Early stage colon cancer: Current treatment standards,evolving paradigms,and future directions

Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.     

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially‐methylated genes between responders and non–responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression‐free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.     

克隆性造血对肿瘤体细胞突变检测的影响

克隆性造血（clonal hematopoiesis，CH）突变是造血干细胞（hematopoietic stem cell，HSC）携带的突变，是年龄和外在环境（吸烟、放化疗等）共同作用的结果。随着肿瘤基因研究的进展，基因检测已成为实体瘤患者全病程管理中一个重要的环节。目前CH在实体瘤中的价值越来越受到关注。将围绕CH的检出，详细阐述实体瘤患者组织样本及循环肿瘤DNA （circulating tumor DNA，ctDNA）样本中CH的检测方法，探讨CH对肿瘤体细胞突变检测的影响和挑战。     

An introduction for the special issue on environmental health and genome integrity

Environmental exposures and genome maintenance mechanisms that respond to environmentally-induced genotoxicity have a profound impact on human health. Eight review articles in this Special Issue (SI) titled “Environmental Health and Genome Integrity” describe emerging new mechanisms by which distinct forms of environmentally-induced DNA damage are remediated, and explain how DNA repair pathway choices impact genome integrity and disease propensity. Here, we provide an introduction to reviews from this SI. Our expanding knowledge of how genotoxic exposures impact the genome will allow us to better predict, prevent and treat environmentally-induced human diseases such as cancer and neurodegenerative disorders.     

着色性干皮病两例ERCC2和ERCC5基因突变分析

【摘要】 目的 分析2例着色性干皮病患儿基因突变。方法 收集2例着色性干皮病患儿临床资料，提取患儿及其父母外周血DNA，采用高通量全外显子组测序方法对患儿进行全外显子组测序，确定致病基因突变位点，再用Sanger测序法对患儿及其父母的DNA进行双向验证，重点关注着色性干皮病相关候选基因XPA、ERCC3、XPC、ERCC2、DDB2、ERCC4、ERCC5及POLH的变异。结果 例1为3岁男孩，面、耳、颈、双手背散发褐色斑点伴色素减退斑2年，步态不稳1年，皮疹夏季加重，以光暴露部位为主。例2为1岁5月龄男孩，面部散发褐色斑点伴少许色素减退斑1年。基因检测显示，例1 ERCC2基因发生复合杂合突变，即父源c.1805G>A（p.Gly602Asp）和母源c.586C>T（p.Arg196Ter）突变，为XPD型。例2 ERCC5基因发生复合杂合突变，即父源c.2533+2T>C和母源c.2453C>T（p.Ala818Val）突变，为XPG型。c.586C>T（p.Arg196Ter）和c.2533+2T>C既往未见报道。嘱防晒、避光，随访2年，患儿皮损较前有所增多，未出现恶性肿瘤。结论 ERCC2基因复合杂合突变可导致XPD型着色性干皮病，表现出皮肤和神经症状；ERCC5基因复合杂合突变可导致XPG型着色性干皮病，表现为轻症表型。早期临床特点结合基因检测有助于着色性干皮病患者的准确诊断及分型。     

DNA hypermethylation is associated with invasive phenotype of malignant melanoma

Tumor cell invasion is one of the key processes during cancer progression, leading to life-threatening metastatic lesions in melanoma. As methylation of cancer-related genes plays a fundamental role during tumorigenesis and may lead to cellular plasticity which promotes invasion, our aim was to identify novel epigenetic markers on selected invasive melanoma cells. Using Illumina BeadChip assays and Affymetrix Human Gene 1.0 microarrays, we explored the DNA methylation landscape of selected invasive melanoma cells and examined the impact of DNA methylation on gene expression patterns. Our data revealed predominantly hypermethylated genes in the invasive cells affecting the neural crest differentiation pathway and regulation of the actin cytoskeleton. Integrative analysis of the methylation and gene expression profiles resulted in a cohort of hypermethylated genes (IL12RB2, LYPD6B, CHL1, SLC9A3, BAALC, FAM213A, SORCS1, GPR158, FBN1 and ADORA2B) with decreased expression. On the other hand, hypermethylation in the gene body of the EGFR and RBP4 genes was positively correlated with overexpression of the genes. We identified several methylation changes that can have role during melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. Interestingly, the down-regulation of the methylcytosine dioxygenase TET2 gene, which regulates DNA methylation, was associated with hypermethylated promoter region of the gene. This can probably lead to the observed global hypermethylation pattern of invasive cells and might be one of the key changes during the development of malignant melanoma cells.     

Photoperiod-induced neurotransmitter plasticity declines with aging: An epigenetic regulation?

Neuroplasticity has classically been understood to arise through changes in synaptic strength or synaptic connectivity. A newly discovered form of neuroplasticity, neurotransmitter switching, involves changes in neurotransmitter identity. Chronic exposure to different photoperiods alters the number of dopamine (tyrosine hydroxylase, TH+) and somatostatin (SST+) neurons in the paraventricular nucleus (PaVN) of the hypothalamus of adult rats and results in discrete behavioral changes. Here, we investigate whether photoperiod-induced neurotransmitter switching persists during aging and whether epigenetic mechanisms of histone acetylation and DNA methylation may contribute to this neurotransmitter plasticity. We show that this plasticity in rats is robust at 1 and at 3 months but reduced in TH+ neurons at 12 months and completely abolished in both TH+ and SST+ neurons by 18 months. De novo expression of DNMT3a catalyzing DNA methylation and anti-AcetylH3 assessing histone 3 acetylation were observed following short-day photoperiod exposure in both TH+ and SST+ neurons at 1 and 3 months while an overall increase in DNMT3a in SST+ neurons paralleled neuroplasticity reduction at 12 and 18 months. Histone acetylation increased in TH+ neurons and decreased in SST+ neurons following short-day exposure at 3 months while the total number of anti-AcetylH3+ PaVN neurons remained constant. Reciprocal histone acetylation in TH+ and SST+ neurons indicates the importance of studying epigenetic regulation at the circuit level for identified cell phenotypes. The findings may be useful for developing approaches for noninvasive treatment of disorders characterized by neurotransmitter dysfunction.     

A review of DNA profiling success for laser microdissected forensic casework samples

ABSTRACT

Laser microdissection (LMD) is a tool that is used in forensic laboratories for the analysis of DNA from specifically targeted cells. Since 2010, the Institute of Environmental Science and Research Limited’s (ESR) Forensic Biology laboratory has applied LMD DNA testing to a variety of sexual assault casework samples where small numbers of sperm are present in cell mixtures. In this paper we review the DNA profiling results obtained from semen-stained casework samples that have been analysed using the LMD DNA methodology developed in our laboratory. Dissected sperm have been analysed using the AmpFISTR Identifiler amplification kit at 28 cycle PCR, the AmpFISTR MiniFiler amplification kit at 30 cycle PCR, or the AmpFISTR SGM Plus amplification kit at 34 cycle PCR, depending on the number of sperm recovered and on consideration of other circumstantial case information, such as the time since intercourse (TSI). From a review of these data, success rates for different sample numbers of sperm recovered from semen-stained samples are determined. The DNA profiling results obtained from three cases where laser microdissection has been used are also presented to demonstrate the success of the LMD testing strategy in a forensic laboratory.