Volume Articles

Epigenetic aberration at enhancer regions in gastric cancer

Atsushi Okabe¹, Atsushi Kaneda^1*

¹Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

Cancer arises through the accumulation of genetic and epigenetic alterations. Comprehensive analyses of human cancer epigenomes over the past decade have revealed that chromatin and epigenetic aberrations induced by genetic, metabolic, and environmental stimuli play important roles in tumor initiation as well as progression. Among these aberrations, DNA hypermethylation at promoter regions is one of the major mechanisms to silence tumor suppressor genes in cancer, and has been studied in detail. For gastric cancer, for example, we and other groups have conducted genome-wide DNA methylation analyses, and classified gastric cancer into several DNA methylation epigenotypes. Gastric cancer with Epstein-Barr virus (EBV) infection exhibits the most extensive hypermethylation phenotype among all the human malignancies, and EBV infection itself is shown to cause aberrant DNA methylation induction. EBV infection also alters histone modifications, not only at promoter regions but also at enhancer regions. Epigenetic alteration at enhancers causes aberrant regulation of cancer-related genes together with epigenetic alteration at promoters, and it is known to contribute to tumorigenesis. We here review epigenetic aberration at enhancer regions in gastric cancer.

Positive Psychological Change in Head and Neck Cancer populations

Sam Harding

DHealthPsych, Pines and Steps Southmead Hospital North Bristol Hospital Trust, Bristol, United Kingdom

Head and neck cancer (HNC) carry a high level of morbidity and mortality, but the impact of HNC on survivors differs widely among individuals, and a significant number of them suffer from negative psychological effects of the disease. However, some people report a significant positive effect of experiencing HNC and its treatment.

This review looks at demographic, clinical and psychological factors associated with positive psychological change (PPC) in HNC populations.

Eight quantitative manuscripts were identified as reporting on PPC in HNC. These studies were split between recruiting participants via cancer clinics and postal surveys, and the majority use a cross-sectional study design.

Demographic factors across the papers showed similar patterns of relationships across PPC; that higher education/qualification and cohabitation/marriage are associated with increased PPC. Limited research reported longitudinal patterns of change and showed that for people with lower stage tumours and those who only had a surgical intervention greater PPC developed over time. Multivariable modeling adjusting for psychosocial variables found that PPC had a quadratic relationship with time since diagnosis, increasing initially and leveling off after 18 months.

Further research would aid the identification of bio-psychosocial factors that influence the development of PPC and inform the development of rehabilitation interventions while enabling consideration of the natural development of the phenomenon.

The ability of long non-coding RNA IGFBP4-1 to modulate Cellular Metabolism is a potential breakthrough in Lung Cancer Therapy

Soham Datta^1,2, Binyao Yang², Jiachun Lu^{1,2 *}

¹The State Key Lab of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, 151 Yanjiangxi Road, Guangzhou, 510120, China.

²The School of Public Health, The Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, Guangzhou Medical University, 195 Dongfengxi Road, Guangzhou, 510182, China

Lung cancer being one of the leading causes of cancer-related deaths around the world has significantly added to the global burden of disease. Late diagnosis, unavailability of definitive treatment and an unclear pathophysiological mechanism behind the role of various genes expressed in lung cancer make it a challenge that needs new techniques and better understanding of the underlying pathology and role of genetics. Long non coding RNAs, once considered insignificant, are now being elucidated to have major roles to play in the regulation and development of carcinogenesis. In this review, the ability of a lncRNA, lncRNA IGFBP4-1 to modulate cellular metabolic processes, eventually affecting lung cancer progression and consequently being a potential biomarker for lung cancer diagnosis has been discussed.

Commentary: Chemoradiotherapy for locally advanced squamous cell carcinoma of the oropharynx: Does completion of systemic therapy affect outcomes?

Richard Sleightholm BS¹ and Michael J Baine MD PhD^2*

¹Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA

^2*Department of Radiation Oncology, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

Concurrent chemoradiotherapy plays a vital role in the treatment of locally advanced squamous cell carcinoma of the oropharynx (LA-OPC). Importantly, only 50-85% of patients undergoing this treatment are able to complete their prescribed chemotherapy courses due to treatment-associated morbidity. The significance of chemotherapy completion, or lack thereof, remains unknown in this setting. To further investigate if chemotherapy non-completion affects patient outcomes, a single institutional retrospective study was undertaken analyzing 73 patients undergoing definitive radiation for LA-OPC and revealed a near-significant trend toward improved overall survival on multivariable analysis (p=0.053) in those completing chemotherapy. We are presently providing a commentary on this manuscript in an attempt to provide context and further interpretation of the presented results as well as suggest areas in need of additional investigation.

Effector and Regulatory CD4⁺ T helper lineages in cancer

Estefanía Nova-Lamperti^1,2*, Marco Fraga¹, Marco Romano³, Giovanna Lombardi^3#

¹Molecular and Translational Immunology Laboratory, Department of Clinical Biochemistry and Immunology, Faculty of Pharmacy, University of Concepcion, 4070386. Concepcion, Chile

²PreveGen Laboratory, Chacabuco 556, Concepcion, Chile

³MRC Centre for Transplantation, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, SE1 9RT. London, United Kingdom

Regulatory CD4+T-cells have been recently classified as regulatory T helper (Th)-like cells according to the expression of specific transcription factors, cytokines and chemokine receptors that mirror effector Th lineages. In our report: “An Atlas of Human Regulatory T Helper-like Cells Reveals Features of Th2-like Tregs that Support a Tumorigenic Environment” we found that Th2-like Tregs were increased in the tumour microenvironment in comparison with Th1-like, Th17-like and Th1/Th17-like Tregs. In addition, despite similar expression of CCR4 between all Tregs subtypes, Th2-like Tregs migrated more toward CCL17 and CCL22, and expressed higher levels of CCR8 than the other Th-like Tregs. Other studies have characterised human tissue-infiltrating Tregs and demonstrated that CCR8 is the main chemokine receptor differentially expressed in Tregs isolated from malignant tissues in comparison with healthy tissues. Given that CCR8 is a marker of Th2 lineages it is possible that Th2-like Tregs and CCR8+ Tregs are the same population of cells involved in tumour progression. However, whether they are recruited or differentiated in situ by the tumour microenvironment is still unknown. In this mini review, we describe the role of the different Th subsets in health and cancer and we present the different hypotheses about the presence of Th2-like Tregs in the tumorigenic environments.

Advances in Clinical Application of ctDNA Detection in NSCLC

¹Kang Qin, ²Helei Hou and ^3*Xiaochun Zhang

^1,2,3*Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China

With high morbidity and mortality, lung cancer has become the leading cause of cancer-related death worldwide, of which 85% are non-small-cell lung cancer (NSCLC). Most patients present with advanced disease at diagnosis and 5-year survival rate is no more than 30% due to lack of appropriate screening and early detection. In spite of tissue samples, ctDNA (circulating tumor DNA) is also widely used for molecular profiling to guide the treatment of NSCLC for lots of advantages. This review mainly focuses on the clinical and investigational applications of ctDNA detection in facilitating the personalized therapy of NSCLC.

Initially reported by Mandel et al. in 1948M¹, cfDNA (cell-free DNA) refers to the acellular, free DNA fragments in circulation (plasma or serum) derived from somatic cells through mechanisms like necrosis, apoptosis and exosome secretion. ctDNA is cfDNA generated by tumor cells, which carries cancer-associated genetic alterations^2,3. In 1977, Leon et al. first reported that the level of plasma ctDNA of patients with cancer was significantly higher than that of normal persons⁴, which was also confirmed in NSCLC^5,6. In NSCLC patients, techniques for targetable genetic ctDNA detection have improved from traditional ARMS, HPLC, BEAMing, FISH to new generations of NGS (next generation sequencing), ddPCR and CAPP-Seq etc. Compared with traditional detection methods, NGS shows extraordinary advantages like massively parallel sequencing, lower-inputs, cost-effectivity, ultra-sensitivity and hyper accuracy^7,8. The main applications of ctDNA detection in the personalized treatment of NSCLC patients will be discussed in this review.

Novel Platforms of Multiplexed Immunofluorescence for Study of Paraffin Tumor Tissues

Edwin Roger Parra

Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Multiplexed immunofluorescence (IF) methods to detect simultaneously different molecules are revolutionizing immunohistochemistry (IHC) in the last years. These new technologies can be valuable for tumor examination in formalin-fixed paraffin-embedded (FFPE) specimens, and for improved new treatment discoveries and translational cancer studies. The aim of this mini-review is to highlight the recent methodologies that using multiplexed IF to study simultaneous proteins identification in FFPE tumor tissues to clinical research and potential translational analysis. Multiplexed IF methods, which permit the identification of up to 4 proteins at the same time, have been increased in the last years the abilities of study cells by cells and their spatial distribution in several tumor tissues. Although, most of the old platforms are not more used after the powerful multiplex IHC methods are continue growing, the basis of these old methodologies have helped to improve the new technologies. Associated with image analysis software’s these technologies can be improved to performance high throughput assay to study these specimens. Each multiplexed IF technique, detailed herein, is associated with important advantages in cancer study as well as translational research studies.

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Wataru Nakajima and Nobuyuki Tanaka*

Department of Molecular Oncology, Institute for Advanced Medical Sciences, Nippon Medical School, Japan

Evasion of apoptosis is one of the typical hallmarks of cancer and a major mechanism for cancer development, tumor growth, and acquisition of resistance to chemotherapy. The anti-apoptotic Bcl-2 protein family, particularly MCL1 and BCL-XL, play an important role in acquisition of apoptosis evasion. MCL1 is a highly unstable protein that is constantly degraded by the ubiquitin-proteasome system. An increase in MCL1 protein has been reported in many cancers, including lung cancer, through high mRNA expression or impairment of its degradation systems. To date, much evidence has shown that MCL1 is important for cancer cell survival and drug resistance in lung cancers. In this review, we discuss the role and mechanism of high MCL1 expression in lung cancer.