Biomarkers in molecular medicine: cancer detection and diagnosis

In spite of advances in diagnostics and therapeutics, cancer remains the second leading cause of death in the U.S. Successful cancer treatment depends not only on better therapies but also on improved methods to assess an individual's risk of developing cancer and to detect cancers at early stages when they can be more effectively treated. Current cancer diagnostic imaging methods are labor-intensive and expensive, especially for screening large asymptomatic populations. Effective screening strategies depend on methods that are noninvasive and detect cancers in their early stages of development. There is increasing interest and enthusiasm in molecular markers as tools for cancer detection and prognosis. It is hoped that newly discovered cancer biomarkers and advances in high-throughput technologies would revolutionize cancer therapies by improving cancer risk assessment, early detection, diagnosis, prognosis, and monitoring therapeutic response. These biomarkers will be used either as stand-alone tests or to complement existing imaging methods.     

Serum-based protein biomarkers for detection of lung cancer

Lung cancer is one of the most common cancers in terms of both incidence and mortality.The major reasons for the increasing number of deaths from lung cancer are late detection and lack of effective therapies. To improve our understanding of lung cancer biology, there is urgent need for blood-based, non-invasive molecular tests to assist in its detection in a cost-effective manner at an early stage when curative interventions are still possible. Recent advances in proteomic technology have provided extensive, high throughput analytical tools for identification, characterization and functional studies of proteomes. Changes in protein expression patterns in response to stimuli can serve as indicators or biomarkers of biological and pathological processes as well as physiological and pharmacological responses to drug treatment, thus aiding in early diagnosis and prognosis of disease. However, only a few biomarkers have been approved by the FDA to date for screening and diagnostic purposes. This review provides a brief overview of currently available proteomic techniques, their applications and limitations and the current state of knowledge about important serum biomarkers in lung cancer and their potential value as prognostic and diagnostic tools.     

SELEX技术在胰腺癌分子诊断及靶向治疗中应用的研究进展

胰腺癌由于起病隐匿,早期诊断率较低,临床治疗效果差,是目前预后最差的恶性肿瘤之一。目前,临床上尚缺乏有效的非创伤早期筛查胰腺癌的手段,因而胰腺癌的早期诊断和治疗显得尤为重要。近年来,指数富集配基的系统进化(SELEX)技术以其在其他疾病中所表现的应用价值为疾病的诊治提供了一个新的途径。对于缺乏有效确诊手段,发病隐匿且病死率高的胰腺癌而言,SELEX技术基于胰腺癌发病的分子机制,可以筛选出特异结合于胰腺癌分子靶标的适配体,对筛选所得适配体进一步化学修饰,可以实现分子水平成像及靶向治疗,进而达到胰腺癌早期诊治的目的,具有重要的临床意义。本文就SELEX技术在胰腺癌分子诊断及靶向治疗中的应用研究进展进行了综述。     

Early detection of colon cancer: new tests on the horizon

This year, the American Cancer Society reported that the rate of decline in both the incidence and mortality of colorectal cancer has increased over the last two decades. This success is felt to be attributable to the early detection and treatment of colonic adenomas and early-stage colorectal cancers. However, the current recommended 'menu of options' for screening is limited by poor patient acceptance, low sensitivity, and both high cost and poor accessibility for application to a large general screening population (colonoscopy). Computerized tomography and magnetic resonance colonography offer an alternative method for the identification of polyps and early lesions in certain patients, but have cost, access, and acceptance limitations that are similar to those of colonoscopy; thus, they present similar barriers to their use in broad population screening. These limitations provide a strong rationale for the development of early colorectal cancer detection biomarkers that are simple to use and are cost effective. A successful biomarker or biomarker panel, coupled with the colonoscopic follow-up of only those patients with positive results, would reduce the burden and morbidity associated with the screening of colonoscopy. This would most likely result in enhanced adherence to colorectal screening, as well as a dramatic reduction in the incidence and mortality rates of colorectal cancer. In this paper, we review recent advances in the discovery of potential colorectal cancer biomarkers. Their applicability to clinical population screening will require large prospective validation.     

Lung Cancer: Are we up to the Challenge?

Lung cancer is the leading cause of cancer deaths worldwide among both men and women, with more than 1 million deaths annually. Non-small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers.Although recent advances have been made in diagnosis and treatment strategies, the prognosis of NSCLC patients is poor and it is basically due to a lack of early diagnostic tools.However, in the last years genetic and biochemical studies have provided more information about the protein and gene's mutations involved in lung tumors. Additionally, recent proteomic and microRNA's approaches have been introduced to help biomarker discovery.Here we would like to discuss the most recent discoveries in lung cancer pathways, focusing on the genetic and epigenetic factors that play a crucial role in malignant cell proliferation, and how they could be helpful in diagnosis and targeted therapy.     

Trends in breast cancer survival in Germany from 1976 to 2008--a period analysis by age and stage

Background: Implementation of mammography screening and advances in breast cancer treatment are considered as main reasons for the decline in breast cancer mortality observed in many industrialized countries during the past two decades. The purpose of this study was to provide a comprehensive assessment of trends in breast cancer incidence, mortality and survival by age and stage in Germany. Methods: Data from the population based Saarland Cancer Registry including patients diagnosed with breast cancer from 1972 to 2007 were used. Period analysis methods were employed to calculate 5-year relative survival and its trends. Results: Mortality started to decline during the 1990s, and a previous increase in incidence levelled off in the early 21st century. Overall age-standardized 5-year relative survival of invasive breast cancer steadily increased during the past three decades to 83% in 2004–2008. This increase was mostly due to an increase in survival for patients with localized cancers and locally or regionally spread tumours (increase of age-standardized 5-year relative survival from 92% to 98% and from 65% to 80%, respectively, between 1992 and 2008), whereas age-standardized 5-year relative survival essentially remained unchanged at levels close to 21% in patients with metastasized cancer. For women aged 70 years or older 5-year relative survival and its increase over time were inferior compared to younger patients. Conclusions: The observed trends in population based survival suggest that advances in treatment of early breast cancer have substantially contributed to the gain in prognosis. The poor prognosis of metastasized breast cancer patients and the increasing age gradient in 5-year relative survival call for enhanced efforts for early detection and more rigorous treatment of elderly patients.     

Progress and challenges in screening for early detection of ovarian cancer

Ovarian cancer is characterize by few early symptoms, presentation at an advanced stage, and poor survival. As a result, it is the most frequent cause of death from gynecological cancer. During the last decade, a research effort has been directed toward improving outcomes for ovarian cancer by screening for preclinical, early stage disease using both imaging techniques and serum markers. Numerous biomarkers have shown potential in samples from clinically diagnosed ovarian cancer patients, but few have been thoroughly assessed in preclinical disease and screening. The most thoroughly investigated biomarker in ovarian cancer screening is CA125. Prospective studies have demonstrated that both CA125 and transvaginal ultrasound can detect a significant proportion of preclinical ovarian cancers, and refinements in interpretation of results have improved sensitivity and reduced the false-positive rate of screening. There is preliminary evidence that screening can improve survival, but the impact of screening on mortality from ovarian cancer is still unclear. Prospective studies of screening are in progress in both the general population and high-risk population, including the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), a randomized trial involving 200,000 postmenopausal women designed to document the impact of screening on mortality. Recent advances in technology for the study of the serum proteome offer exciting opportunities for the identification of novel biomarkers or patterns of markers that will have greater sensitivity and lead time for preclinical disease than CA125. Considerable interest and controversy has been generated by initial results utilizing surface-enhanced laser desorption/ionization (SELDI) in ovarian cancer. There are challenging issues related to the design of studies to evaluate SELDI and other proteomic technology, as well as the reproducibility, sensitivity, and specificity of this new technology. Large serum banks such as that assembled in UKCTOCS, which contain preclinical samples from patients who later developed ovarian cancer and other disorders, provide a unique resource for carefully designed studies of proteomic technology. There is a sound basis for optimism that further developments in serum proteomic analysis will provide powerful methods for screening in ovarian cancer and many other diseases.     

miRNA在防治非小细胞肺癌中的研究进展

微RNA(micro RNAs;mi RNA)是一类长度约为22核苷酸的非编码核苷酸,能在转录后水平抑制蛋白的翻译而调控靶向基因的表达。非小细胞肺癌(NSCLC)占所有肺癌比例的80%,确诊后一般为晚期,且具有早期确诊率低,治疗效果差,治疗后易复发,预后不良等特征。目前用于治疗NSCLC的方法主要是手术、放化疗、中医中药治疗以及生物免疫治疗,总体治疗效果不明显,死亡率高。近年来,大量研究表明mi RNA在癌症的发生发展、转移及复发中具有重要的作用,但目前尚未建立系统规范的使用mi RNA对NSCLC诊断、治疗、预后的标准化方案,临床实施难度大。本文就近几年来mi RNA在NSCLC诊断、治疗及预后功能上进行综述,期望有助于促进mi RNA在实际临床中发挥其应有的作用。     

人附睾蛋白4在卵巢癌中的应用进展

卵巢癌是妇科常见的恶性肿瘤,其死亡率居妇科恶性肿瘤之首,早期发现有助于提高患者的五年生存率。人附睾蛋白(HE4)属于蛋白酶抑制剂家族,是一种新的卵巢癌肿瘤标志物。HE4在卵巢癌组织中及患者血清中处于高表达状态。研究表明在早期诊断方面HE4比糖类抗原125(CA125)有更高的灵敏度和特异度,在疾病的治疗过程中可以预测肿瘤细胞减灭术的满意度及患者对铂类的反应,在卵巢癌的复发及预后的监测中HE4也有很大的临床应用价值。     

Proteomic strategies in the search for novel pancreatic cancer biomarkers and drug targets: recent advances and clinical impact

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers; despite a low incidence rate it is the fourth leading cause of cancer-related death in the world. Improvement of the diagnosis, prognosis and treatment remains the main focus of pancreatic cancer research. Rapid developments in proteomic technologies has improved our understanding of the pancreatic cancer proteome. Here, the authors summarise the recent proteomic strategies undertaken in the search for: novel biomarkers for early diagnosis, pancreatic cancer-specific proteins which may be used for novel targeted therapies and proteins which may be useful for monitoring disease progression post-therapy. Recent advances and findings discussed here provide great promise of having a significant clinical impact and improving the outcome of patients with this malignancy.     

胰腺癌相关肿瘤标志物研究进展

胰腺癌起病隐匿,进展快,预后差,发病率约等于死亡率。胰腺癌死亡率高的原因有发病机制不明,缺乏有效的早期诊断和预后的肿瘤标志物,进展期相关治疗效果不理想。近年来在血清标志物、基因标志物、表观遗传学标志物等分子生物技术及生物信息学方面的发展为胰腺癌的诊断,尤其是早期诊断、评估预后和监测早期复发提供了新的途径。本文就近期胰腺癌相关肿瘤标志物的研究进展作一综述。     

Racial disparity in colorectal cancer:Gut microbiome and cancer stem cells

Over the past two decades there has been remarkable progress in cancer diagnosis, treatment and screening. The basic mechanisms leading to pathogenesis of various types of cancers are also understood better and some patients, if diagnosed at a particular stage go on to lead a normal pre-diagnosis life. Despite these achievements, racial disparity in some cancers remains a mystery. The higher incidence, aggressiveness and mortality of breast, prostate and colorectal cancers(CRCs) in AfricanAmericans as compared to Caucasian-Americans are now well documented. The polyp-carcinoma sequence in CRC and easy access to colonic epithelia or colonic epithelial cells through colonoscopy/colonic effluent provides the opportunity to study colonic stem cells early in course of natural history of the disease. With the advent of metagenomic sequencing, uncultivable organisms can now be identified in stool and their numbers correlated with the effects on colonic epithelia. It would be expected that these techniques would revolutionize our understanding of the racial disparity in CRC and pave a way for the same in other cancers as well. Unfortunately, this has not happened. Our understanding of the underlying factors responsible in African-Americans for higher incidence and mortality from colorectal carcinoma remains minimal. In this review, we aim to summarize the available data on role of microbiome and cancer stem cells in racial disparity in CRC. This will provide a platform for further research on this topic.     

Long non‐coding RNA PVT1: Emerging biomarker in digestive system cancer

The digestive system cancers are leading cause of cancer‐related death worldwide, and have high risks of morbidity and mortality. More and more long non‐coding RNAs (lncRNAs) have been studied to be abnormally expressed in cancers and play a key role in the process of digestive system tumour progression. Plasmacytoma variant translocation 1 (PVT1) seems fairly novel. Since 1984, PVT1 was identified to be an activator of MYC in mice. Its role in human tumour initiation and progression has long been a subject of interest. The expression of PVT1 is elevated in digestive system cancers and correlates with poor prognosis. In this review, we illustrate the various functions of PVT1 during the different stages in the complex process of digestive system tumours (including oesophageal cancer, gastric cancer, colorectal cancer, hepatocellular carcinoma and pancreatic cancer). The growing evidence shows the involvement of PVT1 in both proliferation and differentiation process in addition to its involvement in epithelial to mesenchymal transition (EMT). These findings lead us to conclude that PVT1 promotes proliferation, survival, invasion, metastasis and drug resistance in digestive system cancer cells. We will also discuss PVT1's potential in diagnosis and treatment target of digestive system cancer. There was a great probability PVT1 could be a novel biomarker in screening tumours, prognosis biomarkers and future targeted therapy to improve the survival rate in cancer patients.     

A clinical overview of centrosome amplification in human cancers

The turn of the 21st century had witnessed a surge of interest in the centrosome and its causal relation to human cancer development - a postulate that has existed for almost a century. Centrosome amplification (CA) is frequently detected in a growing list of human cancers, both solid and haematological, and is a candidate "hallmark" of cancer cells. Several lines of evidence support the progressive involvement of CA in the transition from early to advanced stages of carcinogenesis, being also found in pre-neoplastic lesions and even in histopathologically-normal tissue. CA constitutes the major mechanism leading to chromosomal instability and aneuploidy, via the formation of multipolar spindles and chromosomal missegregation. Clinically, CA may translate to a greater risk for initiation of malignant transformation, tumour progression, chemoresistance and ultimately, poor patient prognosis. As mechanisms underlying CA are progressively being unravelled, the centrosome has emerged as a novel candidate target for cancer treatment. This Review summarizes mainly the clinical studies performed to date focusing on the mechanisms underlying CA in human neoplasia, and highlights the potential utility of centrosomes in the diagnosis, prognosis and treatment of human cancers.     

The cancer cell secretome: A good source for discovering biomarkers?

Cancer is a leading cause of death. Early detection is usually associated with better clinical outcomes. Recent advances in genomics and proteomics raised hopes that new biomarkers for diagnosis, prognosis or monitoring therapeutic response will soon be discovered. Proteins secreted by cancer cells, referred also as “the cancer cell secretome”, is a promising source for biomarker discovery. In this review we will summarize recent advances in cancer cell secretome analysis, focusing on the five most fatal cancers (lung, breast, prostate, colorectal, and pancreatic). For each cancer type we will describe the proteomic approaches utilized for the identification of novel biomarkers. Despite progress, identification of markers that are superior to those currently used has proven to be a difficult task and very few, if any, newly discovered biomarker has entered the clinic the last 10 years.     

Genome-wide profiling of gene amplification and deletion in cancer

Accumulations of genetic changes in somatic cells induce phenotypic transformations leading to cancer. Among these genetic changes, gene amplification and deletion are most frequently observed in several kinds of cancers. Amplification of oncogene and/or deletion of tumor suppressor gene, together with dysfunction of the gene by point mutation, are the main causes of cancer. Genome-wide analysis of amplification and deletion of genes in cancers is basic to resolving the mechanisms of carcinogenesis. Comparative genomic hybridization (CGH) developed in 1992 has been utilized to identify DNA copy number abnormalities in various kind of cancers and several reports have shown its usefulness in screening of the genes involved in carcinogenesis, and also in the identification of prognostic factors in cancer. We have shown that 1q23 gain is associated with neuroblastomas that are resistant to aggressive treatment, and have poor prognosis, and 1q and 13q gains are possibly related to drug resistance in ovarian cancers. Recently, the "rough draft" of the human genome was reported and we are ready to utilize the vast information on genomic sequences in cancer research. Moreover, microarray technology enables us to analyze more than ten thousand genes at a time and revealed genetic abnormalities in cancers at a genome-wide level. By combination of microarray and CGH, a powerful screening method for oncogenes and tumor suppressor genes in cancers, called array-CGH, has been developed by several groups. In this article, we overview these genome-wide analytical methods, CGH and array-CGH, and discuss their potential in molecular characterization of cancers.     

Potential applications of DNA methylation testing technology in female tumors and screening methods

DNA methylation is a common epigenetic modification, and the current commonly used methods for DNA methylation detection include methylation-specific PCR, methylation-sensitive restriction endonuclease-PCR, and methylation-specific sequencing. DNA methylation plays an important role in genomic and epigenomic studies, and combining DNA methylation with other epigenetic modifications, such as histone modifications, may lead to better DNA methylation. DNA methylation also plays an important role in the development of disease, and analyzing changes in individual DNA methylation patterns can provide individualized diagnostic and therapeutic solutions. Liquid biopsy techniques are also increasingly well established in clinical practice and may provide new methods for early cancer screening. It is important to find new screening methods that are easy to perform, minimally invasive, patient-friendly, and affordable. DNA methylation mechanisms are thought to have an important role in cancer and have potential applications in the diagnosis and treatment of female tumors. This review discussed early detection targets and screening methods for common female tumors such as breast, ovarian, and cervical cancers and discussed advances in the study of DNA methylation in these tumors. Although existing screening, diagnostic, and treatment modalities exist, the high morbidity and mortality rates of these tumors remain challenging.     

Identification and confirmation of increased fibrinopeptide a serum protein levels in gastric cancer sera by magnet bead assisted MALDI-TOF mass spectrometry

Gastric cancer is the second most common malignancy and prognosis remains dismal. The reasons for the poor prognosis are the lack of sensitive serum markers for early detection and screening of high-risk individuals as well as the limited treatment options in advanced cancer stages. Using MALDI-TOF mass spectrometry after prefractionation of sera with magnet hydrophobic C8 coated beads sera from 14 patients with gastric cancer and 14 healthy controls mass spectra were generated. A peptide fragment was found to be highly elevated in cancer sera and was identified as fibrinopeptide A. To confirm proteome analysis of gastric cancer sera, we then screened a larger series of patients with gastric cancer (n = 99), high-risk individuals (n = 13) and normal controls (n = 111) for fibrinopeptide A serum levels. Interestingly, the mean logarithmic concentrations of serum fibrinopeptide A levels were significantly higher in cancer patients (mean 3.636 +/- 0.3738; p < 0.0001) and high-risk individuals (mean 3.569 +/- 0.4722; p < 0.05) compared to normal controls (mean 3.303 +/- 0.4012). In contrast, we observed no association of fibrinopeptide A levels with tumor stage, tumor location, presence of regional or distant metastasis, and Lauren type of gastric cancer. In conclusion, MALDI-TOF mass spectrometry of prefractionated gastric cancer sera allows the identification of potential biomarkers that may lead to the development of serum based tests for screening of high-risk individuals.     

Mutation analysis of p53 in ovarian tumors by DHPLC

Up to now, ovarian carcinomas represent a major health problem among female cancers because they are the leading cause of death from gynecological malignancy. A high proportion of these tumors selects for mutations in the p53 gene. There is evidence that inactivation of the p53 protein could indicate poor prognosis and chemoresistance of patients. To set up a fast and sensitive test for p53 defects in tumor tissues, we analyzed ovarian cancer cells by denaturing high-performance liquid chromatography (DHPLC). A primer set spanning the whole coding region of p53 with seven fragments was designed and appropriate heteroduplex detection in DHPLC analysis was elaborated. The analysis of 45 ovarian tumor specimens yielded 17 genetic alterations (38%) occurring exclusively in the malignant tissue of the patients. In addition, frequent polymorphisms present in normal compared to tumor tissue could serve as a tool for the rapid identification of loss of heterozygosity (LOH) in the tumor. We observed that LOH in intron 2 or 3 correlated well with a lack of one allele in mutated fragments. In conclusion, DHPLC screening appears to be a sensitive and effective test for genetic alterations in tumors with p53 involvement. Since p53 mutations point to a poor prognosis state in several cancers, a fast screening of tumor material for genetic variations may have implications for further individual treatment of patients.