Demographic shift disproportionately increases cancer burden in an aging nation: current and expected incidence and mortality in Hungary up to 2030

Population aging is a common demographic pattern in developed countries, and aging increases the risk of cancer. The disproportionately high cancer burden, as a consequence, is especially pronounced in Central and Eastern European countries, including Hungary.We summarized current and projected future cancer incidences and mortalities utilizing data from the last two decades. Predictions are based on cancer incidence and mortality collected between 1996 and 2015 in Hungary. In addition to the crude rates, data were age standardized to the European standard population (ESP) of 2013, ESP of 1976, and local census of 2011.The lifetime probability of developing cancer and cancer-related mortality has already reached 56.9% and 27.6% in men, respectively, and 51.9% and 21.7% in women. Between 2016 and 2030, the total population is expected to shrink by 6%, while the number of 60-year olds and above will grow by 18%. This will lead to a 35% increase in cancer incidence and 30% increase in cancer death among 65-85-year olds. Joinpoint regression identified the period 2007-2015 as starting point for this coming increase in new cases. In women, lung and breast cancer will increase yearly by 1.9% and 1.7%, respectively, between 2016 and 2030, while in men, the prostate and colorectal cancer rates will increase yearly by 3.6% and 2.1%.In the aging population of Hungary, cancer incidence will increase considerably over previous projections. Although a large portion of the most rapidly rising cancers are avoidable by implementing public health programs, a substantial portion remains inevitably incurable

Molecular markers and potential therapeutic targets in non-WNT/non-SHH (group 3 and group 4) medulloblastomas

Childhood medulloblastomas (MB) are heterogeneous and are divided into four molecular subgroups. The provisional non-wingless-activated (WNT)/non-sonic hedgehog-activated (SHH) category combining group 3 and group 4 represents over two thirds of all MBs, coupled with the highest rates of metastases and least understood pathology. The molecular era expanded our knowledge about molecular aberrations involved in MB tumorigenesis, and here, we review processes leading to non-WNT/non-SHH MB formations.The heterogeneous group 3 and group 4 MBs frequently harbor rare individual genetic alterations, yet the emerging profiles suggest that infrequent events converge on common, potentially targetable signaling pathways. A mutual theme is the altered epigenetic regulation, and in vitro approaches targeting epigenetic machinery are promising. Growing evidence indicates the presence of an intermediate, mixed signature group along group 3 and group 4, and future clarifications are imperative for concordant classification, as misidentifying patient samples has serious implications for therapy and clinical trials.To subdue the high MB mortality, we need to discern mechanisms of disease spread and recurrence. Current preclinical models do not represent the full scale of group 3 and group 4 heterogeneity: all of existing group 3 cell lines are MYC-amplified and most mouse models resemble MYC-activated MBs. Clinical samples provide a wealth of information about the genetic divergence between primary tumors and metastatic clones, but recurrent MBs are rarely resected. Molecularly stratified treatment options are limited, and targeted therapies are still in preclinical development. Attacking these aggressive tumors at multiple frontiers will be needed to improve stagnant survival rates

Principles of tumorigenesis and emerging molecular drivers of SHH‐activated medulloblastomas

Abstract SHH‐activated medulloblastomas (SHH‐MB) account for 25–30% of all medulloblastomas (MB) and occur with a bimodal age distribution, encompassing many infant and adult, but fewer childhood cases. Different age groups are characterized by distinct survival outcomes and age‐specific alterations of regulatory pathways. Here, we review SHH‐specific genetic aberrations and signaling pathways. Over 95% of SHH‐MBs contain at least one driver event – the activating mutations frequently affect sonic hedgehog signaling (PTCH1, SMO, SUFU), genome maintenance (TP53), and chromatin modulation (KMT2D, KMT2C, HAT complexes), while genes responsible for transcriptional regulation (MYCN) are recurrently amplified. SHH‐MBs have the highest prevalence of damaging germline mutations among all MBs. TP53‐mutant MBs are enriched among older children and have the worst prognosis among all SHH‐MBs. Numerous genetic aberrations, including mutations of TERT, DDX3X, and the PI3K/AKT/mTOR pathway are almost exclusive to adult patients. We elaborate on the newest development within the evolution of molecular subclassification, and compare proposed risk categories across emerging classification systems. We discuss discoveries based on preclinical models and elaborate on the applicability of potential new therapies, including BET bromodomain inhibitors, statins, inhibitors of SMO, AURK, PLK, cMET, targeting stem‐like cells, and emerging immunotherapeutic strategies. An enormous amount of data on the genetic background of SHH‐MB have accumulated, nevertheless, subgroup affiliation does not provide reliable prediction about response to therapy. Emerging subtypes within SHH‐MB offer more layered risk stratifications. Rational clinical trial designs with the incorporation of available molecular knowledge are inevitable. Improved collaboration across the scientific community will be imperative for therapeutic breakthroughs

A személyre szabott terápia legújabb lehetőségei a molekuláris onkológiában = New Options for Personalized Treatment in Molecular Oncology

A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása. A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás jelentőségét

Guidelines for the selection of functional assays to evaluate the hallmarks of cancer

The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-increasing number of mutated/altered candidate genes are being identified within large-scale cancer genomic projects. Therefore, investigators need to be aware of available and appropriate techniques capable of determining characteristic features of each hallmark. We review the methods tailored to experimental cancer researchers to evaluate cell proliferation, programmed cell death, replicative immortality, induction of angiogenesis, invasion and metastasis, genome instability, and reprogramming of energy metabolism. Selecting the ideal method is based on the investigator's goals, available equipment and also on financial constraints. Multiplexing strategies enable a more in-depth data collection from a single experiment — obtaining several results from a single procedure reduces variability and saves time and relative cost, leading to more robust conclusions compared to a single end point measurement. Each hallmark possesses characteristics that can be analyzed by immunoblot, RT-PCR, immunocytochemistry, immunoprecipitation, RNA microarray or RNA-seq. In general, flow cytometry, fluorescence microscopy, and multiwell readers are extremely versatile tools and, with proper sample preparation, allow the detection of a vast number of hallmark features. Finally, we also provide a list of hallmark-specific genes to be measured in transcriptome-level studies. Although our list is not exhaustive, we provide a snapshot of the most widely used methods, with an emphasis on methods enabling the simultaneous evaluation of multiple hallmark features. © 2016 The Author