Current Molecular Medicine - Volume 7, Issue 1, 2007

From a simple observation of Austrian monk Gregor Mendel in 1865, the history of genetics has transitioned from Mendelian genetics, to post-Mendelian genetics, to classical genetics, to molecular genetics. Molecular genetics is driving cancer research and is an integral part of cancer biology. Since the completion of over 90% of the human genome sequence in 2001, a new frontier in molecular medicine has begun to emerge: personalized medicine based on individual molecular profiles. Scientific advances and major discoveries from areas such as genomics, nanotechnology, proteomics, metabolomics, immunology, molecular imaging, and bioinformatics allow us to envision a future when a patient’s genetic, lifestyle, and environmental risks for cancer can be combined with effective prevention and early intervention strategies, especially for those at high risk. In the past two decades, remarkable progress has been made in cancer genetics, which has provided an opportunity for exponential progress fighting the disease. Cancer genetics has a rich history of discoveries and innovations that continue to benefit combinatorial approaches in cancer detection, diagnosis and treatment. Lessons learned from model systems, such as yeast or mouse, have enabled us to understand the carcinogenic process in humans. Mouse models, in particular, have provided biological “footprints” of many human cancers, and are increasingly being used in pre-clinical development of cancer drugs and toxicity assessment. New technologies and increased interest of medical practitioners to utilize molecular genetics in early detection, diagnosis, therapeutic treatments, and predicting the clinical outcomes, have accelerated efforts by the drug discovery communities (pharmaceutical industry) to develop novel molecular biomarkers for several human diseases, including cancer. Development of molecular biomarkers also enables us to develop a new generation of diagnostic products and to integrate diagnostics and therapeutics. This integrated approach will aid in “individualizing” the medical practice. The current issue of Molecular Medicine on Cancer Genetics appears to embody this integrated approach towards fulfilling the needs for “personalized medicine” for cancer patients. A number of drugs like Iressa™ (gefitinib) are targeting a specific molecule, such as EGFR-tyrosine kinase. Recently, the presence of EGFR mutations was found to correlate with a significant proportion of the clinical responses to EGFR inhibitors, such as gefitinib, in non-small cell lung carcinoma. The review on Tyrosine Kinome mutations by Salgia is timely and useful for the field. Molecular-based cancer diagnosis and treatment appears to be the potential beneficiary of genetics. The definition of pre-cancer, or preneoplasia, is being redefined in terms of molecular changes that precede clinical detection of precancerous lesions (see the articles by Wistuba, Milne and Barr). Since pathology of precancerous lesions is subject to the observer’s training and experience, molecular profiles are aiding in removing such subjectivity and enhancing the detection of preneoplastic lesions. Offerhaus' article on inheritable cancers, such as familial polyposis, an inherited condition in which numerous polyps form on the inside walls of the colon and rectum and increase the risk of colorectal cancer, provides a perspective on geneenvironment interaction. It also provides insights into the exposures, genetic risk factors, and lifestyles that have significant impacts on the majority of non-familial cancers. Genetic changes along with epigenetic alterations are good examples of gene-environment interactions. In this issue, Gazdar talks about how epigenetic changes could be used as potential biomarkers for cancer detection and diagnosis. Among epigenetic markers, methylation is thought to be one of the best studied in mammalian cells to modify gene function. Aberrant DNA methylation can confer a selective growth advantage to the respective cell. This occurs when the promoter regions of genes, involved in the control of cell proliferation, are subjected to DNA methylation in their CpG islands, thus silencing gene expression. Hypermethylation of the promoter region CpG islands in cancer cells is frequently observed concomitant with the inhibition of gene function. Environmental and genetic signals can trigger eukaryotic cells to commit a suicide, a process known as programmed cell death (apoptosis). Cancer causes changes not only in the nuclear and cytoplasmic DNA and proteins, but also in specific organelles, such as Golgi and mitochondria. Mitochondria are known to play a pivotal role during apoptosis. A number of mutations, deletions and insertions in the mitochondria genome have been associated with specific cancers.........

From biological, histopathologic, and clinical perspectives, lung cancer is a highly complex neoplasm probably having multiple preneoplastic pathways. The sequence of histopathologic changes in the bronchial mucosa that precedes the development of squamous carcinomas of the lung has been identified. For the other major forms of lung cancer, however, such sequences have been poorly documented. This review summarizes the current knowledge regarding the molecular and histopathologic pathogenesis of lung cancer and discusses the complexity of identifying novel molecular mechanisms involved in the development of the lung premalignant disease, and their relevance to the development of new strategies for early detection and chemoprevention. Although our current knowledge of the molecular pathogenesis of lung cancer is still meager, work over the last decade has taught several important lessons about the molecular pathogenesis of this tumor, including the following: a) Better characterization of the high-risk population is needed. b) There are several histopathologic and molecular pathways associated with the development of the major types of non-small cell lung cancer. c) Although there is a field effect phenomenon for lung preneoplastic lesions, recent data suggest that there are at least two distinct lung airway compartments (central and peripheral) for lung cancer pathogenesis. d) Inflammation may play an important role in lung cancer development and could be an important component of the field effect phenomenon. e) For lung adenocarcinoma, at least two pathways (smoking-related and nonsmoking-related) have been identified. f) Finally, the identification of deregulated molecular signaling pathways in lung cancer preneoplasias may provide a rationale for designing novel strategies for early detection and targeted chemoprevention of lung cancer.

Gastric cancer is thought to result from a combination of environmental factors and the accumulation of specific genetic alterations due to increasing genetic instability, and consequently affects mainly older patients. Less than 10% of patients present with the disease before 45 years of age (early onset gastric carcinoma) and these patients are believed to develop gastric carcinomas with a molecular genetic profile differing from that of sporadic carcinomas occurring at a later age. In young patients, the role of genetics is presumably greater than in older patients, with less of an impact from environmental carcinogens. As a result, hereditary gastric cancers and early onset gastric cancers can provide vital information about molecular genetic pathways in sporadic cancers and may aid in the unraveling of gastric carcinogenesis. This review focuses on the molecular genetics of gastric cancer and also focuses on early onset gastric cancers as well as familial gastric cancers such as hereditary diffuse gastric cancer. An overview of the various pathways of importance in gastric cancer, as discovered through in-vitro , primary cancer and mouse model studies, is presented and the clinical importance of CDH1 mutations is discussed.

Colorectal cancer is one of the leading causes of cancer-related death in the Western society, and the incidence is rising. Rare hereditary gastrointestinal polyposis syndromes that predispose to colorectal cancer have provided a model for the investigation of cancer initiation and progression in the general population. Many insights in the molecular genetic basis of cancer have emerged from the study of these syndromes. This review discusses the genetics and clinical manifestations of the three most common syndromes with gastrointestinal polyposis and an increased risk of colorectal cancer: familial adenomatous polyposis (FAP), juvenile polyposis (JP) and Peutz- Jeghers syndrome (PJS).

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in the pediatric population. Two main histopathologic variants have been described, embryonal (ERMS) and alveolar (ARMS), which demonstrate clinical and genetic differences. In particular, most ARMS but not ERMS tumors are characterized by the presence of recurrent chromosomal translocations, which have been cytogenetically defined as t(2;13)(q35;q14) and t(1;13)(p36;q14). These translocations form PAX3- FKHR and PAX7-FKHR gene fusions, which encode chimeric transcription factors. These chimeric proteins are hypothesized to generate a novel transcriptional program in the target cell, thereby contributing to multiple aspects of ARMS tumorigenesis. This review highlights recent advances in numerous areas of biomedical investigation that are providing new insights into the biology, molecular pathology, and translational science of ARMS: the identification of downstream targets of PAX3-FKHR and collaborating events in the process of tumorigenesis and metastasis; generation of animal models based on the gene fusion and collaborating events; development of new assays for diagnosis, prognosis, and detection of minimal disseminated disease; and exploration of immune recognition of this tumor and the fusion protein. These findings highlight the continued importance of the fusion proteins in understanding the biology of this tumor and developing improved diagnostics for this tumor, and have led to the initiation of efforts to explore therapeutic strategies based on the increasing understanding of the biology of these fusion proteins.

The INK4/ARF locus encodes the p15INK4B, p16INK4A and p14ARF tumor suppressor proteins whose loss of function is associated with the pathogenesis of many human cancers. Dissecting the relative contribution of these genes to growth control in vivo is complicated by their physical contiguity and the frequency of homozygous deletions that inactivate all three components of this locus. While genetically engineered mouse models provide a rigorous system for elucidating cancer gene function, there is some evidence to suggest there are cross-species differences in regulating tumor biology. Given the prevalence of mouse models in cancer research and the potential contribution of such models to preclinical studies, it is important determine to what degree the function of these critical tumor suppressors is conserved between organisms. In this review, we assess the relative biological roles of INK4A, INK4B and ARF in mice and humans with the aim of determining the faithfulness of mouse models and also of obtaining insights into the pattern of specific tumor types that are associated with germline and somatic mutations at components of this locus. We will discuss 1) the contribution of INK4A, INK4B and ARF to growth control in vitro in a series of cell types, 2) the in vivo phenotypes associated with germline loss of function of this locus and 3) the study of Ink4a and Arf in different cancer-specific mouse models.

A subset of tyrosine kinases are activated by mutations which contribute to the malignant transformation, growth, and metastasis of human cancers. Mutations change the expression, conformation and/or stability of tyrosine kinases, often leading to constitutive activation of the signaling pathways the kinases regulate. Given that tyrosine kinases are key members of signaling cascades, mutations have multiple effects on various cellular proteins. This review will focus on four kinases (EGFR, c-Met, c-Kit, and PI3-kinase) known to be mutated in human cancer. It will discuss the effects that these mutations have on the biology of tumors, and how our understanding of the structure and function of kinases and their mutations is currently being used to design targeted treatments.

The spatial arrangement and three-dimensional structure of DNA in the nucleus is controlled through the interdigitation of DNA binding proteins such as histones and their modifiers, the Polycomb- Trithorax proteins, and the DNA methyltransferase enzymes. DNA methylation forms the foundation of chromatin and is crucial to epigenetic gene regulation in mammals. Disease pathogenesis mediated through infectious agents, inflammation, aging, or genetic damage often involves changes in gene expression. In particular, cellular transformation coincides with multiple changes in chromatin architecture, many of which appear to affect genome integrity and gene expression. Infectious agents, such as viruses directly affect genome structure and induce methylation of particular sequences to suppress host immune responses. Hyperproliferative tissues such as those in the gastrointestinal tract and colon have been shown to gradually acquire aberrant promoter hypermethylation. Here we review recent findings on altered DNA methylation in human disease, with particular focus on cancer and the increasingly large number of genes subject to tumor-specific promoter hypermethylation and the possible role of aberrant methylation in tumor development.

The identification of genetic events that are involved in the development of human cancer has been facilitated through the development and application of a diverse series of high resolution, high throughput microarray platforms. Essentially there are two types of array; those that carry PCR products from cloned nucleic acids (e.g. cDNA, BACs, cosmids) and those that use oligonucleotides. Each has advantages and disadvantages but it is now possible to survey genome wide DNA copy number abnormalities and expression levels to allow correlations between losses, gains and amplifications in tumor cells with genes that are over- and under-expressed in the same samples. The gene expression arrays that provide estimates of mRNA levels in tumors have given rise to exonspecific arrays that can identify both gene expression levels, alternative splicing events and mRNA processing alterations. Oligonucleotide arrays are also being used to interrogate single nucleotide polymorphisms (SNPs) throughout the genome for linkage and association studies and these have been adapted to quantify copy number abnormalities and loss of heterozygosity events. To identify as yet unknown transcripts tiling arrays across the genome have been developed which can also identify DNA methylation changes and be used to identify DNA-protein interactions using ChIP on Chip protocols. Ultimately DNA sequencing arrays will allow resequencing of chromosome regions and whole genomes. With all of these capabilities becoming routine in genomics laboratories, the idea of a systematic characterization of the sum genetic events that give rise to a cancer cell is rapidly becoming a reality.

The better part of a century has passed since Otto Warburg first hypothesized that unique phenotypic characteristics of tumor cells might be associated with an impairment in the respiratory capacity of these cells. Since then a number of distinct differences between the mitochondria of normal cells and cancer cells have been observed at the genetic, molecular, and biochemical levels. This article begins with a general overview of mitochondrial structure and function, and then outlines more specifically the metabolic and molecular alterations in mitochondria associated with human cancer and their clinical implications. Special emphasis is placed on mtDNA mutations and their potential role in carcinogenesis. The potential use of mitochondria as biomarkers for early detection of cancer, or as unique cellular targets for novel and selective anti-cancer agents is also discussed.

A revolution is underway in the approach to studying the genetic basis of cancer. Massive amounts of data are now being generated via high-throughput techniques such as DNA microarray technology and new computational algorithms have been developed to aid in analysis. At the same time, standards-based repositories, including the Stanford Microarray Database and the Gene Expression Omnibus have been developed to store and disseminate the results of microarray experiments. Bioinformatics, the convergence of biology, information science, and computation, has played a key role in these developments. Recently developed techniques include Module Maps, SLAMS (Stepwise Linkage Analysis of Microarray Signatures), and COPA (Cancer Outlier Profile Analysis). What these techniques have in common is the application of novel algorithms to find highlevel gene expression patterns across heterogeneous microarray experiments. Large-scale initiatives are underway as well. The Cancer Genome Atlas (TCGA) project is a logical extension of the Human Genome Project and is meant to produce a comprehensive atlas of genetic changes associated with cancer. The Cancer Biomedical Informatics Grid (caBIG™), led by the NCI, also represents a colossal initiative involving virtually all aspects of cancer research and may help to transform the way cancer research is conducted and data are shared.