Loss Of Tumor Suppressor Genes Research Articles

Alisertib is active as single agent in recurrent atypical teratoid rhabdoid tumors in 4 children.

Aurora Kinase A (AURKA) encodes a protein that regulates the formation and stability of the mitotic spindle and is highly active in atypical teratoid rhabdoid tumors (ATRT) through loss of the INI1 tumor suppressor gene. Alisertib (MLN8237) inhibits AURKA in vitro and in vivo. Given the strong preclinical data supporting the use of alisertib for ATRT patients, we sought and obtained permission to use alisertib in single patient treatment plans for 4 recurrent pediatric ATRT patients. Patients with recurrent or progressive ATRT received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle. Disease evaluation (MRI of brain and spine and lumbar puncture) was done after 2 cycles of alisertib and every 2-3 cycles thereafter for as long as the patients remained free from tumor progression. Four patients with median age of 2.5 years (range, 1.39-4.87 y) at diagnosis received alisertib 80 mg/m(2) by mouth once daily for 7 days of a 21-day treatment cycle, and all 4 patients had disease stabilization and/or regression after 3 cycles of alisertib therapy. Two patients continued to have stable disease regression for 1 and 2 years, respectively, on therapy. Single-agent alisertib produced marked and durable regression in disease burden, as detected by brain and spine MRI and by evaluation of spinal fluid cytology. Alisertib has moderate but manageable toxicities, and its chronic administration appears feasible in this pediatric population. These novel data support the incorporation of alisertib in future therapeutic trials for children with ATRT.

Genetic and epigenetic aspects of initiation and progression of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a primary cancer of the liver that is predominant in developing countries and is responsible for nearly 600000 deaths each year worldwide. Similar to many other tumors, the development of HCC must be understood as a multistep process involving the accumulation of genetic and epigenetic alterations in regulatory genes, leading to the activation of oncogenes and the inactivation or loss of tumor suppressor genes. Extensive research over the past decade has identified a number of molecular biomarkers, including aberrant expression of HCC-related genes and microRNAs. The challenge facing HCC research and clinical care at this time is to address the heterogeneity and complexity of these genetic and epigenetic alterations and to use this information to direct rational diagnosis and treatment strategies. The multikinase inhibitor sorafenib was the first molecularly targeted drug for HCC to show some extent of survival benefits in patients with advanced tumors. Although the results obtained using sorafenib support the importance of molecular therapies in the treatment of HCC, there is still room for improvement. In addition, no molecular markers for drug sensitivity, recurrence and prognosis are currently clinically available. In this review, we provide an overview of recently published articles addressing HCC-related genes and microRNAs to update what is currently known regarding genetic and epigenetic aspects of the pathogenesis of HCC and propose novel promising candidates for use as diagnostic and therapeutic targets in HCC.

The putative tumor suppressor gene EphA3 fails to demonstrate a crucial role in murine lung tumorigenesis or morphogenesis.

Treatment of non-small cell lung cancer (NSCLC) is based on histological analysis and molecular profiling of targetable driver oncogenes. Therapeutic responses are further defined by the landscape of passenger mutations, or loss of tumor suppressor genes. We report here a thorough study to address the physiological role of the putative lung cancer tumor suppressor EPH receptor A3 (EPHA3), a gene that is frequently mutated in human lung adenocarcinomas. Our data shows that homozygous or heterozygous loss of EphA3 does not alter the progression of murine adenocarcinomas that result from Kras mutation or loss of Trp53, and we detected negligible postnatal expression of EphA3 in adult wild-type lungs. Yet, EphA3 was expressed in the distal mesenchyme of developing mouse lungs, neighboring the epithelial expression of its Efna1 ligand; this is consistent with the known roles of EPH receptors in embryonic development. However, the partial loss of EphA3 leads only to subtle changes in epithelial Nkx2-1, endothelial Cd31 and mesenchymal Fgf10 RNA expression levels, and no macroscopic phenotypic effects on lung epithelial branching, mesenchymal cell proliferation, or abundance and localization of CD31-positive endothelia. The lack of a discernible lung phenotype in EphA3-null mice might indicate lack of an overt role for EPHA3 in the murine lung, or imply functional redundancy between EPHA receptors. Our study shows how biological complexity can challenge in vivo functional validation of mutations identified in sequencing efforts, and provides an incentive for the design of knock-in or conditional models to assign the role of EPHA3 mutation during lung tumorigenesis.

Distinct Patterns of Genomic Alterations in Adult T-Cell Leukemia-Lymphoma Endemic in the Western World

Introduction: Acute T-cell leukemia/lymphoma (ATLL) is a highly aggressive malignancy caused by HTLV-I, which is endemic in Japan, the Caribbean, and South America. ATLL carries a dismal prognosis and is generally incurable with conventional chemotherapy. ATLL is challenging to study at the molecular level, in part due to its complex genetic alterations likely resulting from years of HTLV-I driven T-cell proliferation and accumulation of genetic damage prior to malignant transformation. While no specific chromosome or genetic abnormalities have been proven to contribute to the pathogenesis of ATLL, older comparative genomic hybridization (CGH) studies performed in Japanese patients have demonstrated frequent genetic lesions (gains and losses) involving specific chromosomal regions, thus limited information exists about the chromosomal abnormalities occurring in the African ATLL variant commonly seen in the Western World.Methods: In this study, we used a high-density oligo array 244K platform CGH platform (Agilent Technologies) with an average resolution of 8.9 Kb, to perform a comprehensive genomic analysis of 47 ATLL patient tumor specimens obtained from African-descendants in the United States, Caribbean and Brazil. Patients were sub-classified as acute-type (A) ATLL (n=31), lymphomatous (L) (n=8), chronic (n=7, six whom had unfavorable features), and one with smouldering type according to Shimoyama criteria. DNA samples were extracted from peripheral blood mononuclear cells or tumor samples from these patients and checked for quality.Results: ATLL tumors exhibited complex genomic abnormalities and high copy number changes (CNCs). The average of copy number (CN) aberrations per sample was 238 in the L-group vs. 114 in acute/unfavorable chronic (A/UC) group. However, many chromosomal alterations were observed in this cohort, which had not been previously reported by other studies. The common CNCs were gains at 1q21-q44, 3, 3p, 7q22-q36, 8, 18, 19p13.1-p13.3, 21q21.1-q22.3, 22q12-q13 and losses at 5q13.2-q32, 6q11-q15, 9q13-q21. Gains in the 14 q32 (IGH) regions and losses in the 7p14.1 (TCRG), 7q34 (TCRB) and 14q11.2 (TCRA) regions involving small DNA segments were frequently observed. Genomic losses involving at least one or more known or candidate tumor suppressor genes were found in nearly all tumors, including some genes not previously implicated in ATLL. Some of the most significant gene or locus specific losses occurring in at least 20 % of the tumors in aggressive ATLL subtypes (A/UC and L) are summarized in Table 1. Losses of CDKN2A and CDKN2B tumor suppressor genes have been previously implicated in ATLL and other cancers. Several other genes found by this analysis have been implicated in apoptosis or cancer (i.e. CBLB, ANKRD11, IKZF1, and EPC1). IMMP2L deletion was associated with shorter survival time (2.3 weeks) compared with those cases without this gene deletion (29 weeks) in the A/UC group (p=0.005). ANKRD11 homo- or heterozygous deletions were seen in 37% of L-type and 19% of acute-type cases, and were associated with a shorter survival (13 vs. 43 weeks, p=<0.05) in the A group. CPN2/LRRC15 locus gains in 32% of A-type were linked to poorer survival (16 vs. 42 weeks, p=0.05).Table 1GENEFUNCTIONLOSSES (n) GAINS (n) NRXN3Membrane receptor, cell adhesion23 A/UC 3 LNSIMMP2LMitochondrial inner membrane peptidase16 A/UC* 5 L4 A/UCCDKN2A/ CDKN2B (P16INK4/p15INK4b)Cyclin-dependent kinase inhibitors, tumor suppressors16 A/UC 2 L1 A/UC 1 LCBLBE3 ubiquitin protein ligase12 A/UC 1 LNSANKRD11Transcriptional inhibitor, co-activator of p536 A/UC* 3 LNSCPN2CarboxypeptidaseNS10 A/UC* 2 LIKZF1Zinc-finger DNA binding proteins , lymphocyte differentiationNS6 A/UC 3 LINSIG1Endoplasmic reticulum membrane protein, intracellular lipid metabolismNS10 A/UC 1 LEPC1Member of the polycomb group family, transcriptional activator and repressor10 A/UC 2 LNS* are genomic imbalances associated with a statistically significant reduction in survival. NS: non-significant.Conclusion: In sum, using a high resolution CGH array we observed distinct patterns ofgenetic aberrations in ATLL endemic in the Western World. We have successfully narrowed the genomic regions containing potential candidate genes that could be relevant to the pathogenesis of this fatal disease. Functional studies are required to determine the role of some of these genes in the pathogenesis of ATLL. DisclosuresO’Hara:BioDiscovery, Inc.: Employment.

Specific type epigenetic changes in cervical cancers.

Cancer is a genetic and epigenetic disease. Multiple genetic and epigenetic changes have been studied in cervical cancer; however, such changes are selected for during tumorigenesis and tumor aggression is not yet clear. Cervical cancer is a multistep process with accumulation of genetic and epigenetic alterations in regulatory genes, leading to activation of oncogenes and inactivation or loss of tumor suppressor genes. In cervical cancer, epigenetic alterations can affect the expression of papillomaviral as well as host genes in relation to stages representing the multistep process of carcinogenesis.

Fastest time to cancer by loss of tumor suppressor genes.

Genetic instability promotes cancer progression (by increasing the probability of cancerous mutations) as well as hinders it (by imposing a higher cell death rate for cells susceptible to cancerous mutation). With the loss of tumor suppressor gene function known to be responsible for a high percentage of breast and colorectal cancer (and a good fraction of lung cancer and other types as well), it is important to understand how genetic instability can be orchestrated toward carcinogenesis. In this context, this paper gives a complete characterization of the optimal (time-varying) cell mutation rate for the fastest time to a target cancerous cell population through the loss of both copies of a tumor suppressor gene. Similar to the (one-step) oncogene activation model previously analyzed, the optimal mutation rate of the present two-step model changes qualitatively with the convexity of the (mutation rate-dependent) cell death rate. However, the structure of the Hamiltonian for the new model differs significantly and intrinsically from that of the one-step model, and a completely new approach is needed for the solution of the present two-step problem. Considerable insight into the biology of optimal switching (between corner controls) is extracted from numerical results for cases with nonconvex death rates.

Abstract 3665: IDO1 is an integrative determinant of tumor-promoting, pathogenic inflammation

Abstract The tryptophan-catabolizing enzyme IDO1 (indoleamine 2,3-dioxygenase 1) has been implicated as a mediator of immune tolerance in the reproductively essential process of shielding the ‘foreign’ fetus from maternal immunity. By extrapolation, we and others hypothesized that tumors might elevate IDO1 under selective pressure by the immune system. Our finding that loss of the Bin1 tumor suppressor gene potentiates the superinduction of IDO1 provided the first discreet example of a molecular pathway through which this immune escape process can occur. However, the involvement of IDO1 in tumorigenesis has turned out to be far more complex. Tumors that inherently lack IDO1 expression have been demonstrated to induce IDO1 expression in antigen presenting cells of the host, providing an alternative mechanism for immune escape. We have also found from studies in the classical DMBA/TPA skin carcinogenesis model that IDO1 can be induced by the inflammatory tumor-promoting process itself independent of the presence of an initiated tumor. Thus, IDO1 can be a factor in tumor promotion throughout the entire immunoediting process. With the rapid pace of development of IDO inhibitors, which are currently being evaluated in clinical trials, we are interested in determining whether mouse tumor models might provide additional insight into the optimal therapeutic application of these agents based on the underlying biology. In current studies, we have found that IDO1-nullizygous mice are resistant to both KRAS-induced lung adenocarcinomas and pulmonary breast carcinoma metastases. Micro-computed tomographic imaging confirmed that lung tumor burden was correspondingly lower in IDO1-nullizygous mice. Surprisingly, this analysis also revealed a significantly reduced pulmonary blood vessel density in IDO1-nullizygous mice. Elevation of the inflammatory cytokine IL6 (interleukin 6) was greatly attenuated in conjunction with the loss of IDO1, consistent with in vitro evidence that IDO1 potentiates IL6 production. MDSCs (myeloid derived suppressor cells) from IDO1-nullizygous animals exhibited reduced T cell suppressive activity that could be rescued by IL6. IL6 could likewise reverse the pulmonary metastasis resistance exhibited by IDO1-nullizygous mice. Together, our findings provide support for the emerging concept of IDO1 as a prototypical, integrative immune modifier that bridges inflammation, vascularization and immune escape to foster the establishment of a pathogenic, tumor-promoting environment. Citation Format: Alexander J. Muller, Courtney Smith, Mee Young Chang, James DuHadaway, Arpita Mondal, Hollie Flick, Katherine Parker, Daniel Beury, Suzanne Ostrand-Rosenberg, George C. Prendergast. IDO1 is an integrative determinant of tumor-promoting, pathogenic inflammation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3665. doi:10.1158/1538-7445.AM2014-3665

Just like the rest of evolution in Mother Nature, the evolution of cancers may be driven by natural selection, and not by haphazard mutations.

Sporadic carcinogenesis starts from immortalization of a differentiated somatic cell or an organ-specific stem cell. The immortalized cell incepts a new or quasinew organism that lives like a parasite in the patient and usually proceeds to progressive simplification, constantly engendering intermediate organisms that are simpler than normal cells. Like organismal evolution in Mother Nature, this cellular simplification is a process of Darwinian selection of those mutations with growth- or survival-advantages, from numerous ones that occur randomly and stochastically. Therefore, functional gain of growth- or survival-sustaining oncogenes and functional loss of differentiation-sustaining tumor suppressor genes, which are hallmarks of cancer cells and contribute to phenotypes of greater malignancy, are not drivers of carcinogenesis but are results from natural selection of advantageous mutations. Besides this mutation-load dependent survival mechanism that is evolutionarily low and of an asexual nature, cancer cells may also use cell fusion for survival, which is an evolutionarily-higher mechanism and is of a sexual nature. Assigning oncogenes or tumor suppressor genes or their mutants as drivers to induce cancer in animals may somewhat coerce them to create man-made oncogenic pathways that may not really be a course of sporadic cancer formations in the human.

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.

Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.

ESPL1 is a candidate oncogene of luminal B breast cancers.

ESPL1/separase is a putative oncogene of luminal B breast cancers. Histoclinical correlations of its expression have never been explored in large series of breast tumors, and specifically in the luminal subtype. In a pooled series of invasive breast carcinomas profiled using DNA microarrays, we identified 3,074 luminal cases, including 1,307 luminal B tumors, in which we searched for correlations between ESPL1 mRNA expression and molecular and histoclinical features. Compared to normal breast samples, ESPL1 was overexpressed in 52% of luminal tumors, and much more frequently in luminal B (83%) than luminal A tumors (29%). In luminal breast cancers, higher ESPL1 expression was associated with poor-prognosis criteria (age≤50years, ductal type, advanced stage, large tumor size, lymph node-positive status, high grade, PR-negative status, luminal B subtype) and with poor metastasis-free survival in both uni- and multivariate analyses. This independent prognostic value was also observed in luminal B tumors only, and persisted when compared with gene expression signatures (PAM50, Recurrence Score, Mammaprint, EndoPredict) currently proposed to refine the indications of adjuvant chemotherapy in hormone receptor-positive/HER2-negative breast cancer. We also confirmed the observations made with experimental mouse models: ESPL1-overexpressing luminal tumors showed complex genomic profiles and molecular features of chromosomal instability and loss of tumor suppressor genes (P53 and Rb). Our results reinforce the idea that ESPL1 is a candidate oncogene in luminal B cancers. Its expression may help improve the prognostication. Inhibiting ESPL1 may represent a promising therapeutic approach for these poor-prognosis tumors.

A neuronal function of the tumor suppressor protein merlin.

Mutagenic loss of the NF2 tumor suppressor gene encoded protein merlin is known to provoke the hereditary neoplasia syndrome, Neurofibromatosis type 2 (NF2). In addition to glial cell-derived tumors in the PNS and CNS, disease-related lesions also affect the skin and the eyes. Furthermore, 60% of NF2 patients suffer from peripheral nerve damage, clinically referred to as peripheral neuropathy. Strikingly, NF2-associated neuropathy often occurs in the absence of nerve damaging tumors, suggesting tumor-independent events. Recent findings indicate an important role of merlin in neuronal cell types concerning neuromorphogenesis, axon structure maintenance and communication between axons and Schwann cells. In this review, we compile clinical and experimental evidences for the underestimated role of the tumor suppressor merlin in the neuronal compartment.

-7/7q- syndrome in myeloid-lineage hematopoietic malignancies: attempts to understand this complex disease entity.

The recurrence of chromosomal abnormalities in a specific subtype of cancer strongly suggests that dysregulated gene expression in the corresponding region has a critical role in disease pathogenesis. -7/7q-, defined as the entire loss of chromosome 7 and partial deletion of its long arm, is among the most frequently observed chromosomal aberrations in myeloid-lineage hematopoietic malignancies such as myelodysplastic syndrome and acute myeloid leukemia, particularly in patients treated with cytotoxic agents and/or irradiation. Tremendous efforts have been made to clarify the molecular mechanisms underlying the disease development, and several possible candidate genes have been cloned. However, the study is still underway, and the entire nature of this syndrome is not completely understood. In this review, we focus on the attempts to identify commonly deleted regions in patients with -7/7q-; isolate the candidate genes responsible for disease development, cooperative genes and the factors affecting disease prognosis; and determine effective and potent therapeutic approaches. We also refer to the possibility that the accumulation of multiple gene haploinsufficiency, rather than the loss of a single tumor suppressor gene, may contribute to the development of diseases with large chromosomal deletions such as -7/7q-.

LOSS OF SPARC IN P53-NULL ASTROCYTES PROMOTES MACROPHAGE ACTIVATION AND PHAGOCYTOSIS RESULTING IN DECREASED TUMOR SIZE AND TUMOR CELL SURVIVAL

BACKGROUND: Both enhanced SPARC expression and the loss of p53 tumor suppressor gene are changes that occur early in glioma development. Both SPARC and p53 regulate glioma cell survival by inverse effects on apoptotic signaling. Therefore, during glioma formation, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival and inhibit apoptosis. This study determined whether the loss of Sparc in astrocytes that are null for p53 would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. METHODS: p53-null and Sparc-null mice were bred to obtain heterozygotes. These were crossed to obtain p53-null/Sparc-null neonates, which served as the source of p53-null/Sparc-null astrocytes for comparison to genetically-matched, control p53-null/Sparc-WT astrocytes. In vitro, Sparc loss was assessed using colony formation in soft agar, proliferation assay, flow cytometry, and Annexin V analysis. Orthotopic xenograft implantation was used to assess Sparc loss on tumor growth, proliferation, collagen deposition, and macrophage/microglia recruitment. RESULTS: In vitro, Sparc loss in p53-null astrocytes resulted in increased cell proliferation (2.7-fold; p < 0.01), but decreased cell survival (WT = 7.2% vs. null = 18.56% apoptotic cells) and a longer cell cycle recovery (2 days) after serum-withdrawal. Furthermore, Sparc loss suppressed growth in soft agar. Histomorphological analysis of CD68 and PAS ± diastase staining of tumor sections demonstrated that Sparc loss promoted macrophage/microglial activation (day 7 = 1.35-fold and day 50 = 1.93-fold; p < 0.001) and phagocytic morphology, respectively. At 7 days, Sparc-null tumors had decreased tumor cell survival, proliferation (MIB-1 for WT = 7.1% vs. null = 0.1%; p = 0.0345), and reduced tumor size (WT = 0.839 mm2 vs. null = 0.199 mm2; p = 0.0091). In addition, Sparc loss altered collagen deposition (WT = collagen bundles vs. null = long fiber structure). CONCLUSIONS: Our results indicate that Sparc loss significantly reduced the ability of p53-null astrocytes to recover from stress in vitro, and to survive and proliferate in vivo. This inability to grow in vivo was associated with an increase in macrophage/microglial activation and phagocytosis. Therefore, we conclude that the loss of p53 in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance. We propose that in the background of p53 loss/mutation, therapeutically suppressing SPARC alone, or in combination with other therapies, should promote the ability of patient's immune system to eradicate the tumor. SECONDARY CATEGORY: Immunobiology & Immunotherapy.

Knockdown of WWP1 inhibits growth and induces apoptosis in hepatoma carcinoma cells through the activation of caspase3 and p53

The activation of oncogenes and the loss of tumor suppressor genes are believed to play critical roles in the pathogenesis of human hepatocellular carcinoma (HCC). The human WW domain containing E3 ubiquitin protein ligase 1 (WWP1) gene is frequently amplified in prostate and breast cancers, however, its role in cancer has not yet been extensively studied. Especially, the role of WWP1 in HCC has not yet been studied. Firstly, we analyzed the expression of WWP1 in HCC samples. We found that protein levels of WWP1 are higher in most HCC cancerous tissues as compared with their matched adjacent non-tumor tissues. Additionally, the WWP1 mRNA was also amplified in all 7 HCC tissues. Knockdown of the endogenous WWP1 using small interfering RNA further showed that deficiency of WWP1 suppressed cell growth and caused apoptosis in HCC cells. Knocking down WWP1 promoted cleaved caspase3 protein and p53 expression in HCC cells, and caspase3 inhibition could prevent cell apoptosis induced by the knockdown of WWP1. All together these results indicate that protein levels of WWP1 in most HCC tissues are higher than non-tumor tissues, and knockdown of WWP1 inhibits growth and induces apoptosis in HCC cells through the activation of caspase3 and p53. Therefore, WWP1 gene might be a potential molecular target of HCC.

Mitochondrial damage and radiation carcinogenesis

Although radiation is a well-established human carcinogen, the mechanism of how radiation induces cancer is not clear. High linear energy transfer (LET) particles such as those used in radiotherapy and found in the natural radiation environment in space are potent clastogens that induce chromosomal breakages and present a potential mechanism for the loss of tumor suppressor genes. Indeed, using an immortalized human bronchial epithelial cell line, we show previously that high LET radiation, including alpha and HZE particles, induces a stepwise neoplastic transformation of these cells and a consistent downregulation of the tumor suppressor TGFBI gene. Furthermore, there is recent evidence that targeted cytoplasmic irradiation induces changes in mitochondrial morphology. Mitochondria are the energy center of a cell and normal mitochondria are highly dynamic organelles that move along microtubules or microfilaments and continuously fuse and divide in healthy cells. A balance between mitochondrial fusion and fission is essential to maintain normal mitochondrial function. In contrast, irradiated cells show shortened and fragmented mitochondria together with a reduction in mitochondrial functions. These included reduced cytochrome C-oxidase as well as succinate dehydrogenase activities when compared with non-irradiated controls, suggestive of reduced respiratory metabolism. Furthermore, irradiated airway epithelial cells showed an increase in mitochondrial superoxide production that was quenched by the radical scavenger, dimethyl sulfoxide. This acute mitochondrial response caused by cytoplasmic irradiation may result in the release of several stress mediators, which are necessary for mitochondria to preserve cellular homeostasis. The observation that progeny of mammalian cells that are irradiation through the cytoplasm show evidence of genomic instability highlights the functional role of mitochondrial damage in radiation carcinogenesis.

Serrated polyps and colorectal cancer risk

SUMMARY Colorectal cancer is among the three most common cancers in the World with a global incidence exceeding 1.2 million new cases and 600,000 deaths per year; yet most cases could be prevented by endoscopic removal of precursor lesions. Efficient screening and follow-up are the best options to reduce the cancer burden caused by colorectal cancer (CRC). Therefore, it is essential to know which colorectal polyps have the potential to progress into cancer. During the last decade, serrated polyps have emerged as the second most important group of CRC precursor lesions, in addition to conventional adenomatous polyps. It has been estimated that up to 30–35% of CRCs have their origin in serrated polyps. Carcinogenesis via serrated polyps, known as the serrated pathway, requires activation of the MAPK pathway by mutations of BRAF and KRAS, and low- or high-level methylation of CpG islands of DNA (CpG island methylator phenotype), and subsequent high-level DNA microsatellite instability in a third of cases. The mechanisms involved in carcinogenesis via the serrated pathway profoundly differ from those of conventional adenoma–carcinoma pathway, and the biology and behavior of serrated polyps also differ from that of adenomatous polyps, which are characterized by chromosomal instability and loss of tumor suppressor genes.

Decreased FAM107A Expression in Patients with Non-small Cell Lung Cancer.

Lung cancer is the leading cause of cancer-related death in the world. Early detection, based on molecular markers, could decrease mortality from this disease. Tumor development is often associated with inactivation or loss of tumor suppressor genes (TSGs). The aim of the present study was to analyze the expression level of FAM107A gene, a TSG located in 3p21.1, in lung cancer tumors and in tumor adjacent normal lung samples. Promoter methylation status of FAM107A was evaluated as the potential mechanism of its epigenetic silencing. The relationship between gene mRNA expression and tumor staging, metastasis status, and non-small cell lung cancer (NSCLC) histopathological subtypes in 60 patients was analyzed. Total RNA was isolated from tissue samples and gene expression was assessed in qPCR assay. Gene promoter methylation status was evaluated in MSP reactions, using bisulfite converted DNA and two pairs of primers: methylated and unmethylated. We found that the expression of the gene was dramatically decreased in all NSCLC samples and was significantly lower than in tumor adjacent normal lung tissue. Promoter methylation of FAM107A gene was confirmed only in the minority of NSCLCs. The results highlight the importance of FAM107A in lung carcinogenesis, although indicate other than promoter hypermethylation mechanism of the gene decreased expression.

A case of myelodysplastic syndrome with a der(1;18)(q10;q10) translocation.

A case of myelodysplastic syndrome with a der(1;18)(q10;q10) translocation.

A neuronal function of the tumor suppressor protein merlin

Mutagenic loss of the NF2 tumor suppressor gene encoded protein merlin is known to provoke the hereditary neoplasia syndrome, Neurofibromatosis type 2 (NF2). In addition to glial cell-derived tumors in the PNS and CNS, disease-related lesions also affect the skin and the eyes. Furthermore, 60% of NF2 patients suffer from peripheral nerve damage, clinically referred to as peripheral neuropathy. Strikingly, NF2-associated neuropathy often occurs in the absence of nerve damaging tumors, suggesting tumor-independent events. Recent findings indicate an important role of merlin in neuronal cell types concerning neuromorphogenesis, axon structure maintenance and communication between axons and Schwann cells. In this review, we compile clinical and experimental evidences for the underestimated role of the tumor suppressor merlin in the neuronal compartment.

Selected topics in the pathology of epithelioid soft tissue tumors

Epithelioid morphology, mimicking carcinoma, is a key or defining feature of several soft tissue tumors and may be seen in a wide variety of other tumors. This review will focus on those tumors defined at least in part by their epithelioid morphology, in particular epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, and sclerosing epithelioid fibrosarcoma. The role of loss of the SMARCB1 tumor-suppressor gene in the pathogenesis of these epithelioid soft tissue tumors will be discussed, as will their differential diagnosis with non-mesenchymal tumors, in particular carcinoma and melanoma.