MARCO

Gene Summary

Gene:MARCO; macrophage receptor with collagenous structure
Aliases: SR-A6, SCARA2
Location:2q14.2
Summary:The protein encoded by this gene is a member of the class A scavenger receptor family and is part of the innate antimicrobial immune system. The protein may bind both Gram-negative and Gram-positive bacteria via an extracellular, C-terminal, scavenger receptor cysteine-rich (SRCR) domain. In addition to short cytoplasmic and transmembrane domains, there is an extracellular spacer domain and a long, extracellular collagenous domain. The protein may form a trimeric molecule by the association of the collagenous domains of three identical polypeptide chains. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:macrophage receptor MARCO
Source:NCBIAccessed: 01 September, 2019

Ontology:

What does this gene/protein do?
Show (9)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 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.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

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: MARCO (cancer-related)

Recagni M, Greco ML, Milelli A, et al.
Distinct biological responses of metastatic castration resistant prostate cancer cells upon exposure to G-quadruplex interacting naphthalenediimide derivatives.
Eur J Med Chem. 2019; 177:401-413 [PubMed] Related Publications
Small molecules able to bind non-canonical G-quadruplex DNA structures (G4) have been recently tested as novel potential agents for the treatment of prostate cancer thanks to their repression of aberrant androgen receptor gene. However, metastatic castration-resistant prostate cancer (mCRPC), a letal form of prostate cancer, is still incurable. Here we tested two naphthalenediimide derivatives, previously reported as multitarget agents, on a couple of relevant mCRPC cell models (DU145 and PC-3). We showed that these compounds interfere with the RAS/MEK/ERK and PI3K/AKT pathways. Interestingly, both these two biological processes depend upon Epidermal Growth Factor Receptor (EGFR) activation. By means of biological and analytical tools we showed that our compounds are efficient inducers of the structural transition of the EGFR promoter towards a G-quadruplex conformation, ultimately leading to a reduction of the receptor production. The overall result is an interesting cytotoxic profile for these two derivatives. Thanks to their activity at different steps, these compounds can open the way to novel therapeutic approaches for mCRPC that could contribute to escape resistance to selective treatments.

Stegmann S, Werner JM, Kuhl S, et al.
Death Receptor 6 (DR6) Is Overexpressed in Astrocytomas.
Anticancer Res. 2019; 39(5):2299-2306 [PubMed] Related Publications
BACKGROUND/AIM: Death receptor 6 (DR6) is a member of the tumor necrosis factor receptor superfamily. The expression of DR6 is elevated in different kinds of tumors including ovarian, breast cancer and adult sarcoma. In these tumors, the receptor may be handled as a new diagnostic and prognostic marker. Thus, we investigated the expression of DR6 in gliomas.
MATERIALS AND METHODS: Tumor and control tissues were extracted during neurosurgery and grouped according to the WHO classification. DR6 expression was investigated in low- and high-grade gliomas PCR (n=70), immunofluorescence staining (n=33) and western blot (n=58). Additional analysis of TCGA-data was performed to assess the general alteration of DR6 in cancer and influence of IDH-mutation on DR6 expression in gliomas.
RESULTS: The expression of DR6 was significantly enhanced in gliomas (p<0.05). It showed a trend towards rising expression with increasing malignancy of the tumor. Chemotherapy treatment could have an influence on DR6 expression.
CONCLUSION: In our investigation, DR6 acts as a potential suitable diagnostic marker for gliomas.

Tjiong R, Stavrinou P, Röhn G, et al.
Heterogeneity of Human Gliomas: Glutathione-S-Transferase Expression Profile During Disease Progression and Under Systemic Therapy.
Anticancer Res. 2019; 39(4):1795-1805 [PubMed] Related Publications
BACKGROUND/AIM: The glutathione S-transferase pi gene (GSTP1) is a polymorphic gene encoding functionally different Gstp1 isoenzyme proteins. These seem to contribute to xenobiotic metabolism and might also play a role in susceptibility to cancer. The aim of this study was to elucidate the potential role of GSTP1 as a biomarker for disease progression and predictor of chemotherapeutic effect in glioma.
MATERIALS AND METHODS: Using quantitative real time PCR and western blotting analysis, a total of 61 astrocytic tumor samples from WHO grade II-IV were investigated.
RESULTS: There were no differences in GSTP1 mRNA expression between diffuse astrocytomas, anaplastic astrocytomas, or GBM. No difference was seen between secondary GBM before and after radio-/chemotherapy.
CONCLUSION: The expression of GSTP was highly heterogeneous within the surgical specimens. No significant differences in gene and protein expression were detected between the different types of gliomas, suggesting that glioma chemoresistance is probably multifactorial and GSTP1-independent.

Horvat N, Veeraraghavan H, Pelossof RA, et al.
Radiogenomics of rectal adenocarcinoma in the era of precision medicine: A pilot study of associations between qualitative and quantitative MRI imaging features and genetic mutations.
Eur J Radiol. 2019; 113:174-181 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
OBJECTIVE: To investigate associations between genetic mutations and qualitative as well as quantitative features on MRI in rectal adenocarcinoma at primary staging.
METHODS: In this retrospective study, patients with rectal adenocarcinoma, genome sequencing, and pretreatment rectal MRI were included. Statistical analysis was performed to evaluate associations between qualitative features obtained from subjective evaluation of rectal MRI and gene mutations as well as between quantitative textural features and gene mutations. For the qualitative evaluation, Fisher's Exact test was used to analyze categorical associations and Wilcoxon Rank Sum test was used for continuous clinical variables. For the quantitative evaluation, we performed manual segmentation of T2-weighted images for radiomics-based quantitative image analysis. Thirty-four texture features consisting of first order intensity histogram-based features (n = 4), second order Haralick textures (n = 5), and Gabor-edge based Haralick textures were computed at two different orientations. Consensus clustering was performed with 34 computed texture features using the K-means algorithm with Euclidean distance between the texture features. The clusters resulting from the algorithm were then used to enumerate the prevalence of gene mutations in those clusters.
RESULTS: In 65 patients, 45 genes were mutated in more than 3/65 patients (5%) and were included in the statistical analysis. Regarding qualitative imaging features, on univariate analysis, tumor location was significantly associated with APC (p = 0.032) and RASA1 mutation (p = 0.032); CRM status was significantly associated with ATM mutation (p = 0.021); and lymph node metastasis was significantly associated with BRCA2 (p = 0.046) mutation. However, these associations were not significant after adjusting for multiple comparisons. Regarding quantitative imaging features, Cluster C1 had tumors with higher mean Gabor edge intensity compared with cluster C2 (θ = 0°, p = 0.018; θ = 45°, p = 0.047; θ = 90°, p = 0.037; cluster C3 (θ = 0°, p = 0.18; θ = 45°, p = 0.1; θ = 90°, p = 0.052), and cluster C4 (θ = 0°, p = 0.016; θ = 45°, p = 0.033; θ = 90°, p = 0.014) suggesting that the cluster C1 had tumors with more distinct edges or heterogeneous appearance compared with other clusters.
CONCLUSIONS: Although this preliminary study showed promising associations between quantitative features and genetic mutations, it did not show any correlation between qualitative features and genetic mutations. Further studies with larger sample size are warranted to validate our preliminary data.

Han Y, Ye X, Cheng J, et al.
Integrative analysis based on survival associated co-expression gene modules for predicting Neuroblastoma patients' survival time.
Biol Direct. 2019; 14(1):4 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: More than 90% of neuroblastoma patients are cured in the low-risk group while only less than 50% for those with high-risk disease can be cured. Since the high-risk patients still have poor outcomes, we need more accurate stratification to establish an individualized precise treatment plan for the patients to improve the long-term survival rate.
RESULTS: We focus on extracting features and providing a workflow to improve survival prediction for neuroblastoma patients. With a workflow for gene co-expression network (GCN) mining in microarray and RNA-Seq datasets, we extracted molecular features from each co-expressed module and summarized them into eigengenes. Then we adopted the lasso-regularized Cox proportional hazards model to select the most informative eigengene features regarding association to the risk of metastasis. Nine eigengenes were selected which show strong association with patient survival prognosis. All of the nine corresponding gene modules also have highly enriched biological functions or cytoband locations. Three of them are unique modules to RNA-Seq data, which complement the modules from microarray data in terms of survival prognosis. We then merged all eigengenes from these unique modules and used an integrative method called Similarity Network Fusion to test the prognostic power of these eigengenes for prognosis. The prognostic accuracies are significantly improved as compared to using all eigengenes, and a subgroup of patients with very poor survival rate was identified.
CONCLUSIONS: We first compared GCNs mined from microarray and RNA-seq data. We discovered that each data modality yields unique GCNs, which are enriched with clear biological functions. Then we do module unique analysis and use lasso-cox model to select survival-associated eigengenes. Integration of unique and survival-associated eigengenes from both data types provides complementary information that leads to more accurate survival prognosis.
REVIEWERS: Reviewed by Susmita Datta, Marco Chierici and Dimitar Vassilev.

Pessolano E, Belvedere R, Bizzarro V, et al.
Annexin A1 May Induce Pancreatic Cancer Progression as a Key Player of Extracellular Vesicles Effects as Evidenced in the In Vitro MIA PaCa-2 Model System.
Int J Mol Sci. 2018; 19(12) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Pancreatic Cancer (PC) is one of the most aggressive malignancies worldwide. As annexin A1 (ANXA1) is implicated in the establishment of tumour metastasis, the role of the protein in PC progression as a component of extracellular vesicles (EVs) has been investigated. EVs were isolated from wild type (WT) and ANXA1 knock-out (KO) PC cells and then characterised by multiple approaches including Western blotting, Field Emission-Scanning Electron Microscopy, and Dynamic Light Scattering. The effects of ANXA1 on tumour aggressiveness were investigated by Wound-Healing and invasion assays and microscopic analysis of the Epithelial to Mesenchymal Transition (EMT). The role of ANXA1 on angiogenesis was also examined in endothelial cells, using similar approaches. We found that WT cells released more EVs enriched in exosomes than those from cells lacking ANXA1. Notably, ANXA1 KO cells recovered their metastatic potential only when treated by WT EVs as they underwent EMT and a significant increase of motility. Similarly, human umbilical vein endothelial cells (HUVEC) migrated and invaded more rapidly when treated by WT EVs whereas ANXA1 KO EVs weakly induced angiogenesis. This study suggests that EVs-related ANXA1 is able to promote cell migration, invasion, and angiogenesis, confirming the relevance of this protein in PC progression.

Lenzi M, Cocchi V, Novaković A, et al.
Meripilus giganteus ethanolic extract exhibits pro-apoptotic and anti-proliferative effects in leukemic cell lines.
BMC Complement Altern Med. 2018; 18(1):300 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: The interest towards botanicals and plant extracts has strongly risen due to their numerous biological effects and ability to counteract chronic diseases development. Among these effects, chemoprevention which represents the possibility to counteract the cancerogenetic process is one of the most studied. The extracts of mushroom Meripilus giganteus (MG) (Phylum of Basidiomycota) showed to exert antimicrobic, antioxidant and antiproliferative effects. Therefore, since its effect in leukemic cell lines has not been previously evaluated, we studied its potential chemopreventive effect in Jurkat and HL-60 cell lines.
METHODS: MG ethanolic extract was characterized for its antioxidant activity and scavenging effect against different radical species. Moreover, its phenolic profile was evaluated by HPLC-MS-MS analyses. Flow cytometry (FCM) analyses of Jurkat and HL-60 cells treated with MG extract (0-750 μg/mL) for 24-72 h- allowed to evaluate its cytotoxicity, pro-apoptotic and anti-proliferative effect. To better characterize MG pro-apoptotic mechanism ROS intracellular level and the gene expression level of FAS, BAX and BCL2 were also evaluated. Moreover, to assess MG extract selectivity towards cancer cells, its cytotoxicity was also evaluated in human peripheral blood lymphocytes (PBL).
RESULTS: MG extract induced apoptosis in Jurkat and HL-60 cells in a dose- and time- dependent manner by increasing BAX/BCL2 ratio, reducing ROS intracellular level and inducing FAS gene expression level. In fact, reduced ROS level is known to be related to the activation of apoptosis in leukemic cells by the involvement of death receptors. MG extract also induced cell-cycle arrest in HL-60 cells. Moreover, IC
CONCLUSIONS: Our data suggest that MG extract might be considered a promising and partially selective chemopreventive agent since it is able to modulate different mechanisms in transformed cells at concentrations lower than in non-transformed ones.

Brooks PJ, Chadwick JW, Caminiti M, et al.
Primary aneurysmal bone cyst of the mandibular condyle with USP6-CDH11 fusion.
Pathol Res Pract. 2019; 215(3):607-610 [PubMed] Related Publications
Primary aneurysmal bone cyst (ABC) is a cystic bone neoplasm characterized by disease-defining gene fusions involving the USP6/Tre2 gene. The literature describing gnathic ABC is limited. This case report describes a 27-year-old man presenting with a long-standing left-sided facial asymmetry. Multi-detector computed tomography imaging demonstrated a large expansile lesion positioned within the left condylar head. The lesion was biopsied and resected. The specimen showed a giant cell-rich cystic neoplasm, with fibrous tissue lined by multinucleated giant cells. Next-generation sequencing confirmed the presence of a USP6-CDH11 fusion gene, consistent with classification as a primary ABC, the first reported to be translocation-positive in the head of the mandibular condyle.

Di Marco M, Ramassone A, Pagotto S, et al.
MicroRNAs in Autoimmunity and Hematological Malignancies.
Int J Mol Sci. 2018; 19(10) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Autoimmunity and hematological malignancies are often concomitant in patients. A causal bidirectional relationship exists between them. Loss of immunological tolerance with inappropriate activation of the immune system, likely due to environmental and genetic factors, can represent a breeding ground for the appearance of cancer cells and, on the other hand, blood cancers are characterized by imbalanced immune cell subsets that could support the development of the autoimmune clone. Considerable effort has been made for understanding the proteins that have a relevant role in both processes; however, literature advances demonstrate that microRNAs (miRNAs) surface as the epigenetic regulators of those proteins and control networks linked to both autoimmunity and hematological malignancies. Here we review the most up-to-date findings regarding the miRNA-based molecular mechanisms that underpin autoimmunity and hematological malignancies.

Fiano V, Trevisan M, Fasanelli F, et al.
Methylation in host and viral genes as marker of aggressiveness in cervical lesions: Analysis in 543 unscreened women.
Gynecol Oncol. 2018; 151(2):319-326 [PubMed] Related Publications
OBJECTIVE: The present study aimed to evaluate the association between altered methylation and histologically confirmed high grade cervical intraepithelial neoplasia (hgCIN).
METHODS: Methylation levels in selected host (CADM1, MAL, DAPK1) and HPV (L1_I, L1_II, L2) genes were measured by pyrosequencing in DNA samples obtained from 543 women recruited in Curitiba (Brazil), 249 with hgCIN and 294 without cervical lesions. Association of methylation status with hgCIN was estimated by Odds Ratio (OR) with 95% confidence interval (CI).
RESULTS: The mean methylation level increased with severity of the lesion in the host and viral genes (p-trend < 0.05), with the exception of L1_II region (p-trend = 0.075). Positive association was found between methylation levels for host genes and CIN2 and CIN3 lesions respectively [CADM1: OR 4.17 (95%CI 2.03-8.56) and OR 9.54 (95%CI 4.80-18.97); MAL: OR 5.98 (95%CI 2.26-15.78) and OR 22.66 (95%CI 9.21-55.76); DAPK1: OR 3.37 (95%CI 0.93-12.13) and OR 6.74 (95%CI 1.92-23.64)]. Stronger risk estimates were found for viral genes [L1_I: OR 10.74 (95%CI 2.66-43.31) and OR 15.00 (95%CI 3.00-74.98); L1_II: OR 73.18 (95%CI 4.07-1315.94) and OR 32.50 (95%CI 3.86-273.65); L2: OR 4.73 (95%CI 1.55-14.44) and OR 10.62 (95%CI 2.60-43.39)]. The cumulative effect of the increasing number of host and viral methylated genes was associated with the risk of CIN2 and CIN3 lesions (p-trend < 0.001).
CONCLUSIONS: Our results, empowered by a wide cervical sample series with a large number of hgCIN, supported the role of methylation as marker of aggressiveness.

Adamska A, Falasca M
ATP-binding cassette transporters in progression and clinical outcome of pancreatic cancer: What is the way forward?
World J Gastroenterol. 2018; 24(29):3222-3238 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and is characterized by high chemoresistance, leading to the lack of effective therapeutic approaches and grim prognosis. Despite increasing understanding of the mechanisms of chemoresistance in cancer and the role of ATP-binding cassette (ABC) transporters in this resistance, the therapeutic potential of their pharmacological inhibition has not been successfully exploited yet. In spite of the discovery of potent pharmacological modulators of ABC transporters, the results obtained in clinical trials have been so far disappointing, with high toxicity levels impairing their successful administration to the patients. Critically, although ABC transporters have been mostly studied for their involvement in development of multidrug resistance (MDR), in recent years the contribution of ABC transporters to cancer initiation and progression has emerged as an important area of research, the understanding of which could significantly influence the development of more specific and efficient therapies. In this review, we explore the role of ABC transporters in the development and progression of malignancies, with focus on PDAC. Their established involvement in development of MDR will be also presented. Moreover, an emerging role for ABC transporters as prognostic tools for patients' survival will be discussed, demonstrating the therapeutic potential of ABC transporters in cancer therapy.

Iafolla MAJ, Selby H, Warner K, et al.
Rational design and identification of immuno-oncology drug combinations.
Eur J Cancer. 2018; 95:38-51 [PubMed] Related Publications
BACKGROUND: Clinical trials investigating immuno-oncology (IO) drug combinations are largely based on empiricism or limited non-clinical evaluations. This study identified the current combination IO drug clinical trials and investigated how tumour molecular profiling can help rationalise IO drug combinations.
METHODS: IO targets were identified via PubMed search and expert opinion. IO drugs were compiled by searching the National Cancer Institute Drug Dictionary and pharmaceutical pipelines, August 2016. Combination IO trials were obtained by searching doublet IO drug combinations in www.clinicaltrials.gov from September to November 2016. IO target gene expressions were extracted from The Cancer Genome Atlas (TCGA) data set and compared with normal tissues from the Genotype-Tissue Expression database. Differentially expressed genes for each cancer were determined using the Wilcoxon rank-sum test, and p-values were corrected for multiple testing.
RESULTS: In total, 178 IO targets were identified; 90 targets have either regulatory approved or investigational therapeutics. In total, 410 combination trials involving ≥2 IO drugs were identified: skin (n = 102) and genitourinary (n = 41) malignancies have the largest number of combination IO trials; 109 trials involved >2 disease sites. Summative patient accrual estimates among all trials are 71,345. Trials combining cytotoxic T lymphocyte antigen 4 (CTLA4) with programmed cell death protein 1 (n = 79) and CTLA4 with programmed cell death ligand 1 (n = 44) are the most common. Gene expression data from TCGA were mined to extract the 178 IO targets in 9089 tumours originating from 19 cancer types. IO target expression-clustered heatmap analysis identified several promising drug combinations.
CONCLUSION: Our review highlights the great interest in combination IO clinical trials. Our analysis can enrich IO combination therapy selection.

Grassi E, Durante S, Astolfi A, et al.
Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis.
Int J Oncol. 2018; 52(6):1972-1980 [PubMed] Related Publications
Despite the genomic characterization of pancreatic cancer (PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30 PC samples were analysed by either whole transcriptome (9 samples) or exome sequencing (21 samples) on an Illumina platform (75X2 or 100X2 bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation-prediction tools. A total of 43 recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25 months) harboured an average of 24 events, whereas samples from patients with an overall survival of <25 months presented an average of 40 mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease.

Vatrano S, Volante M, Duregon E, et al.
Detailed genomic characterization identifies high heterogeneity and histotype-specific genomic profiles in adrenocortical carcinomas.
Mod Pathol. 2018; 31(8):1257-1269 [PubMed] Related Publications
Molecular characterization of adrenocortical carcinoma has been recently established, but the correlation between molecular profiles and clinical and pathological characteristics is still poorly defined with no data available about genetic heterogeneity along disease progression. In this scenario, a detailed molecular profile was correlated with clinical and pathological characteristics in adrenocortical carcinoma patients to identify potentially novel biomarkers. Targeted next-generation sequencing and copy number variation analyses for 18 most frequently altered genes in adrenocortical carcinoma were assessed on 62 adult cases (including 10 with matched primary and metastatic/recurrence samples) and results correlated with major clinical and pathological characteristics of tumors. A total of 433 somatic deleterious genetic alterations (328 gene mutations and 105 copy number variations) were identified in 57/62 cases, five resulted wild type for all genes tested. TERT, CDK4, ZNRF3,and RB1 were altered in more than 30% of cases. Among histological variants genotypes were significantly different. Lowest mutation burden was found in the oncocytic type (p = 0.006), whereas the highest with a prevalence of RB1 (p = 0.001) and CDK4 (p = 0.002) was found in the conventional and myxoid ones, respectively. None of the 10 cases with matched samples showed a stable genotype along tumor progression, although allelic frequencies or percentages of altered nuclei at fluorescence in situ hybridization were in most cases similar among different tumor samples for genes that were stable along tumor progression. Among individual genes, an altered p53/Rb1 pathway was the strongest adverse molecular signature, being associated with high Ki-67 index, high tumor stage, aggressive disease status, and shorter disease-free survival. The genomic signature in adrenocortical carcinoma is changing along tumor progression and is associated with specific clinical and pathological features, including histological variant and prognosis.

Giannoukos G, Ciulla DM, Marco E, et al.
UDiTaS™, a genome editing detection method for indels and genome rearrangements.
BMC Genomics. 2018; 19(1):212 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Understanding the diversity of repair outcomes after introducing a genomic cut is essential for realizing the therapeutic potential of genomic editing technologies. Targeted PCR amplification combined with Next Generation Sequencing (NGS) or enzymatic digestion, while broadly used in the genome editing field, has critical limitations for detecting and quantifying structural variants such as large deletions (greater than approximately 100 base pairs), inversions, and translocations.
RESULTS: To overcome these limitations, we have developed a Uni-Directional Targeted Sequencing methodology, UDiTaS, that is quantitative, removes biases associated with variable-length PCR amplification, and can measure structural changes in addition to small insertion and deletion events (indels), all in a single reaction. We have applied UDiTaS to a variety of samples, including those treated with a clinically relevant pair of S. aureus Cas9 single guide RNAs (sgRNAs) targeting CEP290, and a pair of S. pyogenes Cas9 sgRNAs at T-cell relevant loci. In both cases, we have simultaneously measured small and large edits, including inversions and translocations, exemplifying UDiTaS as a valuable tool for the analysis of genome editing outcomes.
CONCLUSIONS: UDiTaS is a robust and streamlined sequencing method useful for measuring small indels as well as structural rearrangements, like translocations, in a single reaction. UDiTaS is especially useful for pre-clinical and clinical application of gene editing to measure on- and off-target editing, large and small.

Asevedo Campos de Resende T, de Fátima Bernardes V, Carolina da Silva J, et al.
Loss of heterozygosity of MIR15A/MIR16-1, negative regulators of the antiapoptotic gene BCL2, is not common in odontogenic keratocysts.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2018; 125(4):313-316 [PubMed] Related Publications
OBJECTIVES: The odontogenic keratocyst (OKC) is an aggressive odontogenic cyst that has a high recurrence rate. Apart from PTCH1 mutations, few molecular alterations are described in OKCs. Low expression of microRNAs (miRNAs) miR-15a and/or miR-16-1 in association with increased expression of their target, Bcl-2, have been previously found in OKC. In humans, MIR15A and MIR16-1 are clustered at chromosome position 13 q14, and loss of heterozygosity (LOH) at this locus occurs in different tumors. We aimed to determine whether deletion at 13 q14 is a potential mechanism leading to miR-15a/16-1 aberrant expression in OKC.
METHODS: Genomic DNA was extracted from 15 formalin-fixed, paraffin-embedded microdissected OKC cases. The polymorphic DNA markers D13S272 and D13S273 on chromosome 13 q14.3, around MIR15A/MIR16-1, were amplified by polymerase chain reaction. LOH was examined by capillary electrophoresis DNA-fragment analysis.
RESULTS: The D13S272 marker had no LOH in 12 informative cases, whereas 2 out of 9 informative cases (22%) had LOH at the D13S273 marker.
CONCLUSIONS: An LOH event at MIR15A/MIR16-1 locus is not common in OKC. The mechanism underlying the regulation of miR-15a and miR-16-1 expression in OKC remains to be determined.

De Vitis M, Berardinelli F, Sgura A
Telomere Length Maintenance in Cancer: At the Crossroad between Telomerase and Alternative Lengthening of Telomeres (ALT).
Int J Mol Sci. 2018; 19(2) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Eukaryotic cells undergo continuous telomere shortening as a consequence of multiple rounds of replications. During tumorigenesis, cells have to acquire telomere DNA maintenance mechanisms (TMMs) in order to counteract telomere shortening, to preserve telomeres from DNA damage repair systems and to avoid telomere-mediated senescence and/or apoptosis. For this reason, telomere maintenance is an essential step in cancer progression. Most human tumors maintain their telomeres expressing telomerase, whereas a lower but significant proportion activates the alternative lengthening of telomeres (ALT) pathway. However, evidence about the coexistence of ALT and telomerase has been found both in vivo in the same cancer populations and in vitro in engineered cellular models, making the distinction between telomerase- and ALT-positive tumors elusive. Indeed, after the development of drugs able to target telomerase, the capability for some cancer cells to escape death, switching from telomerase to ALT, was highlighted. Unfortunately, to date, the mechanism underlying the possible switching or the coexistence of telomerase and ALT within the same cell or populations is not completely understood and different factors could be involved. In recent years, different studies have tried to shed light on the complex regulation network that controls the transition between the two TMMs, suggesting a role for embryonic cancer origin, epigenetic modifications, and specific genes activation-both in vivo and in vitro. In this review, we examine recent findings about the cancer-associated differential activation of the two known TMMs and the possible factors implicated in this process. Furthermore, some studies on cancers are also described that did not display any TMM.

Schrader A, Crispatzu G, Oberbeck S, et al.
Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.
Nat Commun. 2018; 9(1):697 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.

Petiti J, Rosso V, Lo Iacono M, et al.
Prognostic significance of The Wilms' Tumor-1 (WT1) rs16754 polymorphism in acute myeloid leukemia.
Leuk Res. 2018; 67:6-11 [PubMed] Related Publications
Acute myeloid leukemia is a genetically heterogeneous disease characterized by the accumulation of mutations in hematopoietic progenitor cells. For its heterogeneity, prognostic markers are very useful for therapeutic choice. The most important prognostic markers are age, white blood cell count, chromosomal alterations and gene mutations. Recent works have studied the prognostic significance of WT1 polymorphisms and mutations, highlighting the role of SNP rs16754 as a positive prognostic factor in AML patients. Nevertheless, the data are still unclear. To investigate the role of WT1 rs16754 polymorphism in AML, we designed a new tool for the detection using PNA directed PCR Clamping technology. Our data were able to establish a correlation between SNP rs16754 and the clinical outcome. Our results support the hypothesis that rs16754 polymorphism is an independent positive prognostic molecular marker that could be useful for therapeutic choice. In view of this, we described a novel assay faster, more sensitive and cheaper than DNA sequencing. The assay allows evaluating WT1 rs16754 polymorphism in diagnostic routine to improve prognostic information faster and without over-costing for diagnostic laboratories.

Vitelli V, Falvo P, G Nergadze S, et al.
Telomeric Repeat-Containing RNAs (TERRA) Decrease in Squamous Cell Carcinoma of the Head and Neck Is Associated with Worsened Clinical Outcome.
Int J Mol Sci. 2018; 19(1) [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Telomeres are transcribed into noncoding telomeric repeat-containing RNAs (TERRA), which are essential for telomere maintenance. Deregulation of TERRA transcription impairs telomere metabolism and a role in tumorigenesis has been proposed. Head and neck cancer (HNC) is one of the most frequent cancers worldwide, with head and neck squamous cell carcinoma (HNSCC) being the predominant type. Since HNSCC patients are characterized by altered telomere maintenance, a dysfunction in telomere transcription can be hypothesized. In this prospective study, we compared TERRA levels in the tumor and matched normal tissue from 23 HNSCC patients. We then classified patients in two categories according to the level of TERRA expression in the tumor compared to the normal tissue: (1) lower expression in the tumor, (2) higher or similar expression in tumor. A significant proportion of patients in the first group died of the disease within less than 34 months postsurgery, while the majority of patients in the second group were alive and disease-free. Our results highlight a striking correlation between TERRA expression and tumor aggressiveness in HNSCC suggesting that TERRA levels may be proposed as a novel molecular prognostic marker for HNSCC.

Gamberi G, Morandi L, Benini S, et al.
Detection of H3F3A p.G35W and p.G35R in giant cell tumor of bone by Allele Specific Locked Nucleic Acid quantitative PCR (ASLNAqPCR).
Pathol Res Pract. 2018; 214(1):89-94 [PubMed] Related Publications
Giant Cell Tumor (GCT) represents about 20% of benign bone tumors, is locally aggressive although malignant transformation is extremely rare, <1% of cases but 2-3% give pulmonary metastasis. Age at onset is between 20 and 40 years with a slight predominance for the female gender. GCT is characterized by specific mutations in H3F3A gene encoding the protein histone 3.3. The study of these mutations is important for the differential diagnosis with giant cell rich sarcomas, chondroblastoma and aneurysmal bone cyst. To identify the most frequent H3F3A mutations we developed a novel allele specific Real Time Polymerase Chain Reaction method, based on Allele Specific Locked Nucleic Acid (ASLNAqPCR) that is here described. Molecular analyses were performed on 20 GCT and 2 osteosarcoma arising on a previous GCT. All cases were verified by Sanger sequencing. We demonstrated that ASLNAqPCR is a quick, sensitive and reliable method to identify mutations of the H3F3A gene, in giant cell tumor of bone, to support diagnosis in morphologically ambiguous cases.

Del Vecchio F, Mastroiaco V, Di Marco A, et al.
Next-generation sequencing: recent applications to the analysis of colorectal cancer.
J Transl Med. 2017; 15(1):246 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Since the establishment of the Sanger sequencing method, scientists around the world focused their efforts to progress in the field to produce the utmost technology. The introduction of next-generation sequencing (NGS) represents a revolutionary step and promises to lead to massive improvements in our understanding on the role of nucleic acids functions. Cancer research began to use this innovative and highly performing method, and interesting results started to appear in colorectal cancer (CRC) analysis. Several studies produced high-quality data in terms of mutation discovery, especially about actionable or less frequently mutated genes, epigenetics, transcriptomics. Analysis of results is unveiling relevant perspectives aiding to evaluate the response to therapies. Novel evidences have been presented also in other directions such as gut microbiota or CRC circulating tumor cells. However, despite its unquestioned potential, NGS poses some issues calling for additional studies. This review intends to offer a view of the state of the art of NGS applications to CRC through examination of the most important technologies and discussion of recent published results.

Werner JM, Kuhl S, Stavrinou P, et al.
Expression of FAS-L Differs from Primary to Relapsed Low-grade Gliomas and Predicts Progression-free Survival.
Anticancer Res. 2017; 37(12):6639-6648 [PubMed] Related Publications
BACKGROUND/AIM: The tumor necrosis factor FAS is overexpressed in high-grade gliomas (HGG). Only little is known about FAS or FAS ligand (FAS-L) in low-grade gliomas (LGG). We explored FAS/FAS-L expression in LGG, focusing on differences in primary and relapsed LGG and on its prognostic value.
PATIENTS AND METHODS: A total of 133 glioma samples (73 LGG, 60 HGG) were collected. The LGG samples included 15 matched pairs of primary and relapsed tumors. RT-PCR was performed to measure FAS/FAS-L expression, using subunit A, flavoprotein variant (SDHA) as housekeeper. Clinical data included progression free- (PFS) and overall survival (OS).
RESULTS: LGG showed significantly lower FAS but higher FAS-L expression than HGG. The FAS-L expression was higher in primary compared to relapsed LGG and had a positive prognostic value concerning PFS (median 45.20 vs. 31.37 months).
CONCLUSION: FAS-L could act as a prognostic marker and potential target in primary LGG.

Abbruzzese C, Matteoni S, Signore M, et al.
Drug repurposing for the treatment of glioblastoma multiforme.
J Exp Clin Cancer Res. 2017; 36(1):169 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Glioblastoma Multiforme is the deadliest type of brain tumor and is characterized by very poor prognosis with a limited overall survival. Current optimal therapeutic approach has essentially remained unchanged for more than a decade, consisting in maximal surgical resection followed by radiotherapy plus temozolomide.
MAIN BODY: Such a dismal patient outcome represents a compelling need for innovative and effective therapeutic approaches. Given the development of new drugs is a process presently characterized by an immense increase in costs and development time, drug repositioning, finding new uses for existing approved drugs or drug repurposing, re-use of old drugs when novel molecular findings make them attractive again, are gaining significance in clinical pharmacology, since it allows faster and less expensive delivery of potentially useful drugs from the bench to the bedside. This is quite evident in glioblastoma, where a number of old drugs is now considered for clinical use, often in association with the first-line therapeutic intervention. Interestingly, most of these medications are, or have been, widely employed for decades in non-neoplastic pathologies without relevant side effects. Now, the refinement of their molecular mechanism(s) of action through up-to-date technologies is paving the way for their use in the therapeutic approach of glioblastoma as well as other cancer types.
SHORT CONCLUSION: The spiraling costs of new antineoplastic drugs and the long time required for them to reach the market demands a profoundly different approach to keep lifesaving therapies affordable for cancer patients. In this context, repurposing can represent a relatively inexpensive, safe and fast approach to glioblastoma treatment. To this end, pros and cons must be accurately considered.

Giacomini A, Ghedini GC, Presta M, Ronca R
Long pentraxin 3: A novel multifaceted player in cancer.
Biochim Biophys Acta Rev Cancer. 2018; 1869(1):53-63 [PubMed] Related Publications
Since its discovery in 1992, long pentraxin 3 (PTX3) has been characterized as soluble patter recognition receptor, a key player of the innate immunity arm with non-redundant functions in pathogen recognition and inflammatory responses. As a component of the extra-cellular matrix milieu, PTX3 has been implicated also in wound healing/tissue remodeling, cardiovascular diseases, fertility, and infectious diseases. Consequently, PTX3 levels in biological fluids have been proposed as a fluid-phase biomarker in different pathological conditions. In the last decade, experimental evidences have shown that PTX3 may exert a significant impact also on different aspects of cancer biology, including tumor onset, angiogenesis, metastatic dissemination and immune-modulation. However, it remains unclear whether PTX3 acts as a good cop or bad cop in cancer. In this review, we will summarize and discuss the scientific literature data focusing on the role of PTX3 in experimental and human tumors, including its putative translational implications.

Ruella M, Kenderian SS
Next-Generation Chimeric Antigen Receptor T-Cell Therapy: Going off the Shelf.
BioDrugs. 2017; 31(6):473-481 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Autologous, patient-specific chimeric antigen receptor T-cell (CART) therapy has emerged as a powerful and potentially curative therapy for cancer, especially for CD19-positive hematological malignancies. Indeed, on August 30, 2017, the University of Pennsylvania-designed CD19-directed CART (CART-19) cell therapy (CTL019, tisagenlecleucel-t, Kymriah - Novartis) became the first CART therapy approved by the Food and Drug Administration (FDA) for acute lymphoblastic leukemia. However, the development of CART technology and its wider application is partly limited by the patient-specific nature of such a platform and by the time required for manufacturing. The efficacious generation of universal allogeneic CART cells would overcome these limitations and represent a major advance in the field. However, several obstacles in the generation of universal CART cells need to be overcome, namely the risk of CART rejection and the risk of graft-versus-host disease mediated by the allogeneic CART. In this review, we discuss the different strategies being employed to generate universal CART and provide our perspective on the successful development of a truly off-the-shelf CART product.

Medoro A, Bartollino S, Mignogna D, et al.
Complexity and Selectivity of γ-Secretase Cleavage on Multiple Substrates: Consequences in Alzheimer's Disease and Cancer.
J Alzheimers Dis. 2018; 61(1):1-15 [PubMed] Related Publications
The processing of the amyloid-β protein precursor (AβPP) by β- and γ-secretases is a pivotal event in the genesis of Alzheimer's disease (AD). Besides familial mutations on the AβPP gene, or upon its overexpression, familial forms of AD are often caused by mutations or deletions in presenilin 1 (PSEN1) and 2 (PSEN2) genes: the catalytic components of the proteolytic enzyme γ-secretase (GS). The "amyloid hypothesis", modified over time, states that the aberrant processing of AβPP by GS induces the formation of specific neurotoxic soluble amyloid-β (Aβ) peptides which, in turn, cause neurodegeneration. This theory, however, has recently evidenced significant limitations and, in particular, the following issues are debated: 1) the concept and significance of presenilin's "gain of function" versus "loss of function"; and 2) the presence of several and various GS substrates, which interact with AβPP and may influence Aβ formation. The latter consideration is suggestive: despite the increasing number of GS substrates so far identified, their reciprocal interaction with AβPP itself, even in the AD field, is significantly unexplored. On the other hand, GS is also an important pharmacological target in the cancer field; inhibitors or GS activity are investigated in clinical trials for treating different tumors. Furthermore, the function of AβPP and PSENs in brain development and in neuronal migration is well known. In this review, we focused on a specific subset of GS substrates that directly interact with AβPP and are involved in its proteolysis and signaling, by evaluating their role in neurodegeneration and in cell motility or proliferation, as a possible connection between AD and cancer.

Lim EL, Trinh DL, Ries RE, et al.
MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia.
J Clin Oncol. 2017; 35(35):3964-3977 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples-1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples-127 primary and 37 relapse samples-were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

Singh N, Shi J, June CH, Ruella M
Genome-Editing Technologies in Adoptive T Cell Immunotherapy for Cancer.
Curr Hematol Malig Rep. 2017; 12(6):522-529 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
PURPOSE OF REVIEW: In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy.
RECENT FINDINGS: Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies. As CART19 enters routine clinical use, improving the efficacy of this exciting platform is the next step in broader application. Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells.

Couto PP, Bastos-Rodrigues L, Schayek H, et al.
Spectrum of germline mutations in smokers and non-smokers in Brazilian non-small-cell lung cancer (NSCLC) patients.
Carcinogenesis. 2017; 38(11):1112-1118 [PubMed] Related Publications
Lung cancer (LC) is a leading cause of cancer-related mortality. Although smoking is the major risk factor, ~15% of all cases occur in never-smokers, suggesting that genetic factors play a role in LC predisposition. Indeed, germline mutations in the TP53 gene predispose to multiple cancer types, including LC. To date, few studies compared the somatic and germline mutational profiles of LC cases by smoking status, and none was reported in Brazilians. Whole-exome sequencing (WES) was performed on two pools (seven smokers and six non-smokers) of tumor-derived DNA using the Illumina HiSeq2000 platform. Files from pools were analyzed separately using Ingenuity®Variant AnalysisTM and Mendel,MD. Validation of all candidate variants was performed by Sanger sequencing. Subsequently, validated mutations were analyzed in germline DNA from the same patients and in ethnically matched controls. In addition, a single recurring Brazilian TP53 germline mutation (R337H) was genotyped in 45 non-small-cell lung cancer patients.Four novel germline variants in the ATAD2, AURKA, PTPRD and THBS1 genes were identified exclusively in smoker patients, and four germline missense variants in PLCD1, RAD52, CP and CDC6 genes were identified solely in non-smokers. There were 4/45 (8.9%) germline carriers of the R337H TP53 mutation. In conclusion, the recurring Brazilian TP53 mutation should be genotyped in all non-small-cell lung cancer in Brazil, regardless of smoking status. Distinct pathogenic mutations and novel sequence variants are detected in Brazilian non-small-cell lung cancer patients, by smoking status. The contribution of these sequence variants to LC pathogenesis remains to be further explored.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. MARCO, Cancer Genetics Web: http://www.cancer-genetics.org/MARCO.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 01 September, 2019     Cancer Genetics Web, Established 1999