Acute myeloid leukaemia (AML) is the second haematological malignancy in the paediatric population, and one of the leading causes of childhood cancer mortality. Survival is currently around 60%, with no improvement in last decades, suggesting that new therapeutic approaches are needed. The anti-leukaemia effect mediated by the lymphocytes and natural killer (NK) cells of the immune system has been established in haematopoietic stem cell transplantation, and also as adoptive immunotherapy after consolidation chemotherapy schemes.

We propose the hypothesis that for a particular type of cancer there exists a key pair of oncogene (OCG) and tumor suppressor gene (TSG) that is normally involved in strong stabilizing negative feedback loops (nFBLs) of molecular interactions, and it is these interactions that are sufficiently perturbed during cancer development. These nFBLs are thought to regulate oncogenic positive feedback loops (pFBLs) that are often required for the normal cellular functions of oncogenes. Examples given in this paper are the pairs of MYC and p53, KRAS and INK4A, and E2F1 and miR-17-92. We propose dynamical models of the aforementioned OCG-TSG interactions and derive stability conditions of the steady states in terms of strengths of cycles in the qualitative interaction network. Although these conditions are restricted to predictions of local stability, their simple linear expressions in terms of competing nFBLs and pFBLs make them intuitive and practical guides for experimentalists aiming to discover drug targets and stabilize cancer networks.

The tumor suppressor p53 controls DNA repair, cell cycle, apoptosis, autophagy and numerous other cellular processes. Imiquimod (IMQ), a synthetic toll-like receptor (TLR) 7 ligand for the treatment of superficial basal cell carcinoma (BCC), eliminates cancer cells by activating cell-mediated immunity and directly inducing apoptosis and autophagy in cancer cells.

High-level expression of kinesin family member 23 (KIF23), a member of microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division, has been observed in a variety of human malignancies. The aims of the present study were to observe the expression of KIF23 in lung cancer, examine the role of KIF23 in lung cancer cell growth and/or survival by small interfering RNA experiments, and explore its clinicopathologic significance and evaluate KIF23 expression as a prognostic marker.

Altered expressions of receptor tyrosine kinases drive the growth and metastasis of several cancers. RON is a single pass transmembrane receptor tyrosine kinase (RTK) shown to be aberrantly expressed in various cancer types. However, target validation and successful therapeutic targeting of RON in cancers is hampered by the co-existence of unknown number/types of isoforms, which are structurally similar but functionally diverse.

KRAS mutations are the most commonly found mutations in patients with non-small cell lung cancer (NSCLC) adenocarcinoma histology. The clinical implications of KRAS mutations in patients with advanced NSCLC are not well defined. We sought to determine if there is a correlation between KRAS mutation status, response to cytotoxic chemotherapy, and survival in patients with metastatic or recurrent NSCLC.

The emergence of acquired anaplastic lymphoma kinase (ALK) resistant mutations is a common molecular mechanism underpinning disease progression during crizotinib treatment of ALK-positive (ALK+) non-small cell lung cancer (NSCLC) patients. Identifying acquired resistance mutations in ALK is paramount for tailoring future therapy with second generation ALK inhibitors and beyond. Comprehensive genomic profiling using hybrid-capture next generation sequencing has been successful in identifying acquired ALK resistance mutations. Here we described the emergence of an ALK F1245C mutation in an advanced ALK+ NSCLC patient (EML4-ALK variant 3a/b) who developed slow disease progression after a durable response to crizotinib. The patient was eventually switched to ceritinib with on-going clinical response. This is the first patient report that ALK F1245C is an acquired resistance mutation to crizotinib that can be overcome by ceritinib.

A 63-year-old caucasian woman, presenting with metastatic primitive lung adenocarcinoma was treated with ALK inhibitor crizotinib treatment for six month. After rapid regression of all known lesions, tumor progression appeared six month later on all the already known lesions. A biopsy of subclavicular lymphadenopathy revealed a carcinoma with neuroendocrine phenotype with both immunohistochemical expression of ALK protein and ALK-rearrangement. It was associated with acquired resistance to crizotinib with ALK-rearrangement but without point mutation or amplification of the ALK gene. We herein report the first case of histological neuroendocrine transformation after ALK inhibitor crizotinib treatment, associated with acquired resistance to crizotinib.

Consistency of procedures for the evaluation of a predictive biomarker (including sample collection, processing, assay and scoring system) based on adequate evidence is necessary to implement research findings in clinical practice. As a case study we evaluated how a particular predictive biomarker, ERCC1, was assessed in research on platinum-based chemotherapy in non-small-cell lung cancer and what motivated the choice of procedure.

Cervical cancer markers are not well known for accurate detection of the disease.

MicroRNA-206 plays important roles in tumorigenesis and tumor progression of various human malignancies. However, its involvement in cervical cancer has remained unclear.

Microsatellite instability (MSI) is a hallmark of defective mismatch repair and is present in approximately 20% of ovarian cancers. It is not known if the presence of MSI predicts survival in women with epithelial ovarian cancer.

Cyclooxygenase-2 (COX-2) is highly expressed in tumor cells and has been regarded as a hallmarker for cancers, but the excise regulatory mechanism of COX-2 in tumorigenesis remains largely unknown. Here, we pulled down and identified a novel COX-2 regulator, heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), which could specifically bind to COX-2 core promoter and regulate tumor growth in non-small-cell lung cancers (NSCLCs). Knockdown of hnRNPA2/B1 by shRNA or siRNA downregulated COX-2 expression and prostaglandin E2 (PGE2) production, and suppressed tumor cell growth in NSCLC cells in vitro and in vivo. Conversely, overexpression of hnRNPA2/B1 up-regulated the levels of COX-2 and PGE2 and promoted tumor cell growth. We also showed that hnRNPA2/B1 expression was positively correlated with COX-2 expression in NSCLC cell lines and tumor tissues, and the up-regulated expression of hnRNPA2/B1 and COX-2 predicted worse prognosis in NSCLC patients. Furthermore, we demonstrated that the activation of COX-2 expression by hnRNPA2/B1 was mediated through the cooperation with p300, a transcriptional co-activator, in NSCLC cells. The hnRNPA2/B1 could interact with p300 directly and be acetylated by p300. Exogenous overexpression of p300, but not its histone acetyltransferase (HAT) domain deletion mutation, augmented the acetylation of hnRNPA2/B1 and enhanced its binding on COX-2 promoter, thereby promoted COX-2 expression and lung cancer cell growth. Collectively, our results demonstrate that hnRNPA2/B1 promotes tumor cell growth by activating COX-2 signaling in NSCLC cells and imply that the hnRNPA2/B1/COX-2 pathway may be a potential therapeutic target for human lung cancers.

Most solid tumors, including colorectal cancers, shed cell-free DNA (ctDNA) in the blood. ctDNA can be analyzed to generate molecular profiles which capture the heterogeneity of the disease more comprehensively then tumor tissue biopsies. This approach commonly called 'liquid biopsy' can be applied to monitor response to therapy, to assess minimal residual disease and to uncover the emergence of drug resistance. This review will discuss current and future developments of ctDNA analysis in the clinical management of colorectal cancer patients.

Germline mutations in the tumor suppressor gene, BRCA-1 associated protein (BAP1), underlie a tumor predisposition syndrome characterized by increased risk for numerous cancers including uveal melanoma, melanocytic tumors and mesothelioma, among others. In the present study we report the identification of a novel germline BAP1 mutation, c.1777C>T, which produces a truncated BAP1 protein product and segregates with cancer. Family members with this mutation demonstrated a primary clinical phenotype of autosomal dominant, early-onset melanocytic neoplasms with immunohistochemistry (IHC) of these tumors demonstrating lack of BAP1 protein expression. In addition, family members harboring the BAP1 c.1777C>T germline mutation developed other neoplastic disease including thyroid cancer. IHC analysis of the thyroid cancer, as well, demonstrated loss of BAP1 protein expression. Our investigation identifies a new BAP1 mutation, further highlights the relevance of BAP1 as a clinically important tumor suppressor gene, and broadens the range of cancers associated with BAP1 inactivation. Further study will be required to understand the full scope of BAP1-associated neoplastic disease.

Genetic and epigenetic alterations in genes associated with distinct cellular pathways were checked in fibroepithelial tumors, including fibroadenomas, benign and malignant phyllode and atypical ductal hyperplasia. A panel of 22 genes associated with different cellular pathways such as stem cell renewal (Wnt and Hedgehog), DNA damage response [homologous recombination (HR), mismatch repair (MMR) and nucleotide excision repair (NER)] and cell proliferation signaling pathway were tested. Alterations (genetic/epigenetic) of the genes associated with Wnt signaling pathway were detected in 100% (20/20) of the breast tumors for at least one out of the six Wnt antagonists tested. Frequent molecular alterations (57-64%) were detected in HR and MMR pathway and low frequency of alterations (8-25%) were seen in cell-proliferation and cell signaling pathways showing a differential pattern of alterations in different tumor types. The patterns of alterations, in particular the epigenetic alterations, differed little from that seen previously in breast carcinoma cells, suggesting epigenetic alterations to be an early event in the development of the tumors. In gene ontology analysis, it was evident that Wnt signaling pathway [GO: 0030111, Kegg: 04310], cell proliferation pathway [GO: 0008285] and pathways in cancer [Kegg: 05200] were significantly enriched by differentially altered genes in fibroadenoma and phyllode tumor types. All these results may provide a new breakthrough in early diagnosis, prognosis and treatment of these tumors.

Prostate cancer (PCa) is one of the most common male malignancies. Serum prostate-specific antigen (PSA) is one of the most valuable biomarkers in tumor biology and remains the standard marker in detecting and monitoring PCa. However, the high number of serum PSA false positive and false negative results make the identification of novel biomarkers extremely welcome to improve our diagnostic accuracy in detecting PCa and distinguishing the aggressive from the indolent ones. In this study, we analyzed the current role of urinary gene fusion transcripts involving v-ets erythroblastosis virus E26 oncogene homolog, commonly known as ERG, and the androgen-regulated gene transmembrane protease, serine 2 (TMPRSS2), as a biomarker for PCa. Used as a single marker, urinary TMPRSS2:ERG has low sensitivity but high specificity. However, its combination with the other urinary marker PCa antigen 3 (PCA3) has been reported to provide high specificity and sensitivity. Finally, a commercially available assay combining serum PSA with urinary PCA3 and TMPRSS2:ERG provides a 90% specificity and 80% sensitivity in diagnosing PCa. Urinary TMPRSS2:ERG also seems to be indicative of PCa aggressiveness upon biopsy. Should these findings be confirmed in larger studies, urinary TMPRSS2:ERG might become a valuable test not only for diagnosing PCa but also for distinguishing the aggressive tumors from the indolent ones.

Optic pathway glioma (OPG) is the most common central nervous system tumor in children with neurofibromatosis type 1 (NF1), affecting 15-20% of patients. We reviewed the medical records of children systematically screened by ophthalmologic and MRI examinations to determine the influence of screening on the therapeutic management of children with OPG.

Adenomatoid tumor is a relatively rare disease that predominantly involves male and female internal genital tracts. Although its clinical and pathologic features are well characterized, there is still controversy regarding its nature as a true neoplasm or a variant of mesothelial hyperplasia of a reactive nature. We sought to resolve this debate by investigating the clonality of uterine adenomatoid tumor from 13 female cases. The mesothelial cells and surrounding normal myometrium were precisely harvested using laser capture microdissection, and genomic DNA was extracted for clonal analysis by assessing the patterns of X-chromosome inactivation. Fluorescent polymerase chain reaction amplification of a highly polymorphic short tandem repeat of the human androgen receptor (HUMARA) gene with and without methylation-sensitive restriction endonuclease HpaII digestion was performed on DNA extracted from mesothelial cells, using normal myometrium and male blood sample as controls. Of the 13 cases successfully amplified, all 10 informative cases showed concordant nonrandom X-chromosome inactivation pattern consistent with monoclonality. In comparison, surrounding normal myometrium showed a polyclonal pattern of X-chromosome inactivation, and male blood sample failed to be amplified after HpaII treatment. Our results demonstrate that adenomatoid tumor is a monoclonal disease favoring a neoplastic process. This neoplastic rather than reactive nature probably accounts for its frequently observed infiltrative growth pattern and the occurrence of diffuse adenomatoid tumor, especially when host immunity is compromised. Additional studies with larger sample sizes will be needed to conclusively prove our conclusion.