BACKGROUND: Prognostic factors in breast cancer are often measured on a continuous scale, but categorized for clinical decision-making. The primary aim of this study was to evaluate if accounting for continuous non-linear effects of the three factors age at diagnosis, tumor size, and number of positive lymph nodes improves prognostication. These factors will most likely be included in the management of breast cancer patients also in the future, after an expected implementation of gene expression profiling for adjuvant treatment decision-making.
METHODS: Four thousand four hundred forty seven and 1132 women with primary breast cancer constituted the derivation and validation set, respectively. Potential non-linear effects on the log hazard of distant recurrences of the three factors were evaluated during 10 years of follow-up. Cox-models of successively increasing complexity: dichotomized predictors, predictors categorized into three or four groups, and predictors transformed using fractional polynomials (FPs) or restricted cubic splines (RCS), were used. Predictive performance was evaluated by Harrell's C-index.
RESULTS: Using FP-transformations, non-linear effects were detected for tumor size and number of positive lymph nodes in univariable analyses. For age, non-linear transformations did, however, not improve the model fit significantly compared to the linear identity transformation. As expected, the C-index increased with increasing model complexity for multivariable models including the three factors. By allowing more than one cut-point per factor, the C-index increased from 0.628 to 0.674. The additional gain, as measured by the C-index, when using FP- or RCS-transformations was modest (0.695 and 0.696, respectively). The corresponding C-indices for these four models in the validation set, based on the same transformations and parameter estimates from the derivation set, were 0.675, 0.700, 0.706, and 0.701.
CONCLUSIONS: Categorization of each factor into three to four groups was found to improve prognostication compared to dichotomization. The additional gain by allowing continuous non-linear effects modeled by FPs or RCS was modest. However, the continuous nature of these transformations has the advantage of making it possible to form risk groups of any size.

Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.

Lynch syndrome (LS) is an autosomal dominant disorder characterized by an increased risk of extracolonic cancers and early age of onset. It is associated with germline mutations in the DNA mismatch repair (MMR) genes. We report a case of a patient with colorectal cancer referred to our medical genetics department for molecular analysis and genetic counseling. The proband is a 64-year-old woman diagnosed with a tumor of the cecum. Histopathological examination showed a moderately differentiated mucinous adenocarcinoma categorized by pT3 N0. Analysis of her pedigree revealed three siblings who had colon cancer, as well as one relative with brain cancer. Based on these findings, molecular genetic investigation was found to be necessary in order to identify the disease-causing mutation. Immunohistochemistry staining of MMR proteins was performed on the tumor sample of the index proband. Mutational analysis of the MLH1/MSH2 genes was carried out. Analysis was extended to the family members and the general population. This led to the identification of a heterozygous frameshift duplication in the MLH1 gene at position 910 (c.910dupG). Three siblings had inherited the mutation from their mother, two of whom were asymptomatic at the time of diagnosis. To the best of our knowledge, this is a novel pathogenic duplication that has not been reported in the databases and literature. The outcome of the present case suggests that this mutation was the primary cause of LS in the family.

BRAFV600E is a mutant Ser-Thr protein kinase that plays a crucial role in many types of cancer, including melanoma. Despite several aspects of BRAFV600E biology have been already elucidated, the proteins that regulate its expression and activity remain largely unknown, hampering our capacity to control its unrestrained effects. Here, we propose yeast Saccharomyces cerevisiae as a model system that can be used to achieve a better understanding of the regulation of human BRAFV600E.By showing that in osmotic stress conditions hBRAFV600E can rescue the growth of strains carrying a double or triple deletion in MAPKKK belonging to the HOG pathway, we demonstrate that this oncogenic kinase is active in yeast even if it does not have an ortholog. Moreover, we report that, in the yeast ptp3∆ptc1∆ strain that is deleted in the genes encoding for two phosphatases responsible for Hog1 de-phoshorylation, hBRAFV600E mimics the toxicity observed in the presence of constitutive Hog1 activation. Finally, we exploit such a toxicity to perform a functional screening of a human cDNA library, looking for cDNAs able to rescue yeast growth. In this way, we identify SMIM10, a mitochondrial protein that in melanoma cells selectively downregulates BRAFV600E RNA and protein levels, by acting indirectly at the post-transcriptional level. Upon SMIM10 overexpression, BRAFV600E melanoma cells show disrupted mitochondrial structure/function and undergo senescence. They also show decreased ability to proliferate and form colonies, as well as increased sensitivity to the BRAF inhibitor vemurafenib. Interestingly, the analysis of TCGA melanoma samples indicates that patients with higher SMIM10 levels have a better prognosis. Therefore, these data suggest that SMIM10 exerts an oncosuppressive role in melanoma cells.Taken together, our results unveil the potential of S. cerevisiae to study hBRAFV600E, to populate the network of its functional interactors and, in doing so, to uncover new cancer-associated genes with therapeutic potential.

Many cancer types carry mutations in protein tyrosine kinase (PTK) and such alterations frequently drive tumor progression. One category is gene translocation of PTKs yielding chimeric proteins with transforming capacity. In this study, we characterized the role of ITK-FER [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with Feline Encephalitis Virus-Related kinase (FER) gene] and ITK-SYK [Interleukin-2-inducible T-cell Kinase (ITK) gene fused with the Spleen Tyrosine Kinase (SYK)] in Peripheral T Cell Lymphoma (PTCL) signaling. We observed an induction of tyrosine phosphorylation events in the presence of both ITK-FER and ITK-SYK. The downstream targets of ITK-FER and ITK-SYK were explored and STAT3 was found to be highly phosphorylated by these fusion kinases. In addition, the CD69 T-cell activation marker was significantly elevated. Apart from tyrosine kinase inhibitors acting directly on the fusions, we believe that drugs acting on downstream targets could serve as alternative cancer therapies for fusion PTKs.

BACKGROUND: Despite the progress in neuroblastoma therapies the mortality of high-risk patients is still high (40-50%) and the molecular basis of the disease remains poorly known. Recently, a mathematical model was used to demonstrate that the network regulating stress signaling by the c-Jun N-terminal kinase pathway played a crucial role in survival of patients with neuroblastoma irrespective of their MYCN amplification status. This demonstrates the enormous potential of computational models of biological modules for the discovery of underlying molecular mechanisms of diseases.
RESULTS: Since signaling is known to be highly relevant in cancer, we have used a computational model of the whole cell signaling network to understand the molecular determinants of bad prognostic in neuroblastoma. Our model produced a comprehensive view of the molecular mechanisms of neuroblastoma tumorigenesis and progression.
CONCLUSION: We have also shown how the activity of signaling circuits can be considered a reliable model-based prognostic biomarker.
REVIEWERS: This article was reviewed by Tim Beissbarth, Wenzhong Xiao and Joanna Polanska. For the full reviews, please go to the Reviewers' comments section.

INTRODUCTION: Lynch syndrome (LS) is an autosomal dominant disorder characterized by early age of onset and increased risk of developing extracolonic tumors. Molecular diagnosis of LS requires identification of germline mutations in one of the Mismatch Repair (MMR) genes.
AIM: The objective of the study was to investigate the prevalence of MLH1/MSH2 mutation carriers among Moroccan patients with colorectal cancer (CRC) in a hospital-based cohort.
METHODS: In this study, 214 CRC patients from COLORECFez cohort were included. Patients whose tumors showed MMR deficiency (MMR-D) and wild-type BRAF were selected to undergo mutational analysis of the MLH1 and MSH2 genes using Sanger sequencing.
RESULTS: A total of 24 MMR-D tumors were identified (11.2%) among 214 CRC tested for MMR protein expression. The BRAF p.Val600Glu mutation was absent in all tumors deficient for MLH1 protein. Molecular screening showed germline MMR mutations (MLH1/MSH2) in four cases, two of which fulfilled Amsterdam criteria II and two met at least one of the revised Bethesda guidelines. The estimated frequency of MLH1/MSH2 mutations in Moroccan CRC patients was 1.87%.
CONCLUSIONS: The present study reports a relatively high incidence of MLH1/MSH2 (1.87%). These results confirm the contribution of MMR genes to CRC susceptibility in our population and provide evidence regarding the requirement of implementing a national screening program for LS in Morocco.

Triple-negative breast cancer (TNBC) has been clinically difficult to manage because of tumor aggressiveness, cellular and histological heterogeneity, and molecular mechanisms' complexity. All this in turn leads us to evaluate that tumor biological behavior is not yet fully understood. Additionally, the heterogeneity of tumor cells represents a great biomedicine challenge in terms of the complex molecular-genetical-transcriptional and epigenetical-mechanisms, which have not been fully elucidated on human solid tumors. Recently, human breast cancer, but specifically TNBC is under basic and clinical-oncology research in the discovery of new molecular biomarkers and/or therapeutic targets to improve treatment responses, as well as for seeking algorithms for patient stratification, seeking a positive impact in clinical-oncology outcomes and life quality on breast cancer patients. In this sense, important knowledge is emerging regarding several cancer molecular aberrations, including higher genetic mutational rates, LOH, CNV, chromosomal, and epigenetic alterations, as well as transcriptome aberrations in terms of the total gene-coding ribonucleic acids (RNAs), known as mRNAs, as well as non-coding RNA (ncRNA) sequences. In this regard, novel investigation fields have included microRNAs (miRNAs), as well as long ncRNAs (lncRNAs), which have been importantly related and are likely involved in the induction, promotion, progression, and/or clinical therapeutic response trackers of TNBC. Based on this, in general terms according with the five functional archetype classification, the lncRNAs may be involved in the regulation of several molecular mechanisms which include genetic expression, epigenetic, transcriptional, and/or post-transcriptional mechanisms, which are nowadays not totally understood. Here, we have reviewed the main dis-regulated and functionally non- and well-characterized lncRNAs and their likely involvement, from a molecular enrichment and mechanistic point of view, as tumor biomarkers for breast cancer and its specific histological subtype, TNBC. In reference to the abovementioned, it has been described that some lncRNA expression profiles correspond or are associated with the TNBC histological subtype, potentially granting their use for TNBC malignant progression, diagnosis, tumor clinical stage, and likely therapy. Based on this, lncRNAs have been proposed as potential biomarkers which might represent potential predictive tools in the differentiated breast carcinomas versus TNBC malignant disease. Finally, elucidation of the specific or multi-functional archetypal of lncRNAs in breast cancer and TNBC could be fundamental, as these molecular intermediary-regulator "lncRNAs" are widely involved in the genome expression, epigenome regulation, and transcriptional and post-transcriptional tumor biology, which in turn will probably represent a new prospect in clinical and/or therapeutic molecular targets for the oncological management of breast carcinomas in general and also for TNBC patients.

Next-generation sequencing (NGS) has become a promising approach for tumor somatic mutation detection. However, stringent validation is required for its application on clinical specimens, especially for low-quality formalin-fixed paraffin-embedded (FFPE) tissues. Here, we validated the performance of an amplicon-based targeted NGS assay, OncoAim™ DNA panel, on both commercial reference FFPE samples and clinical FFPE samples of Chinese colorectal cancer (CRC) patients. Then we profiled the mutation spectrum of 648 Chinese CRC patients in a multicenter study to explore its clinical utility. This NGS assay achieved 100% test specificity and 95-100% test sensitivity for variants with mutant allele frequency (MAF) ≥ 5% when median read depth ≥ 500×. The orthogonal methods including amplification refractory mutation system (ARMS)-PCR and Sanger sequencing validated that NGS generated three false negatives (FNs) but no false positives (FPs) among 516 clinical samples for KRAS aberration detection. Genomic profiling of Chinese CRC patients with this assay revealed that 63.3% of the tumors harbored clinically actionable alterations. Besides the commonly mutated genes including TP53 (52.82%), KRAS (46.68%), APC (24.09%), PIK3CA (18.94%), SMAD4 (9.47%), BRAF (6.15%), FBXW7 (5.32%), and NRAS (4.15%), other less frequently mutated genes were also identified. Statistically significant association of specific mutated genes with certain clinicopathological features was detected, e.g., both BRAF and PIK3CA were more prevalent in right-side CRC (p < 0.001 and p = 0.002, respectively). We concluded this targeted NGS assay is qualified for clinical practice, and our findings could help the diagnosis and prognosis of Chinese CRC patients.

BACKGROUND: A subset of breast carcinomas harbors overexpression of the human epidermal growth factor receptor 2 (HER2). Fluorescence in situ hybridization (FISH) should be performed in breast carcinomas with equivocal HER2 immunostaining (immunohistochemistry [IHC] HER2 2+). The aim of our study is to investigate clinicopathologic factors associated with HER2 status in breast invasive carcinomas with IHC HER2 2+ through FISH analysis.
METHODS: This is a retrospective study including the FISH analysis of 111 patients with invasive breast carcinomas with equivocal HER2 immunostaining.
RESULTS: The mean age was 49.51 ± 10.48 years, and invasive breast carcinoma of no special type was the most histological type in our study (96.4%). Most patients had tumors positive for hormones receptors (88.2% positive for estrogen receptor and 81.4% for progesterone receptor). On FISH, the HER2 amplification rate was 22.5%. There was no significant association of HER2 status with any clinicopathologic factors ( P > .05).
CONCLUSIONS: Our study shows that there are no reliable clinicopathologic factors to predict the HER2 status in breast tumors with equivocal HER2 immunostaining, supporting the necessary usage of FISH in such circumstances.

Heterogeneity of estrogen receptor (ER) expression in breast cancer is recognized. However, knowledge about varying expression across metastases and surrounding normal tissue in patients is scarce. We therefore analyzed 16α-

BACKGROUND This study assessed the prognostic value of GLI1 in gastric cancer and analyzed the possible GLI1-related signaling network in chemosensitivity. MATERIAL AND METHODS Bioinformatic data mining was performed by using data in the TCGA-Stomach Cancer (TCGA-STAD) and the Kaplan-Meier plotter. GLI1 co-expressed genes in TCGA-STAD were subjected to KEGG pathway analysis. The genes enriched in the KEGG pathways were further subjected to Protein-Protein Interaction (PPI) analysis. RESULTS In TCGA-STAD, high GLI1 gene/exon expression was associated with significantly worse survival (p=0.016 and 0.0023 respectively). In the Kaplan-Meier plotter, high GLI1 expression was associated with unfavorable overall survival (OS) (HR: 1.68, 95%CI: 1.42-2, p<0.0001) and first progression-free survival (FPS) (HR: 1.72, 95%CI: 1.4-2.11, p<0.0001). In TCGA-STAD, 600 GLI1 co-expressed genes were identified (absolute Pearson's r ≥0.5). The most significant pathways were pathways in cancer (p=230.0E-12) and the Hedgehog signaling pathway (p=6.9E-9). PI3K-AKT pathway (p=17.0E-9) has the largest proportion of gene enrichment. Some GLI1 co-expressed genes in the PI3K-AKT pathway are central nodes in the PPI network and also play important roles in chemosensitivity of gastric cancer. Nevertheless, the mechanisms underlying their co-expression are still largely unexplored. CONCLUSIONS High GLI1 expression is associated with unfavorable OS and FPS in patients with gastric cancer. As a member of the Hedgehog signaling pathway, GLI1 co-expressed genes are also largely enriched in PI3K/AKT pathway in gastric cancer, which is closely related to chemoresistance. The underlying mechanisms are still largely unexplored and need further study.

INTRODUCTION: A novel radiotracer 1‑(2‑(2‑(2‑[
METHODS: The tosylate precursor 3 was radiolabeled with
RESULTS: [
CONCLUSIONS: A novel 17α‑ethinyl‑estradiol-based ER probe [

Malignant pleural mesothelioma (MPM) is a rare but aggressive tumor that originates in the pleura, is diagnosed in advanced stages and has a poor prognosis. Accurate diagnosis of MPM is often difficult and complex, and the gold standard diagnosis test is based on qualitative analysis of markers in pleural tissue by immunohistochemical staining. Therefore, it is necessary to develop quantitative and non-subjective alternative diagnostic tools. MicroRNAs are non-coding RNAs that regulate essential cellular mechanisms at the post-transcriptional level. Recent evidence indicates that miRNA expression in tissue and body fluids is aberrant in various tumors, revealing miRNAs as promising diagnostic biomarkers. This review summarizes evidence regarding secreted and tissue miRNAs as biomarkers of MPM and the biological characteristics associated with their potential diagnostic value. In addition to studies regarding miRNAs with potential diagnostic value for MPM, studies that aimed to identify the miRNAs involved in molecular mechanisms associated with MPM development are described with an emphasis on relevant aspects of the experimental designs that may influence the accuracy, consistency and real diagnostic value of currently reported data.

Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed.

PURPOSE: The feline sarcoma oncogene protein (FES) is a non-receptor tyrosine kinase implicated in both oncogenesis and tumor suppression. Here, cancer cell lines and human tissues were employed to clarify the pathological and prognostic significance of FES in bladder cancer.
METHODS: The relationship between FES expression and cancer aggressiveness was investigated using 3 cell lines (T24: corresponding to grade 3, 5637: corresponding to grade 2, and RT4: corresponding to grade 1) and 203 tissues derived from human bladder malignancies. Proliferation, invasion, and migration of cancer cells were assessed following the knockdown (KD) of FES expression by the siRNA method. Relationships between FES expression and pathological features, aggressiveness, and outcome were investigated.
RESULTS: FES-KD inhibited the proliferation, migration, and invasion of T24 cells but not of RT4 cells and 5637 cells. Considering all patients, FES expression demonstrated a negative relationship with grade but no association with muscle invasion or cancer cell proliferation. However, it was positively correlated with pT stage and cell proliferation in high-grade tumors (p = 0.002); no such association was found for low-grade tumors. In addition, elevated FES expression was a negative prognostic indicator of metastasis after radical surgery for patients with high-grade tumors (p = 0.021) but not for those with low-grade malignancies.
CONCLUSIONS: FES appeared to act as a suppressor of carcinogenesis, being associated with low tumor grade in the overall patient group. However, its expression correlated with cancer aggressiveness and poor outcome in high-grade bladder cancer. FES, therefore, represents a potential therapeutic target and useful prognostic factor for such patients.

Li-Fraumeni syndrome is a clinically heterogeneous familial cancer predisposition syndrome with autosomal-dominant inheritance caused by heterozygous germline mutations in the TP53 gene. We here analyze the genetic background of a family with a 4-year-proband presented with a Li-Fraumeni tumor. The mother developed breast cancer at age 37 and the proband died at age 8. We performed Sanger sequencing and whole-exome sequencing on peripheral blood DNA from proband and relatives. Data analysis selected only high-quality score and depth reads, rare variants and protein impact involving missense, non-sense, frameshift and splice disrupt mutations. Disease implicated variants and predicted deleterious alterations were also chosen. TP53 genetic testing revealed a never reported TP53 deletion arose as de novo mutation in the mother and inherited by the proband. We then performed whole-exome analysis of the trio to uncover inherited variants from the father that potentially worsen the already altered genetic background in the proband. No pathogenic variants were inherited in autosomal recessive, de novo dominant or X-linked recessive manner. Comparing proband and father exome we detected 25 predicted deleterious variants including a nonsense mutation in ERCC3. Those inherited mutations are possible candidate modifiers linked to TP53, explaining the proband accelerated tumor onset compared to the mother and providing a possible explanation of the genetic anticipation event in this Li-Fraumeni family.

Respiratory diseases hold several genome, epigenome, and transcriptional aberrations as a cause of the accumulated damage promoted by, among others, environmental risk factors. Such aberrations can also come about as an adaptive response when faced with therapeutic oncological drugs. In epigenetic terms, aberrations in DNA methylation patterns, histone code marks balance, and/or chromatin-remodeling complexes recruitment, among Polycomb Repressive Complex-2 (PRC2) versus Trithorax (TRX) Activator Complex, have been proposed to be affected by several previously characterized functional long non-coding RNAs (lncRNAs). Such molecules are involved in modulating and/or controlling lung cancer epigenome and genome expression, as well as in malignancy and clinical progression in lung cancer. Several recent reports have described diverse epigenetic modifications in lung cancer cells and solid tumors, among others genomic DNA methylation and post-translational modifications (PTMs) on histone tails, as well as lncRNAs patterns and levels of expression. However, few systematic approaches have attempted to demonstrate a biological function and clinical association, aiming to improve therapeutic decisions in basic research and lung clinical oncology. A widely used example is the lncRNA HOTAIR and its functional histone mark H3K27me3, which is directly associated to the PRC2; however, few systematic pieces of solid evidence have been experimentally performed, conducted and/or validated to predict lung oncological therapeutic efficacy. Recent evidence suggests that chromatin-remodeling complexes accompanied by lncRNAs profiles are involved in several comprehensive lung carcinoma clinical parameters, including histopathology progression, prognosis, and/or responsiveness to unique or combined oncological therapies. The present manuscript offers a systematic revision of the current knowledge about the major epigenetic aberrations represented by changes in histone PTMs and lncRNAs expression levels and patterns in human lung carcinomas in cancer drug-based treatments, as an important comprehensive knowledge focusing on better oncological therapies. In addition, a new future direction must be refocusing on several gene target therapies, mainly on pharmaceutical EGFR-TKIs compounds, widely applied in lung cancer, currently the leading cause of death by malignant diseases.

Oncogenic KRas activity is central to several cancer types including pancreatic ductal adenocarcinoma (PDAC) but has been determined to be "undruggable". Recent studies have indicated that oncogenic KRas is not constitutively active but relies on a feed-forward stimulatory mechanism involving NFκB mediated inflammation. In the current study, we investigated the role of the receptor for advanced glycation end-products (RAGE) in maintaining oncogenic signaling in PDAC. We observed that there was a shift in the levels of specific RAGE isoforms and altered cellular localization in PDAC. Furthermore, inhibition of RAGE using a pharmacological antagonist, FPS-ZM1, or a blocking antibody, decreased phosphorylation of IKBα and inhibited Erk activity down-stream of Kras in PDAC cell lines. In vivo, inhibition of RAGE using FPS-ZM1 reduced the growth of PDAC syngeneic orthotopic xenografts and prolonged survival. These data indicate that RAGE plays a central role in maintaining inflammatory signaling in PDAC that benefits tumor growth. These observations support the development of approaches to inhibit the carcinogenic actions of Kras indirectly by blocking the mechanisms which maintain its activity.

Cervical cancer is one of the leading causes of death in women worldwide, which mainly affects developing countries. The patients who suffer a recurrence and/or progression disease have a higher risk of developing distal metastases. Proteases comprising the degradome given its ability to promote cell growth, migration, and invasion of tissues play an important role during tumor development and progression. In this study, we used high-density microarrays and quantitative reverse transcriptase polymerase chain reaction to evaluate the degradome profile and their inhibitors in 112 samples of patients diagnosed with locally advanced cervical cancer. Clinical follow-up was done during a period of 3 years. Using a correlation analysis between the response to treatment and the development of metastasis, we established a molecular signature comprising eight degradome-related genes (FAM111B, FAM111A, CFB, PSMB8, PSMB9, CASP7, PRSS16, and CD74) with the ability to discriminate patients at risk of distal metastases. In conclusion, present results show that molecular signature obtained from degradome genes can predict the possibility of metastasis in patients with locally advanced cervical cancer.

BACKGROUND: To date, a limited number of BRCA1/2 germline mutations have been reported in hereditary breast and/or ovarian cancer in the Moroccan population. Less than 20 different mutations of these two genes have been identified in Moroccan patients, and recently we reported a further BRCA2 mutation (c.1310_1313delAAGA; p.Lys437IlefsX22) in three unrelated patients, all from the North-East of the country. We aimed in this study to evaluate the frequency and geographic distribution of this BRCA2 frameshift mutation, in order to access its use as the first-line BRCA genetic testing strategy for Moroccan patients. We enrolled in this study 122 patients from different regions of Morocco, with suggestive inherited predisposition to breast and ovarian cancers. All subjects gave written informed consent to BRCA1/2 genetic testing. According to available resources of our lab and enrolled families, 51 patients were analyzed by the conventional individual exon-by-exon Sanger sequencing, 23 patients were able to benefit from a BRCA next generation sequencing and a target screening for exon 10 of BRCA2 gene was performed in 48 patients.
RESULTS: Overall, and among the 122 patients analyzed for at least the exon 10 of the BRCA2 gene, the c.1310_1313delAAGA frameshift mutation was found in 14 patients. Genealogic investigation revealed that all carriers of this mutation shared the same geographic origin and were descendants of the North-East of Morocco.
DISCUSSION: In this study, we highlighted that c.1310_1313delAAGA mutation of BRCA2 gene is recurrent with high frequency in patients from the North-East region of Morocco. Therefore, we propose to use, in public health strategies, the detection of this mutation as the first-line screening tests in patients with breast and ovarian cancer originated from this region.

Identification and functional validation of oncogenic drivers are essential steps toward advancing cancer precision medicine. Here, we have presented a comprehensive analysis of the somatic genomic landscape of the widely used BRAFV600E- and NRASQ61K-driven mouse models of melanoma. By integrating the data with publically available genomic, epigenomic, and transcriptomic information from human clinical samples, we confirmed the importance of several genes and pathways previously implicated in human melanoma, including the tumor-suppressor genes phosphatase and tensin homolog (PTEN), cyclin dependent kinase inhibitor 2A (CDKN2A), LKB1, and others. Importantly, this approach also identified additional putative melanoma drivers with prognostic and therapeutic relevance. Surprisingly, one of these genes encodes the tyrosine kinase FES. Whereas FES is highly expressed in normal human melanocytes, FES expression is strongly decreased in over 30% of human melanomas. This downregulation correlates with poor overall survival. Correspondingly, engineered deletion of Fes accelerated tumor progression in a BRAFV600E-driven mouse model of melanoma. Together, these data implicate FES as a driver of melanoma progression and demonstrate the potential of cross-species oncogenomic approaches combined with mouse modeling to uncover impactful mutations and oncogenic driver alleles with clinical importance in the treatment of human cancer.

MicroRNAs are non-coding short RNAs that target the 3' untranslated region of messenger RNAs (mRNAs) and lead to their degradation or to translational repression. Several microRNAs have been designated as oncomirs, owing to their regulating tumor suppressor genes. Interestingly, a few of them have been found to target multiple genes whose simultaneous suppression contributes to the development of a tumoral phenotype. Here, we have showed that miR-26a is overexpressed in colorectal cancer data obtained from TCGA Research Network and in human colon cancer pathological specimens; moreover, an orthotopic in vivo model of colon cancer showed overexpression of miR-26a, while Rb1 expression inversely correlated to miR-26a in TCGA Research Network data, pathological samples, and the in vivo model. Then, by means of luciferase assay, we demonstrated that miR-26a targets the 3' untranslated region of Rb1 mRNA directly. This is, to our knowledge, the first report of miR-26a targeting Rb1 in colon cancer. The results of this study suggested that miR-26a could serve as a progression biomarker in colorectal cancer. Further validation studies are still needed to confirm our findings.

MicroRNA-125b (miR-125b) has been reported to be upregulated in several kinds of leukemia, suggesting that miR-125b plays a role in Leukemia development. In this study, it was shown that miR-125b expression level decreased in response to 1α, 25-dihydroxy-vitamin D3 (1,25D

Radiotherapy is an important treatment option for non-small cell lung carcinoma patients. Despite the appropriate use of radiotherapy, radioresistance is a biological behavior of cancer cells that limits the efficacy of this treatment. Deregulation of microRNAs contributes to the molecular mechanism underlying resistance to radiotherapy in cancer cells. Although the functional roles of microRNAs have been well described in lung cancer, their functional roles in radioresistance are largely unclear. In this study, we established a non-small cell lung carcinoma Calu-1 radioresistant cell line by continuous exposure to therapeutic doses of ionizing radiation as a model to investigate radioresistance-associated microRNAs. Our data show that 50 microRNAs were differentially expressed in Calu-1 radioresistant cells (16 upregulated and 34 downregulated); furthermore, well-known and novel microRNAs associated with resistance to radiotherapy were identified. Gene ontology and enrichment analysis indicated that modulated microRNAs might regulate signal transduction, cell survival, and apoptosis. Accordingly, Calu-1 radioresistant cells were refractory to radiation by increasing cell survival and reducing the apoptotic response. Among deregulated microRNAs, miR-29c was significantly suppressed. Reestablishment of miR-29c expression in Calu-1 radioresistant cells overcomes the radioresistance through the activation of apoptosis and downregulation of Bcl-2 and Mcl-1 target genes. Analysis of The Cancer Genome Atlas revealed that miR-29c is also suppressed in tumor samples of non-small cell lung carcinoma patients. Notably, we found that low miR-29c levels correlated with shorter relapse-free survival of non-small cell lung carcinoma patients treated with radiotherapy. Together, these results indicate a new role of miR-29c in radioresistance, highlighting their potential as a novel biomarker for outcomes of radiotherapy in lung cancer.

Papillary thyroid carcinoma is the most frequent histologic type of thyroid tumor. Few studies investigated the role of c-KIT expression in thyroid tumors, suggesting a role for this receptor and its ligand in differentiation and growth control of thyroid epithelium and a receptor loss following malignant transformation. We investigated and correlated c-KIT expression levels and two known markers of thyrocytes differentiation, PAX8 and TTF-1, in malignant and benign cytological thyroid samples. Moreover, we performed functional studies on human papillary thyroid carcinoma cell line to associated c-KIT expression to thyrocytes differentiation and tumor proliferation. c-KIT and PAX8 expression resulted higher in benign samples compared to the malignant ones, and the expression levels of these two genes were significantly correlated to each other. We also observed that c-KIT overexpression led to an increase of PAX8 expression level together with a decrease of proliferation. Furthermore, c-KIT overexpressing cells showed a regression of typical morphological features of malignancy. Taken together these results suggest that c-KIT could be involved in the differentiation of thyroid cells and in tumor progression.

Chromosome translocations involving the mixed lineage leukemia (

Helicobacter pylori (H. pylori) infection induces inflammation of the gastric mucosa, which may progress to precancerous lesions leading to gastric cancer. Pathological determinism is associated to some virulence genes of the bacterium, notably the vacA and cagA genes. The present study aimed to determine the H. pylori genotypes distribution and their association with sex, age and gastric diseases in a Moroccan population. Gastric biopsy was taken from 1079 consenting patients. The specimens were processed by PCR to identify H. pylori and to determine the genotypic profile by PCR characterizing vacA s, vacA m and vacA i regions directly from biopsies H. pylori positives. VacA genotyping revealed the predominance of vacA m2 (53.2%), vacA s2 (52.9%) and vacA i2 (52%). The most virulent vacA alleles (s1, i1 and m1) are more predominant in men (47.3%, 41.9% and 46.1% respectively) than in women (38.3%, 33.3% and 37% respectively). However, the association between vacA genotypes and age did not reach a statistical significant value. Logistic regression analysis results show that vacA i1m1 and vacA i1m2 genotypes were strongly associated with the risk of GC, the Odds Ratio (95% confidence interval) was 29.73 [5.08-173.73] and 9.17 [2.06-40.82] respectively, while vacAs1/cagA+ seems to be a risk factor for DU since it is inversely associated with GC (OR was 0.13 [0.02-0.75]. The results of this study suggest that vacA i1 genotype independently to vacAm status may be of a clinical usefulness and will help to identify patients at a high risk of GC development.

Fluorescent proteins (FPs) displaying distinct spectra have shed their light on a wide range of biological functions. Moreover, sophisticated biosensors engineered to contain single or multiple FPs, including Förster resonance energy transfer (FRET)-based biosensors, spatiotemporally reveal the molecular mechanisms underlying a variety of pathophysiological processes. However, their usefulness for applied life sciences has yet to be fully explored. Recently, our research group has begun to expand the potential of FPs from basic biological research to the clinic. Here, we describe a method to evaluate the responsiveness of leukemia cells from patients to tyrosine kinase inhibitors using a biosensor based on FP technology and the principle of FRET. Upon phosphorylation of the tyrosine residue of the biosensor, binding of the SH2 domain to phosphotyrosine induces conformational change of the biosensor and brings the donor and acceptor FPs into close proximity. Therefore, kinase activity and response to kinase inhibitors can be monitored by an increase and a decrease in FRET efficiency, respectively. As in basic research, this biosensor resolves hitherto arduous tasks and may provide innovative technological advances in clinical laboratory examinations. State-of-the-art detection devices that enable such innovation are also introduced.