Chromatin alterations are integral to the pathogenic process of cancer, as demonstrated by recent discoveries of frequent mutations in chromatin-modifier genes and aberrant DNA methylation states in different cancer types. Progress is being made on elucidating how chromatin alterations, and how proteins catalyzing these alterations, mechanistically contribute to tissue-specific tumorigenesis. In parallel, technologies enabling the genome-wide profiling of histone modifications have revealed the existence of noncoding driver genetic alterations in cancer. In this review, we survey the current knowledge of coding and noncoding cancer drivers, and discuss their impact on the chromatin landscape. Translational implications of these findings for novel cancer therapies are also presented.

The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation. Here we review the impact that epigenetic changes, and specifically DNA methylation, have on these extraordinary sequences in driving cancer progression.

Human cancers harbor great numbers of genomic alterations. One of the most common alterations is aneuploidy, an imbalance at the chromosome level. Some aneuploid cancer cell populations show varying chromosome copy number alterations over time, a phenotype known as 'chromosomal instability' (CIN). Chromosome segregation errors in mitosis are the most common cause for CIN in vitro, and these are also thought to underlie the aneuploidies seen in clinical cancer samples. However, CIN and aneuploidy are different traits and they are likely to have distinct impacts on tumor evolution and clinical tumor behavior. In this opinion article, we discuss these differences and describe scenarios in which distinguishing them can be clinically relevant.

Cancer is a heterogeneous disease and many cancer types do not represent a single entity, but are composed of biologically and clinically diverse subtypes. The subtype affiliation can influence prognosis and response to therapy. Recently, a multicenter colorectal cancer (CRC) subtyping consortium introduced a consensus molecular classification system for CRC. This will be of great benefit for future basic and clinical research since it enables uniform categorization of CRC specimens across different institutes and studies. The biological conformity observed within each consensus molecular subtype (CMS) holds promise for the design of subtype-specific treatment regimens. Herein, we review the CMSs of CRC with a focus on how multiple parameters, such as the origin, developmental route, and microenvironmental regulation shape distinct subtypes.

Colorectal cancer (CRC) diagnosis often occurs at late stages when tumor cells have already disseminated. Current therapies are poorly effective for metastatic disease, the main cause of death in CRC. Despite mounting evidence implicating the tumor microenvironment in CRC progression and metastasis, clinical practice remains predominantly focused on targeting the epithelial compartment. Because CRCs remain largely refractory to current therapies, we must devise alternative strategies. Transforming growth factor (TGF)-β has emerged as a key architect of the microenvironment in poor-prognosis cancers. Disseminated tumor cells show a strong dependency on a TGF-β-activated stroma during the establishment and subsequent expansion of metastasis. We review and discuss the development of integrated approaches focused on targeting the ecosystem of poor-prognosis CRCs.

Oncological therapy resembles a military force that eliminates the central power of a country (dominant clone of a cancer) to create a vacuum where insurgents (subclones) thrive and instigate rebellion (relapse). We suggest that military counterinsurgency doctrine can inspire a discussion of cancer that uniquely embraces both cancer cell evolution and tumour microenvironment.

Several studies have been conducted to investigate the association of the peroxisome proliferator-activated receptor (PPAR) alpha (PPAR A) and PPAR gamma (PPAR G) polymorphism and breast cancer (BC) risk, but the results were inconsistent, and, until now, no study focused on the impact of gene-gene interactions between PPAR A and PPAR G on BC risk; thus, the aim of this study was to investigate the impact of interaction between PPAR A and PPAR G on BC risk in the Chinese Han population.

Philadelphia chromosome positive de novoacute myeloid leukemia (AML)is a rare disease with reported incidence of less than 1% of newly diagnosed cases of AML. Outcome of the disease is poor, owing to its resistance to conventional chemotherapy and variable response to imatinib besylate. We report a case of 24-year man who reported to our unit in November 2014 and was treated with conventional induction and consolidation chemotherapy with imatinib besylate. He achieved complete remission after induction chemotherapy and remained in remission. His cytogenetics also reverted to normal after consolidation chemotherapy. He relapsed after 3 months of maintenance imatinib besylate.

Recent advances in high-throughput technologies have given rise to collecting large amounts of multidimensional heterogeneous data that provide diverse information on the same biological samples. Integrative analysis of such multisource datasets may reveal new biological insights into complex biological mechanisms and therefore remains an important research field in systems biology. Most of the modern integrative clustering approaches rely on independent analysis of each dataset and consensus clustering, probabilistic or statistical modeling, while flexible distance-based integrative clustering techniques are sparsely covered. We propose two distance-based integrative clustering frameworks based on bi-level and bi-objective extensions of the p-median problem. A hybrid branch-and-cut method is developed to find global optimal solutions to the bi-level p-median model. As to the bi-objective problem, an -constraint algorithm is proposed to generate an approximation to the Pareto optimal set. Every solution found by any of the frameworks corresponds to an integrative clustering. We present an application of our approaches to integrative analysis of NCI-60 human tumor cell lines characterized by gene expression and drug activity profiles. We demonstrate that the proposed mathematical optimization-based approaches outperform some state-of-the-art and traditional distance-based integrative and non-integrative clustering techniques.

MUTYH is involved in DNA damage repair. Bi-allelic MUTYH mutations predispose to polyposis and gastrointestinal malignancies, distinct genetically from autosomal dominant familial adenomatous polyposis coli. Two common European MUTYH mutations account for 90% of MUTYH-associated polyposis (MAP). We aimed to examine the incidence of MAP in Ireland. A retrospective cohort study was undertaken. Patients undergoing MUTYH testing from 2003-2016 were identified by searching electronic databases using terms "MUTYH" and "MYH". Phenotypic and genotypic details were obtained by chart review. Bi-allelic mutations were confirmed in 26 individuals (17 families), of whom 16 (62%) developed colorectal malignancies, and 22(85%) polyposis. Eleven families had bi-allelic status for one/both common European mutations. Regional variation was noted, with over-representation of bi-allelic mutation carriers in the South-west of Ireland. MAP is under-diagnosed in Ireland. Increased awareness is required to facilitate appropriate identification and surveillance of bi-allelic mutation carriers for colorectal pathology.

Malignant mesothelioma is an aggressive cancer largely associated with asbestos exposure. In this review, we will discuss the significant advancements in our understanding of its genetics and molecular biology and their translational relevance. Remarkable findings included the discovery of germline and somatic mutations of BRCA1 associated protein-1 (BAP1) in patients, and the genome-wide characterization of pathways altered in mesothelioma that could be potentially exploited to design novel therapeutic approaches. Nevertheless, the clinical translation of these molecular findings has been slow and insufficient. In order to rapidly move translation from the bench to the bedside, we believe that cooperative research efforts have to be further endorsed and promoted at all levels.

Recent genome-wide studies of malignancies of the central nervous system (CNS) have revolutionized our understanding of the biology of these tumors. This newly gained knowledge provides a wealth of opportunity for biomarker driven clinical research. To date, however, only few of the available molecular markers truly influence clinical decision-making and treatment. The most widely validated markers in neuro-oncology presently are: 1) MGMT promoter methylation as a prognostic and predictive marker in glioblastoma, 2) co-deletion of 1p and 19q differentiating oligodendrogliomas from astrocytomas, 3) IDH1/2 mutations, and 4) select pathway-associated mutations. This article focuses on currently impactful biomarkers in adult and pediatric brain cancers and it provides a perspective on the direction of research in this field.

Advances in translational research are often driven by new technologies. The advent of microarrays, next-generation sequencing, proteomics and RNA interference (RNAi) have led to breakthroughs in our understanding of the mechanisms of cancer and the discovery of new cancer drug targets. The discovery of the bacterial clustered regularly interspaced palindromic repeat (CRISPR) system and its subsequent adaptation as a tool for mammalian genome engineering has opened up new avenues for functional genomics studies. This review will focus on the utility of CRISPR in the context of cancer drug target discovery.

To determine the correlations between AML1-ETO fusion gene and clinical characteristics of patients with AML,and its association with the prognosis of AML-M2.

To determine the correlation between fms-like tyrosine kinase 3 gene (FLT3) expression and FLT3-internal tandem duplication (ITD) mutations in acute myeloid leukemia patients,and the association between expression of FLT3 gene and clinical and laboratory features of patients.