publications
The human genome encodes thousands of long noncoding RNA (lncRNA) genes; the function of majority of them is poorly understood. Aberrant expression of a significant number of lncRNAs is observed in various diseases, including cancer. To gain insights into the role of lncRNAs in breast cancer progression, we performed genome-wide transcriptome analyses in an isogenic, triple negative breast cancer (TNBC/basal-like) progression cell lines using a 3D cell culture model. We identified significantly altered expression of 1853 lncRNAs, including ~500 natural antisense transcript (NATs) lncRNAs. A significant number of breast cancer-deregulated NATs displayed co-regulated expression with oncogenic and tumor suppressor protein-coding genes in cis. Further studies on one such NAT, PDCD4-AS1 lncRNA reveal that it positively regulates the expression and activity of the tumor suppressor PDCD4 in mammary epithelial cells. Both PDCD4-AS1 and PDCD4 show reduced expression in TNBC cell lines and in patients, and depletion of PDCD4-AS1 compromised the cellular levels and activity of PDCD4. Further, tumorigenic properties of PDCD4-AS1-depleted TNBC cells were rescued by exogenous expression of PDCD4, implying that PDCD4-AS1 acts upstream of PDCD4. Mechanistically, PDCD4-AS1 stabilizes PDCD4 RNA by forming RNA duplex and controls the interaction between PDCD4 RNA and RNA decay promoting factors such as HuR. Our studies demonstrate crucial roles played by NAT lncRNAs in regulating post-transcriptional gene expression of key oncogenic or tumor suppressor genes, thereby contributing to TNBC progression.

Baldur-Felskov B, Mwaiselage J, Faber MT, et al.
Factors associated with a cervical high-grade lesion on cytology or a positive visual inspection with acetic acid among more than 3300 Tanzanian women.
Trop Med Int Health. 2019; 24(2):229-237 [PubMed] Related Publications
OBJECTIVES: Cervical cancer screening by visual inspection with acetic acid (VIA) is a widely used alternative to cytology in developing countries. This study aimed to evaluate risk factors associated with a positive VIA test and with cervical high-grade lesions on cytology.
METHODS: We conducted a large cross-sectional study among 3339 women from urban and rural Tanzania. Study participants were interviewed about socio-demographic, reproductive and lifestyle factors. Blood samples were tested for HIV, and a gynaecological examination was performed. Human papillomavirus (HPV) status was determined by Hybrid Capture 2, and HPV genotyping was done using the LiPA Extra test. We used multivariable logistic regression to estimate adjusted odds ratios (ORs) and confidence intervals (CIs).
RESULTS: The strongest risk factors for VIA positivity were positivity to HIV (OR = 3.48; 95% CI: 2.34-5.17) or to high-risk HPV (HrHPV) (OR = 1.97; 95% CI: 1.37-2.85). HrHPV was by far the strongest predictor of high-grade cytology (OR = 110.1; 95% CI: 50.4-240.4), while there was no significant association with HIV in the multivariable analysis (OR = 1.27; 95% CI: 0.78-2.08). After adjustment for HrHPV, HIV and age, the risk of high-grade cytology also increased with increasing age, number of births and low body mass index (BMI), while high BMI decreased the risk of VIA positivity.
CONCLUSIONS: Infection with HrHPV is a major risk factor for high-grade cytology, while VIA positivity is associated with HIV and to a lesser extent with HrHPV.

Ramazzotti D, Lal A, Wang B, et al.
Multi-omic tumor data reveal diversity of molecular mechanisms that correlate with survival.
Nat Commun. 2018; 9(1):4453 [PubMed] Free Access to Full Article Related Publications
Outcomes for cancer patients vary greatly even within the same tumor type, and characterization of molecular subtypes of cancer holds important promise for improving prognosis and personalized treatment. This promise has motivated recent efforts to produce large amounts of multidimensional genomic (multi-omic) data, but current algorithms still face challenges in the integrated analysis of such data. Here we present Cancer Integration via Multikernel Learning (CIMLR), a new cancer subtyping method that integrates multi-omic data to reveal molecular subtypes of cancer. We apply CIMLR to multi-omic data from 36 cancer types and show significant improvements in both computational efficiency and ability to extract biologically meaningful cancer subtypes. The discovered subtypes exhibit significant differences in patient survival for 27 of 36 cancer types. Our analysis reveals integrated patterns of gene expression, methylation, point mutations, and copy number changes in multiple cancers and highlights patterns specifically associated with poor patient outcomes.

Meyer SE, Muench DE, Rogers AM, et al.
miR-196b target screen reveals mechanisms maintaining leukemia stemness with therapeutic potential.
J Exp Med. 2018; 215(8):2115-2136 [PubMed] Free Access to Full Article Related Publications
We have shown that antagomiR inhibition of miRNA miR-21 and miR-196b activity is sufficient to ablate MLL-AF9 leukemia stem cells (LSC) in vivo. Here, we used an shRNA screening approach to mimic miRNA activity on experimentally verified miR-196b targets to identify functionally important and therapeutically relevant pathways downstream of oncogenic miRNA in MLL-r AML. We found

Ishii H, Vodnala SK, Achyut BR, et al.
miR-130a and miR-145 reprogram Gr-1
Nat Commun. 2018; 9(1):2611 [PubMed] Free Access to Full Article Related Publications
Tumor-derived soluble factors promote the production of Gr-1

Garg R, Blando JM, Perez CJ, et al.
COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer.
Oncogene. 2018; 37(34):4735-4749 [PubMed] Free Access to Full Article Related Publications
The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE

Lal G, Rajala MS
Recombinant viruses with other anti-cancer therapeutics: a step towards advancement of oncolytic virotherapy.
Cancer Gene Ther. 2018; 25(9-10):216-226 [PubMed] Related Publications
Cancer as a disease is a multifaceted foe which sometimes succumbs to the prescribed treatment and sometimes develops resistance against various therapies. Conventional cancer therapies suffer from many limitations, the least of which is their specificity and systemic side effects. In a majority of cases, acquired mutations render the cancer cells resistant to therapy and lower the prognostic outcome. In the constant effort to devise a therapeutic moiety which can comprehensively eliminate cancer cells, oncolytic viruses provide an attractive avenue as they selectively infect and lyse cancer cells sparing normal cells from their effects. Viruses can be engineered for their host specificity and toxicity as a promising anti-cancer tool. As it is essential to devise a strategy to address all targets involved in cancer development and progression, the idea of using oncolytic viruses with enhanced anti-cancer activity through arming with foreign genes gained merit and is showing promising advent in clinical studies. The use of oncolytic viruses as an agent of combination therapy for cancer treatment also gained much attention in the recent past. This review focuses on the emerging role of oncolytic viruses as vital components of anti-cancer regimen presenting a new dimension in an ever-changing cancer therapy scenario.

Zacapala-Gómez AE, Navarro-Tito N, Alarcón-Romero LDC, et al.
Ezrin and E-cadherin expression profile in cervical cytology: a prognostic marker for tumor progression in cervical cancer.
BMC Cancer. 2018; 18(1):349 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Cervical cancer (CC) is the fourth cause of mortality by neoplasia in women worldwide. The use of immunomarkers is an alternative tool to complement currently used algorithms for detection of cancer, and to improve selection of therapeutic schemes. Aberrant expression of Ezrin and E-cadherin play an important role in tumor invasion. In this study we analyzed Ezrin and E-cadherin expression in liquid-based cervical cytology samples, and evaluated their potential use as prognostic immunomarkers.
METHODS: Immunocytochemical staining of Ezrin and E-cadherin was performed in cervical samples of 125 patients. The cytological or histological diagnostic was performed by Papanicolaou staining or H&E staining, respectively. HPV genotyping was determined using INNO-LIPA Genotyping Extra kit and the HPV physical status by in situ hybridization. Ezrin expression in HaCaT, HeLa and SiHa cell lines was determined by immunocytochemistry, immunofluorescence and Western blot.
RESULTS: High Ezrin expression was observed in cervical cancer samples (70%), samples with multiple infection by HR-HPV (43%), and samples with integrated viral genome (47%). High Ezrin expression was associated with degree of SIL, viral genotype and physical status. In contrast, low E-cadherin expression was found in cervical cancer samples (95%), samples with multiple infection by HR-HPV/LR-HPV (87%) and integrated viral genome (72%). Low E-cadherin expression was associated with degree of SIL and viral genotype. Interestingly, Ezrin nuclear staining was associated with degree of SIL and viral genotype. High Ezrin expression, high percent of nuclear Ezrin and low E-cadherin expression behaved as risk factors for progression to HSIL and cervical cancer.
CONCLUSIONS: Ezrin and E-cadherin expression profile in cervical cytology samples could be a potential prognostic marker, useful for identifying cervical lesions with a high-risk of progression to cervical cancer.

Oyinlade O, Wei S, Lal B, et al.
Targeting UDP-α-D-glucose 6-dehydrogenase inhibits glioblastoma growth and migration.
Oncogene. 2018; 37(20):2615-2629 [PubMed] Free Access to Full Article Related Publications
UDP-glucose 6-dehydrogenase (UGDH) produces UDP-α-D-glucuronic acid, the precursors for glycosaminoglycans (GAGs) and proteoglycans of the extracellular matrix. Elevated GAG formation has been implicated in a variety of human diseases, including glioblastoma (GBM). In our previous study, we found that Krüppel-like factor 4 (KLF4) promotes GBM cell migration by binding to methylated DNA, mainly methylated CpGs (mCpG) and transactivating gene expression. We identified UDGH as one of the downstream targets of KLF4-mCpG binding activity. In this study, we show that KLF4 upregulates UGDH expression in a mCpG-dependent manner, and UGDH is required for KLF4-induced cell migration in vitro. UGDH knockdown decreases GAG abundance in GBM cells, as well as cell proliferation and migration in vitro. In intracranial xenografts, reduced UGDH inhibits tumor growth and migration, accompanied by a decrease in the expression of extracellular matrix proteins such as tenascin C, brevican. Our studies demonstrate a novel DNA methylation-dependent UGDH upregulation by KLF4. Developing UGDH antagonists to decrease the synthesis of extracellular matrix components will be a useful strategy for GBM therapy.

Gutierrez-Camino Á, Umerez M, Martin-Guerrero I, et al.
Mir-pharmacogenetics of Vincristine and peripheral neurotoxicity in childhood B-cell acute lymphoblastic leukemia.
Pharmacogenomics J. 2018; 18(6):704-712 [PubMed] Related Publications
Vincristine (VCR), an important component of childhood acute lymphoblastic leukemia (ALL) therapy, can cause sensory and motor neurotoxicity. This neurotoxicity could lead to dose reduction or treatment discontinuation, which could in turn reduce survival. In this line, several studies associated peripheral neurotoxicity and polymorphisms in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) of VCR. Nowadays, it is well known that these genes are regulated by microRNAs (miRNAs) and SNPs in miRNAs could modify their levels or function. Therefore, the aim of this study was to determine whether SNPs in miRNAs could be associated with VCR-induced neurotoxicity. To achieve this aim, we analyzed all the SNPs in miRNAs (minor allele frequency (MAF) ≥ 0.01) which could regulate VCR-related genes in a large cohort of Spanish children with B-cell precursor ALL (B-ALL) homogeneously treated with LAL/SHOP protocols. We identified the A allele of rs12402181 in the seed region of miR-3117-3p, that could affect the binding with ABCC1 and RALBP1 gene, and C allele of rs7896283 in pre-mature sequence of miR-4481, which could be involved in peripheral nerve regeneration, significantly associated with VCR-induced neurotoxicity. These findings point out the possible involvement of two SNPs in miRNA associated with VCR-related neurotoxicity.

Lal N, White BS, Goussous G, et al.
KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer.
Clin Cancer Res. 2018; 24(1):224-233 [PubMed] Free Access to Full Article Related Publications

Li XL, Subramanian M, Jones MF, et al.
Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.
Cell Rep. 2017; 20(10):2408-2423 [PubMed] Free Access to Full Article Related Publications
Basal p53 levels are tightly suppressed under normal conditions. Disrupting this regulation results in elevated p53 levels to induce cell cycle arrest, apoptosis, and tumor suppression. Here, we report the suppression of basal p53 levels by a nuclear, p53-regulated long noncoding RNA that we termed PURPL (p53 upregulated regulator of p53 levels). Targeted depletion of PURPL in colorectal cancer cells results in elevated basal p53 levels and induces growth defects in cell culture and in mouse xenografts. PURPL associates with MYBBP1A, a protein that binds to and stabilizes p53, and inhibits the formation of the p53-MYBBP1A complex. In the absence of PURPL, MYBBP1A interacts with and stabilizes p53. Silencing MYBBP1A significantly rescues basal p53 levels and proliferation in PURPL-deficient cells, suggesting that MYBBP1A mediates the effect of PURPL in regulating p53. These results reveal a p53-PURPL auto-regulatory feedback loop and demonstrate a role for PURPL in maintaining basal p53 levels.

Datta A, Kim H, Lal M, et al.
Manumycin A suppresses exosome biogenesis and secretion via targeted inhibition of Ras/Raf/ERK1/2 signaling and hnRNP H1 in castration-resistant prostate cancer cells.
Cancer Lett. 2017; 408:73-81 [PubMed] Free Access to Full Article Related Publications
Emerging evidence links exosomes to cancer progression by the trafficking of oncogenic factors and neoplastic reprogramming of stem cells. This necessitates identification and integration of functionally validated exosome-targeting therapeutics into current cancer management regimens. We employed quantitative high throughput screen on two libraries to identify exosome-targeting drugs; a commercially available collection of 1280 pharmacologically active compounds and a collection of 3300 clinically approved compounds. Manumycin-A (MA), a natural microbial metabolite, was identified as an inhibitor of exosome biogenesis and secretion by castration-resistant prostate cancer (CRPC) C4-2B, but not the normal RWPE-1, cells. While no effect was observed on cell growth, MA attenuated ESCRT-0 proteins Hrs, ALIX and Rab27a and exosome biogenesis and secretion by CRPC cells. The MA inhibitory effect is primarily mediated via targeted inhibition of the Ras/Raf/ERK1/2 signaling. The Ras-dependent MA suppression of exosome biogenesis and secretion is partly mediated by ERK-dependent inhibition of the oncogenic splicing factor hnRNP H1. Our findings suggest that MA is a potential drug candidate to suppress exosome biogenesis and secretion by CRPC cells.

Califano R, Greystoke A, Lal R, et al.
Management of ceritinib therapy and adverse events in patients with ALK-rearranged non-small cell lung cancer.
Lung Cancer. 2017; 111:51-58 [PubMed] Related Publications
Anaplastic lymphoma kinase rearrangement (ALK+) occurs in approximately 2-7% of patients with non-small cell lung cancer (NSCLC), contributing to a considerable number of patients with ALK+ NSCLC worldwide. Ceritinib is a next generation ALK inhibitor (ALKi), approved by the European Medicines Agency in 2015. In the first-in-human, phase I study, ceritinib demonstrated rapid and durable responses in ALK patients previously treated with a different ALKi and in those who were ALKi-naive. As ceritinib is starting to be used routinely for the treatment of patients with ALK+ NSCLC, experience is growing with regard to ideal therapy management. In this review we provide a brief background to the development of ceritinib. The optimal treatment management and adverse events associated with ceritinib in clinical trials and in clinical practice are then discussed in detail, and where applicable, an expert consensus on specific recommendations are made. In clinical trials, the most common adverse events related to ceritinib are nausea, vomiting, and diarrhea. However, the majority of these are mild and, in the opinion of the authors, can be effectively managed with dose modifications. Based on clinical data, ceritinib has demonstrated efficacy as a first-line therapy and in patients who have relapsed on crizotinib, including those with brain metastases at baseline. Unfortunately, at some point, all patients experience progressive disease, with the central nervous system being a common site of metastases. Recommendations are made for continuing treatment beyond disease progression as long as a clinical benefit to patients is observed. Here, we review management of ceritinib treatment and adverse events and make recommendations on optimal management of patients.

Lal S, McCart Reed AE, de Luca XM, Simpson PT
Molecular signatures in breast cancer.
Methods. 2017; 131:135-146 [PubMed] Related Publications
The use of molecular signatures to add value to standard clinical and pathological parameters has impacted clinical practice in many cancer types, but perhaps most notably in the breast cancer field. This is, in part, due to the considerable complexity of the disease at the clinical, morphological and molecular levels. The adoption of molecular profiling of DNA, RNA and protein continues to reveal important differences in the intrinsic biology between molecular subtypes and has begun to impact the way patients are managed. Several bioinformatic tools have been developed using DNA or RNA-based signatures to stratify the disease into biologically and/or clinically meaningful subgroups. Here, we review the approaches that have been used to develop gene expression signatures into currently available diagnostic assays (e.g., OncotypeDX® and Mammaprint®), plus we describe the latest work on genome sequencing, the methodologies used in the discovery process of mutational signatures, and the potential of these signatures to impact the clinic.

Singh DK, Gholamalamdari O, Jadaliha M, et al.
PSIP1/p75 promotes tumorigenicity in breast cancer cells by promoting the transcription of cell cycle genes.
Carcinogenesis. 2017; 38(10):966-975 [PubMed] Free Access to Full Article Related Publications
Breast cancer (BC) is a highly heterogeneous disease, both at the pathological and molecular level, and several chromatin-associated proteins play crucial roles in BC initiation and progression. Here, we demonstrate the role of PSIP1 (PC4 and SF2 interacting protein)/p75 (LEDGF) in BC progression. PSIP1/p75, previously identified as a chromatin-adaptor protein, is found to be upregulated in basal-like/triple negative breast cancer (TNBC) patient samples and cell lines. Immunohistochemistry in tissue arrays showed elevated levels of PSIP1 in metastatic invasive ductal carcinoma. Survival data analyses revealed that the levels of PSIP1 showed a negative association with TNBC patient survival. Depletion of PSIP1/p75 significantly reduced the tumorigenicity and metastatic properties of TNBC cell lines while its over-expression promoted tumorigenicity. Further, gene expression studies revealed that PSIP1 regulates the expression of genes controlling cell-cycle progression, cell migration and invasion. Finally, by interacting with RNA polymerase II, PSIP1/p75 facilitates the association of RNA pol II to the promoter of cell cycle genes and thereby regulates their transcription. Our findings demonstrate an important role of PSIP1/p75 in TNBC tumorigenicity by promoting the expression of genes that control the cell cycle and tumor metastasis.

Chaudhary R, Gryder B, Woods WS, et al.
Prosurvival long noncoding RNA
Elife. 2017; 6 [PubMed] Free Access to Full Article Related Publications
Thousands of long noncoding RNAs (lncRNAs) have been discovered, yet the function of the vast majority remains unclear. Here, we show that a p53-regulated lncRNA which we named

Paul D, Sinha AN, Ray A, et al.
A-to-I editing in human miRNAs is enriched in seed sequence, influenced by sequence contexts and significantly hypoedited in glioblastoma multiforme.
Sci Rep. 2017; 7(1):2466 [PubMed] Free Access to Full Article Related Publications
Editing in microRNAs, particularly in seed can significantly alter the choice of their target genes. We show that out of 13 different human tissues, different regions of brain showed higher adenosine to inosine (A-to-I) editing in mature miRNAs. These events were enriched in seed sequence (73.33%), which was not observed for cytosine to uracil (17.86%) editing. More than half of the edited miRNAs showed increased stability, 72.7% of which had ΔΔG values less than -6.0 Kcal/mole and for all of them the edited adenosines mis-paired with cytosines on the pre-miRNA structure. A seed-editing event in hsa-miR-411 (with A - C mismatch) lead to increased expression of the mature form compared to the unedited version in cell culture experiments. Further, small RNA sequencing of GBM patients identified significant miRNA hypoediting which correlated with downregulation of ADAR2 both in metadata and qRT-PCR based validation. Twenty-two significant (11 novel) A-to-I hypoediting events were identified in GBM samples. This study highlights the importance of specific sequence and structural requirements of pre-miRNA for editing along with a suggestive crucial role for ADAR2. Enrichment of A-to-I editing in seed sequence highlights this as an important layer for genomic regulation in health and disease, especially in human brain.

Gopakumar KG, Thankamony P, Nampoothiri S, et al.
Wolman Disease: A Mimic of Infant Leukemia.
J Pediatr Hematol Oncol. 2017; 39(8):e489-e492 [PubMed] Related Publications
BACKGROUND: Infant leukemia most commonly present with pallor and hepatosplenomegaly. The possibility of other differential diagnosis also has to be kept in mind during evaluation, as identifying the precise etiology for this clinical presentation is crucial for management.
OBSERVATION: An infant, was referred to us with suspected infant leukemia and was subsequently diagnosed to have lysosomal acid lipase deficiency/Wolman disease with a novel 5 bp deletion "c.1180_1184del" in the last exon (exon 10) of the lipase A (LIPA) gene.
CONCLUSIONS: Hepatosplenomegaly and pallor resulting from nutritional deficiency or bone marrow involvement in Wolman disease can mimic infant leukemia.

Jain D, Gupta S, Marwah N, et al.
Evaluation of role of alpha-methyl acyl-coenzyme A racemase/P504S and high molecular weight cytokeratin in diagnosing prostatic lesions.
J Cancer Res Ther. 2017 Jan-Mar; 13(1):21-25 [PubMed] Related Publications
BACKGROUND: In recent years basal cell markers (high molecular weight cytokeratin [HMWCK]) and prostate biomarker alpha-methyl acyl-coenzyme A racemase (AMACR) have been used as adjuvant to morphology in diagnostically challenging cases with a very high sensitivity and specificity. This has increased the diagnostic accuracy of prostate cancer worldwide.
MATERIALS AND METHODS: In this prospective study, total of 50 cases including 37 cases of malignant lesions and 13 cases of benign lesions of the prostate were taken. Tumor grade was determined according to Gleason's grading system. AMACR and HMWCK expressions were determined by immunohistochemical staining. The obtained results were analyzed and evaluated using Chi-square statistical test (SPSS version 20).
RESULTS: AMACR was not expressed in any of the 13 cases of benign lesions of the prostate while in malignant lesions of prostate it was expressed in 33 of 37 (89.18%) cases. All 4 (100%) cases of well-differentiated carcinoma were positive for AMACR expression. 21 of 25 (84%) moderately differentiated and all 10 (100%) cases of poorly differentiated tumors were positive for AMACR. There was statistically significant difference in expression of AMACR between benign and malignant lesions of the prostate, indicated byP = 0.001. In benign lesions, HMWCK was expressed in all the 13 (100%) cases while in malignant lesions of prostate it was not expressed in any of the (0%) case. All 13 benign lesions were positive for HMWCK only. AMACR expression was not seen in any of the benign lesion. Out of 37 malignant cases, 4 cases were negative for both, 33 cases were positive only for AMACR, but no case was positive only for HMWCK.
CONCLUSIONS: As an adjunct to biopsy, AMACR and HMWCK have value for resolving diagnostically challenging cases.

Jain V, Ratre YK, Amle D, et al.
Polymorphism of CYP1A1 gene variants rs4646903 and rs1048943 relation to the incidence of cervical cancer in Chhattisgarh.
Environ Toxicol Pharmacol. 2017; 52:188-192 [PubMed] Related Publications
Cytochrome P450 CYP1A1 is a phase 1 xenobiotic metabolizing enzyme involved in the metabolism of toxins, endogenous hormones and pharmaceutical drugs. It is therefore possible that polymorphism of CYP1A1 gene producing functional changes in the enzyme may be susceptible factors in cervical carcinogenesis. This study was aimed to look association of CYP1A1m1 (T>C) and m2 (A>G) gene polymorphisms in Chhattisgarh population. In this case-control study, we analyzed leukocyte DNA from a total of 200 subjects form Chhattisgarh (100 cases and 100 controls). All subjects were genotyped for CYP1A1m1 (T>C) and m2 (A>G) using PCR-RFLP with statistical analysis by using SPSS version 16.0 and VassarStats (online). Among the two gene variants rs4646903 (T>C) and rs1048943 (A>G), individuals with AG and GG genotypes of CYP1A1m2 polymorphism have significantly higher and increased risk of cervical cancer (OR=2.0, 95%CI=1.04-3.84, p=0.035; OR=62.9, 95%CI=3.72-1063.83, p=0.004 respectively) and the association of CYP1A1m1 polymorphism did not show any significant relationship with cervical cancer patients (p=0.23). The 'G' allele showed strong association with the disease (p<0.0001). Thus, CYP1A1m2 polymorphism showed an increased risk in the population leading to cervical cancer. Our study suggested that the presence of 'C' allele of rs4646903 (T>C) showed no risk and 'G' allele of rs1048943 (A>G) might be a leading allele to cause increased cervical cancer susceptibility due to significant association of CYP1A1m2 gene polymorphism.

Lal S, Cheung EC, Zarei M, et al.
CRISPR Knockout of the HuR Gene Causes a Xenograft Lethal Phenotype.
Mol Cancer Res. 2017; 15(6):696-707 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States, whereas colorectal cancer is the third most common cancer. The RNA-binding protein HuR (ELAVL1) supports a pro-oncogenic network in gastrointestinal (GI) cancer cells through enhanced HuR expression. Using a publically available database, HuR expression levels were determined to be increased in primary PDA and colorectal cancer tumor cohorts as compared with normal pancreas and colon tissues, respectively. CRISPR/Cas9 technology was successfully used to delete the HuR gene in both PDA (MIA PaCa-2 and Hs 766T) and colorectal cancer (HCT116) cell lines. HuR deficiency has a mild phenotype,

Saini H, Lal SP, Naidu VV, et al.
Gene masking - a technique to improve accuracy for cancer classification with high dimensionality in microarray data.
BMC Med Genomics. 2016; 9(Suppl 3):74 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: High dimensional feature space generally degrades classification in several applications. In this paper, we propose a strategy called gene masking, in which non-contributing dimensions are heuristically removed from the data to improve classification accuracy.
METHODS: Gene masking is implemented via a binary encoded genetic algorithm that can be integrated seamlessly with classifiers during the training phase of classification to perform feature selection. It can also be used to discriminate between features that contribute most to the classification, thereby, allowing researchers to isolate features that may have special significance.
RESULTS: This technique was applied on publicly available datasets whereby it substantially reduced the number of features used for classification while maintaining high accuracies.
CONCLUSION: The proposed technique can be extremely useful in feature selection as it heuristically removes non-contributing features to improve the performance of classifiers.

Besbes S, Hamadou WS, Boulland ML, et al.
Combined IKZF1 and IG markers as new tools for diagnosis and minimal residual disease assessment in Tunisian B-ALL.
Bull Cancer. 2016; 103(10):822-828 [PubMed] Related Publications
INTRODUCTION: The monitoring of minimal residual disease (MRD) approach in patients diagnosed with B-acute lymphoblastic leukemia (B-ALL) allows an early detection of residual clones inducing relapses and therefore appropriate therapy strategy. The molecular markers may identify and quantify the residual blasts in B-ALL with normal cytology. In this study, we aimed to use combined IKZF1, IGH and IGK immunoglobulin genes for diagnosis and MRD monitoring in B-ALL sample using MLPA, multiplex PCR and real-time quantitative PCR.
MATERIAL: We showed that multiplex PCR and MLPA are necessary and complementary to detect IKZF1 deletions.
RESULTS: We have identified at the diagnosis clonal IGH rearrangement (VH3-JH5) and IKZF1 deletion (Δ4-7), which we have used it for MRD evaluation after induction chemotherapy. Despite the absence of chromosome abnormality, the patient may be classified in high-risk group with a relapse rate of residual blasts>10
CONCLUSION: The combined IKZF1 and immunoglobulin genes will be used as appropriate molecular tools for diagnosis and MRD assessment of B-lineage leukemias and introduced as a routine tests in Tunisian clinical laboratories. They will be useful to stratify patients into risk groups leading to better treatment strategy.

Gómez-Contreras P, Ramiro-Díaz JM, Sierra A, et al.
Extracellular matrix 1 (ECM1) regulates the actin cytoskeletal architecture of aggressive breast cancer cells in part via S100A4 and Rho-family GTPases.
Clin Exp Metastasis. 2017; 34(1):37-49 [PubMed] Free Access to Full Article Related Publications
ECM1 overexpression is an independent predictor of poor prognosis in primary breast carcinomas, however the mechanisms by which ECM1 affects tumor progression have not been completely elucidated. ECM1 was silenced in the triple-negative breast cancer cell lines Hs578T and MDAMB231 using siRNA and the cells were evaluated for changes in morphology, migration, invasion and adhesion. Actin cytoskeleton alterations were evaluated by fluorescent staining and levels of activated Rho GTPases by pull down assays. ECM1 downregulation led to significantly diminished cell migration (p = 0.0005 for Hs578T and p = 0.02 for MDAMB231) and cell adhesion (p < 0.001 for Hs578T and p = 0.01 for MDAMB231). Cell invasion (matrigel) was reduced only in the Hs578T cells (p < 0.01). Silencing decreased the expression of the prometastatic molecules S100A4 and TGFβR2 in both cell lines and CD44 in Hs578T cells. ECM1-silenced cells also exhibited alterations in cell shape and showed bundles of F-actin across the cell (stress fibers) whereas NT-siRNA treated cells showed peripheral membrane ruffling. Downregulation of ECM1 was also associated with an increased F/G actin ratio, when compared to the cells transfected with NT siRNA (p < 0.001 for Hs578T and p < 0.00035 for MDAMB231) and a concomitant decline of activated Rho A in the Hs578T cells. Re-expression of S100A4 in ECM1-silenced cells rescued the phenotype in the Hs578T cells but not the MDAMB231 cells. We conclude that ECM1 is a key player in the metastatic process and regulates the actin cytoskeletal architecture of aggressive breast cancer cells at least in part via alterations in S100A4 and Rho A.

Iparraguirre L, Gutierrez-Camino A, Umerez M, et al.
MiR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia.
Pharmacogenet Genomics. 2016; 26(11):517-525 [PubMed] Related Publications
OBJECTIVES: Methotrexate (MTX), the key drug in childhood B-cell acute lymphoblastic leukemia (B-ALL) therapy, often causes toxicity. An association between genetic variants in MTX transport genes and toxicity has been found. It is known that these transporters are regulated by microRNAs (miRNAs), and miRNA single nucleotide polymorphisms (SNPs) interfere with miRNA levels or function. With regard to B-cell ALL, we have previously found rs56103835 in miR-323b that targets ABCC4 associated with MTX plasma levels. Despite these evidences and that nowadays a large amount of new miRNAs have been annotated, studies of miRNA polymorphisms and MTX toxicity are almost absent. Therefore, the aim of this study was to determine whether there are other variants in miRNAs associated with MTX levels.
PATIENTS AND METHODS: Blood samples of 167 Spanish patients with pediatric B-cell ALL treated with the LAL-SHOP protocol were analyzed. We selected all the SNPs described in pre-miRNAs with a minor allele frequency more than 1% (213 SNPs in 206 miRNAs) that could regulate MTX transporters because the miRNAs that target MTX transporter genes are not completely defined. Genotyping was performed with VeraCode GoldenGate platform.
RESULTS: Among the most significant results, we found rs56292801 in miR-5189, rs4909237 in miR-595, and rs78790512 in miR-6083 to be associated with MTX plasma levels. These miRNAs were predicted, in silico, to regulate genes involved in MTX uptake: SLC46A1, SLC19A1, and SLCO1A2.
CONCLUSION: In this study, we detected three SNPs in miR-5189, miR-595, and miR-6083 that might affect SLC46A1, SLC19A1, and SLCO1A2 MTX transport gene regulation and could affect MTX levels in patients with pediatric B-cell ALL.

Reck M, Rodríguez-Abreu D, Robinson AG, et al.
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.
N Engl J Med. 2016; 375(19):1823-1833 [PubMed] Related Publications
BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1).
METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety.
RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%).
CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 number, NCT02142738 .).

Freitas VG, Focchi GR, Pereira ER, et al.
HPV genotyping and p16 expression in Xingu Indigenous Park, Brazil.
Genet Mol Res. 2016; 15(3) [PubMed] Related Publications
The association between high-risk human papillomavirus (HPV) genotypes and p16 expression in indigenous women from the Xingu Indigenous Park, Brazil, was unknown. This study evaluated p16 expression in women with a histological diagnosis of cervical intraepithelial neoplasia (CIN) 3 or higher and correlated this expression with HPV genotypes to determine possible discrepancies in the expression of this marker. We evaluated 37 previously collected samples with different HPV genotypes and high-grade lesions diagnosed based on cytology, histology, and colposcopy. Immunohistochemical analysis was performed using paraffin-embedded tissue sections and the CINtec® Histology Kit. p16 protein expression was investigated by immunostaining with an anti-p16 antibody. HPV genotyping was performed by reverse hybridization. The age of the study population ranged from 22-75 years (43.81 ± 15.89 years) and parity ranged from 1-11 (5.92 ± 2.58). Thirteen different HPV genotypes were found using the INNO-LiPA kit. Single and multiple infections by HPV were found with prevalence of single infections (P = 0.029). Comparison between HPV genotype and simple or multiple infections was highly significant; it was observed more HPV 52 followed by HPV 16 in single infections (P < 0.001). p16 expression was predominantly diffuse, which was observed in 91.7% of lesions, whereas 8.3% were focal (P < 0.001). HPV 52, HPV 16 and 31 were the most prevalent HPV types in high-grade CIN in these indigenous women. Diffuse p16 expression in high-grade CIN was not influenced by the viral genotype; however, more studies are necessary to further our understanding of this restricted group.

Lal S, Zarei M, Chand SN, et al.
WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner.
Sci Rep. 2016; 6:33323 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDA) is a lethal disease, in part, because of the lack of effective targeted therapeutic options. MK-1775 (also known as AZD1775), a mitotic inhibitor, has been demonstrated to enhance the anti-tumor effects of DNA damaging agents such as gemcitabine. We evaluated the efficacy of MK-1775 alone or in combination with DNA damaging agents (MMC or oxaliplatin) in PDA cell lines that are either DNA repair proficient (DDR-P) or deficient (DDR-D). PDA cell lines PL11, Hs 766T and Capan-1 harboring naturally selected mutations in DNA repair genes FANCC, FANCG and BRCA2 respectively, were less sensitive to MK-1775 as compared to two out of four representative DDR-P (MIA PaCa2 and PANC-1) cell lines. Accordingly, DDR-P cells exhibit reduced sensitivity to MK-1775 upon siRNA silencing of DNA repair genes, BRCA2 or FANCD2, compared to control cells. Only DDR-P cells showed increased apoptosis as a result of early mitotic entry and catastrophe compared to DDR-D cells. Taken together with other recently published reports, our results add another level of evidence that the efficacy of WEE1 inhibition is influenced by the DNA repair status of a cell and may also be dependent on the tumor type and model evaluated.

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