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Stephen B Baylin is a codirector of the Cancer Biology Program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the Virginia and DK Ludwig Professor of Oncology and Medicine. Baylin attended Duke University, where he earned his medical degree and completed his internship and first year residency in internal medicine. He then worked for 2 years at the National Heart and Lung Institute of the NIH. In 1971, he joined the departments of oncology and medicine at Johns Hopkins University School of Medicine. His research interests include cellular biology and genetics of cancer, specifically epigenetics or genetic modifications other than those in DNA that can affect cell behavior, and silencing of tumor suppressor genes and tumor progression. His research has looked at the mechanisms through which variations in tumor cells derive, and cell differentiation in cancers such as medullary thyroid carcinoma and small-cell lung carcinoma. He has served on the American Association for Cancer Research Board of Directors, and is an associate editor of Cancer Research. He has also presented frequently at AACR conferences and chaired the special conference on ‘DNA Methylation, Imprinting and the Epigenetics of Cancer’. He has authored or coauthored more than 370 publications.

The past decade has witnessed a rapid progress in our understanding of the genetics of cancer and its progression. Probabilistic and statistical modeling played a pivotal role in the discovery of general patterns from cancer genomics datasets and continue to be of central importance for personalized medicine. Scientists have programmed the living organisms using these circuits to attain multiple, delicate and well-defined functions. With the integration of tools or technologies from other disciplines, these rewired cells can achieve even more complex tasks. In this review we introduce cancer genomics from a probabilistic and statistical perspective. We start from (1) functional classification of genes into oncogenes and tumor suppressor genes, then (2) demonstrate the importance of comprehensive analysis of different mutation types for individual cancer genomes, followed by (3) tumor purity analysis, which in turn leads to (4) the concept of ploidy and clonality, that is next connected to (5) tumor evolution under treatment pressure, which yields insights into cancer drug resistance. We also discuss future challenges including the non-coding genomic regions, integrative analysis of genomics and epigenomics, as well as early cancer detection. We believe probabilistic and statistical modeling will continue to play important roles for novel discoveries in the field of cancer genomics and personalized medicine.

Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counseling for families and to a wider understanding of a specific genetic landscape of the tumor for target therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.

Significant strides have been made in our understanding of the genetics of cancer, beginning with the initial identification of oncogenes and tumor suppressor genes and culminating in the genomic profiling of tumors being routinely available in clinical practice. This progress has also led to some remarkable successes in molecularly targeted therapy, with the development of agents that target genetically driven tumor dependencies and vulnerabilities. This chapter will discuss the broad principles underlying targeted therapy and the difficulties that have been encountered, using illustrative examples from a range of cancer types.

The Sleeping Beauty (SB) transposon insertional mutagenesis system offers a streamlined approach to identify genetic drivers of cancer. With a relatively random insertion profile, SB is uniquely positioned for conducting unbiased forward genetic screens. Indeed, SB mouse models of cancer have revealed insights into the genetics of tumorigenesis. In this review, we highlight experiments that have exploited the SB system to interrogate the genetics of cancer in distinct biological contexts. We also propose experimental designs that could further our understanding of the relationship between tumor microenvironment and tumor progression.

Despite considerable progress in understanding the biology and genetics of cancer progression, the development of effective therapies against cancer need physiological and predictive preclinical models. In this context, patient-derived xenograft (PDX) models has become a standard tool as they reproduce accurately the behavior of tumor of origin, in term of histological and molecular phenotype and response to chemotherapy. Although PDXs in vivo models are indispensable for preclinical studies, they suffer from some limitations due to study costs related to tumor maintenance on mice, variable engraftment rate, growth delay and limited throughput for large-scale drug screening. To address this problem and propose a time a cost effective preclinical screening tool, we developed a panel of PDX-derived low-passage 2D cell lines as a convenient in vitro pre-screening platform to profile compound activity. Different PDX models including breast, lung, colon, melanoma, glioblastoma and hepatoblastoma were tested for their capacity to generate cell lines maintaining the characteristics of the parental PDX tumor and usable for in vitro assays. Today, we succeeded with a series of 50 PDX models with 83% success rate. Tumor cells isolated from PDX tumor tissue were cultured under different media and matrix conditions, allowing at least 5 passages in culture. A Short Tandem Repeat (STR) comparison profile was done with the parental PDX before performing a master bank. We performed short term 2D cytotoxicity assays and long term colony assays to compare cell lines in vitro drug sensitivity with their parental PDX in vivo drug response and overall, the results show that this panel reproduced the drug response profile of the original PDXs with chemotherapies, PARP inhibitors, an ADC (T-DM1) and FGFR-targeting therapies. Moreover, cellular models engrafted back onto mice showed in vivo response to chemotherapies similar to that of the parental PDX confirming the identical behavior of cell line/PDX couples. As the use of cellular models is still considered as a standard for early preclinical test to evaluate drug response before moving to in vivo assays, our PDX-derived cell line platform appeared to be a robust and relevant tool. Furthermore, since the main concern when using in vitro models is the representativeness of the results obtained when transposed to in vivo models, the similarities between cell lines and parental PDX should maximize success of further in vivo preclinical drug development. Citation Format: Olivier Deas, Sophie Banis, Kathleen Flosseau, Lea Sinayen, Enora Le Ven, Jean-Gabriel Judde, Stefano Cairo. A preclinical platform of PDX-derived cell lines as a tool for pharmacological screening and functional studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3014.

Dr David Adams speaks to Editor of Oncology Central, Jade Parker: Based at Wellcome Trust Sanger Institute as a senior group leader, David Adams uses DNA sequencing of patients and genetic screens in human cells and mice to identify cancer genes and genetic interactions. The Adams group studies the mechanisms of cancer development, particularly skin cancer (melanoma) and colorectal cancer. They sequence DNA from families with a high incidence of cancer and also tumors from patients to understand why some people are at greater risk of tumor development and how cancers evolve. The group also performs functional studies in cultured cells and in mice to understand how factors such as DNA mutations and the immune system influence tumor growth.

The exact cause of cancer is one of the most immutable medical questions of the century. Cancer as an evolutionary disease must have a purpose and understanding the purpose is more important than decoding the cause. The model of cancer proposed herein, provides a link between the cellular biochemistry and cellular genetics of cancer evolution. We thus call this model as the “Nexus model” of cancer. The Nexus model is an effort to identify the most apparent route to the disease. We have tried to utilize existing cancer literature to identify the most plausible causes of cellular transition in cancer, where the primary cancer-causing agents (physical, chemical or biological) act as inducing factors to produce cellular impeders. These cellular impeders are further linked to the Nexus. The Nexus then generates codes for epigenetics and genetics in cancer development.

Cancer of unknown primary site (CUP) is a fatal cancer diagnosed through metastases at various organs. Little is known about germline genetics of CUP which appears worth of a search in view of reported familial associations in CUP. In the present study, samples from CUP patients were identified from 2 Swedish biobanks and a German clinical trial, totaling 578 CUP patients and 7628 regionally matched controls. Diagnostic data specified the organ where metastases were diagnosed. We carried out a genome-wide association study on CUP cases and controls. In the whole sample set, 6 loci reached an allelic p-value in the range of 10-7 and were supported by data from the three centers. Three associations were located next to non-coding RNA genes. rs2660852 flanked 5'UTR of LTA4H (leukotriene A4 hydrolase), rs477145 was intronic to TIAM1 (T-cell lymphoma invasion and metastases) and rs2835931 was intronic to KCNJ6 (potassium channel, inwardly rectifying subfamily J, member 6). In analysis of subgroups of CUP patients (smokers, non-smokers and CUP with liver metastases) genome-wide significant associations were noted. For patients with liver metastases associations on chromosome 6 and 11, the latter including a cluster of genes DHCR7 and NADSYN1, encoding key enzymes in cholesterol and NAD synthesis, and KRTAP5-7, encoding a keratin associated protein. This first GWAS on CUP provide preliminary evidence that germline genes relating to inflammation (LTA4H), metastatic promotion (TIAM1) in association with lipid metabolic disturbance (chromosome 11 cluster) may contribute to the risk of CUP.

In recent years, partly due to aging populations and partly due to worsening environmental factors, the frequency of cancer has increased significantly. Fortunately, thanks to the modern technological revolution, the end of the twentieth and the first years of the twenty-first centuries witnessed a progress of epical proportions in the molecular biology, immunology and genetics of cancer. This progress was reflected as remarkable advances in diagnosis and treatment of cancer. Yet the definition of “cancer” remained the same for centuries.

The first joint meeting of the International Society for Cellular Oncology (ISCO) and the European Workshop on Cytogenetics and Molecular Genetics of Solid Tumors (EWCMST), organized by Bauke Ylstra, Juan Cigudosa and Nick Gilbert, was held from 4 to 8 March, 2012 in Palma de Mallorca, Spain. This meeting provided a novel and unique opportunity to jointly present the latest updates on the genetics of cancer and its implications for diagnosis, prognosis and therapy, now and in the future. Various aspects were highlighted, including the identification of effective therapeutic targets, the role of cellular senescence in tumor development and therapy, chromosome translocations in leukemias and solid tumors, mechanisms underlying fragile sites and chromosome instability, tumor-associated ‘omics’ landscapes, genetic and epidemiologic risk factors, the role of tissue and cancer stem cells, angiogenesis and the tumor micro-environment, and the epigenetics of cancer. In this report, new insights and clinical advancements related to these various topics are provided, based on information presented at the meeting.

Constitutional (hereditary) genetic variation and somatic genetic alterations acquired during transformation to the neoplastic phenotype are both critical determinants of cancer outcome, and can ultimately have a significant effect on cancer survivorship. This article discusses the role of constitutional and somatic genetics in determining outcome and survivorship following a diagnosis of cancer using illustrative examples primarily from the hematologic malignancies.

An evolutionary perspective can help unify disparate observations and make testable predictions. We consider an evolutionary model in relation to two mechanistic frameworks of cancer biology: multistage carcinogenesis and the hallmarks of cancer. The multistage model predicts that cancer risk increases with body size and longevity; however, this is not observed across species (Peto's paradox), but the paradox is resolved by invoking the evolution of additional genetic mechanisms to suppress cancer in large, long-lived species. It is when cancer cells overcome these defence mechanisms that they exhibit the hallmarks of cancer, driving the ongoing evolution of these defences, which in turn is expected to create the differences observed in the genetics of cancer across species and tissues. To illustrate the utility of an evolutionary model we examined some recently published data linking stem-cell divisions and cancer incidence across a range of tissues and show why the original analysis was faulty, and demonstrate that the data are consistent with a multistage model varying from three to seven mutational hits across different tissues. Finally, we demonstrate how an evolutionary model can both define patterns of inherited (familial) cancer and explain the prevalence of cancer in post-reproductive years, including the dominance of epithelial cancers.

Cancer affects approximately 1 in 3 individuals. An individual's susceptibility to cancer is partly determined by environmental exposures and by the combination of inherited cancer susceptibility and resistance genes. Initial mapping of these low penetrance cancer susceptibility genes has been done in the mouse because human low penetrance genes are extremely difficult to find using traditional methods due to heterogeneity and interacting factors. Also, the choice of candidate genes for human association studies can miss the unknown or unexpected. Mouse models also have limitations; it can be difficult to identify causal polymorphisms in the mouse because linkage disequilibrium often extends across several genes. To exploit the strengths of both systems, we outline a cross-species strategy to identify human variants associated with increased cancer risk. This approach uses linkage analysis and haplotyping, allelic imbalance in tumors, and gene expression studies in the mouse, combined with association studies and tumor imbalance studies in humans to identify causal cancer susceptibility variants. Allelic variants in both mouse and human can then be used to better understand the mechanisms behind cancer risk and as targets for intervention.

The last few decades have seen tremendous advances in the understanding of human genetics, especially since the sequencing of the human genome in 2003. With rectal cancer, as with all cancers, genetics is at the center of its etiology, whether it is associated with an inherited syndrome or a somatic mutation from environmental or other oncogenic factors. Understanding the genetics of cancer has improved the understanding of all aspects of oncology and cancer biology, such as cancer progression and spread, cancer prevention, and cancer treatment, especially considering “personalized medicine” that allows an individual’s cancer “genetic signature” to be used to tailor therapy. Unlike the surgical treatment of rectal cancer addressed in this textbook, there is little unique to rectal cancer relative to colon cancer when discussing cancer genetics and cancer biology. Instead, most of the research and advances in this field have focused on both colon and rectal cancer (CRC) based on their indistinguishable genetic signature [1], and therefore this chapter will focus on the genetics of CRC with particular attention to the impact of genetics on cancer development as well as cancer outcomes and chemotherapeutic treatment. Additionally, CRC screening and chemoprevention options, critical for early detection and prevention efforts and also not often specific to rectal cancer, will be addressed.

Improvements in cancer care have historically been predicated on significant scientific and technological advances, such as antisepsis in surgery, and the discovery of the therapeutic benefits of radiation and chemotherapeutic drugs. The past 30 years have seen an exponential increase in our knowledge of the biology and genetics of cancer, built on a massive and sustained research effort worldwide. Yet over the same period, significant changes in cancer outcomes have occurred largely as a result of public health measures and through incremental advances in existing technologies. The present paper examines the extent to which the new knowledge of cancer genetics has impacted on current patient care. It considers some of the issues that may have served to lessen this impact, as well as some of the reasons for this apparent imbalance between action and outcome.

Metastasis is the most lethal attribute of a cancer. There is a critical need for markers that will accurately distinguish those histologic lesions and disseminated cells that have a high probability of causing clinically important metastatic disease from those cells that will remain indolent. Despite the explosion in new information regarding the genetics of cancer, only six human genes have thus far been shown to functionally suppress metastasis. The present review and perspective describes the evolving view of the mechanisms that regulate metastasis, and the importance of metastasis-suppressor genes in this process. Specifically, the clinical problem of metastatic prostate cancer, the identification of metastatic colonization as a therapeutic target, and the identification and functional characterization of prostate cancer metastasis-suppressor genes are discussed.

Background The etiology of cancer involves a complex series of genetic and environmental conditions. To better represent and study the intricate genetics of cancer onset and progression, we construct a network of biological interactions to search for groups of genes that compose cancer-related modules. Three cancer expression datasets are investigated to prioritize genes and interactions associated with cancer outcomes. Using a graph-based approach to search for communities of phenotype-related genes in microarray data, we find modules of genes associated with cancer phenotypes in a weighted interaction network. Results We implement Walktrap, a random-walk-based community detection algorithm, to identify biological modules predisposing to tumor growth in 22 hepatocellular carcinoma samples (GSE14520), adenoma development in 32 colorectal cancer samples (GSE8671), and prognosis in 198 breast cancer patients (GSE7390). For each study, we find the best scoring partitions under a maximum cluster size of 200 nodes. Significant modules highlight groups of genes that are functionally related to cancer and show promise as therapeutic targets; these include interactions among transcription factors (SPIB, RPS6KA2 and RPS6KA6), cell-cycle regulatory genes (BRSK1, WEE1 and CDC25C), modulators of the cell-cycle and proliferation (CBLC and IRS2) and genes that regulate and participate in the map-kinase pathway (MAPK9, DUSP1, DUSP9, RIPK2). To assess the performance of Walktrap to find genomic modules (Walktrap-GM), we evaluate our results against other tools recently developed to discover disease modules in biological networks. Compared with other highly cited module-finding tools, jActiveModules and Matisse, Walktrap-GM shows strong performance in the discovery of modules enriched with known cancer genes. Conclusions These results demonstrate that the Walktrap-GM algorithm identifies modules significantly enriched with cancer genes, their joint effects and promising candidate genes. The approach performs well when evaluated against similar tools and smaller overall module size allows for more specific functional annotation and facilitates the interpretation of these modules.

Cancer is a disease of aberrant gene expression. While the genetic causes of cancer have been intensively studied, it is becoming evident that a large proportion of cancer susceptibility cannot be attributed to variation in protein-coding sequences. This is highlighted by genome-wide association studies in cancer that reveal that more than 80% of cancer-associated SNPs occur in noncoding regions of the genome. In this review, we posit that a significant fraction of the genetic aetiology of cancer is exacted by noncoding regulatory sequences, particularly by long noncoding RNAs (lncRNAs). Recent studies indicate that several cancer risk loci are transcribed into lncRNAs and these transcripts play key roles in tumorigenesis. We discuss the epigenetic and other mechanisms through which lncRNAs function and how they contribute to each stage of cancer progression, understanding of which will be crucial for realising new opportunities in cancer diagnosis and treatment. Long noncoding RNAs play important roles in almost every aspect of cell biology from nuclear organisation and epigenetic regulation to post-transcriptional regulation and splicing, and we link these processes to the hallmarks and genetics of cancer. Finally, we highlight recent progress and future potential in the application of lncRNAs as therapeutic targets and diagnostic markers.

Thirty‐one seminars have been held in the 16 years since 1981. A principal interest from the beginning was the genetics of cancer, well before this subject became widely popular. This interest arose in part because of marked binational differences in type‐specific cancer rates, such as the very low rates among Japanese for Hodgkin's disease in the young, testicular cancer, Ewing's sarcoma, superficial spreading melanoma, chronic lymphocytic leukemia, and Wilms’ tumor (half the U.S. frequency). Three seminars were devoted to the seeming reciprocal relationship between B‐cell lymphoma (low in Japan) and certain autoimmune diseases (high in Japan), which is perhaps similar in origin to the male/female differences in the rates for these diseases. A seminar on Li‐Fraumeni syndrome led to the recognition of cases among Japanese pedigrees brought to the meeting, and generated a study of its occurrence in Japanese families with adrenocortical carcinoma in a child. Another seminar revealed a marked clustering of rare cancers in Werner's (premature aging) syndrome in Japan, and led to a binational study and analysis of case‐reports worldwide. Three seminars on pathology heightened appreciation of the importance of subclassifying cancer by subsite and subtype for racial and other comparisons. Four seminars on biostatistics in cancer research generated a substantial exchange of specialists and trainees in this field.

In the past forty to fifty years, clever scientific insight and innovation has rapidly advanced our understanding of the molecular mechanisms of cancer biology . The discoveries of oncogenes and tumor suppressors and the elucidation of their functions has greatly aided our understanding of the molecular etiology of primary tumors. In the last decade, there has been an explosion in the technology available to scientists to study the genetics of cancer cells at several different levels. It is now possible to study a particular cancer at the whole genome , transcriptome, and proteome levels. This vast increase in available information has led to significant advancements in our understanding of the genetic variations and mutations, which can drive the development of a primary tumor in patients.

The laboratory mouse is the premier model organism for understanding the genetic basis of human cancer and is a powerful platform for investigating novel targets for therapeutic intervention. Research using genetically engineered mouse models has led to key insights into the genetics of cancer susceptibility, the function of tumor suppressors and oncogenes, and therapy responses in pre-clinical and co-clinical studies. Patient Derived Xenografts (PDX) models are another model system for in vivo cancer studies. PDX models are created by implanting patient tumors into immunodeficient or humanized mouse hosts. PDX models are a powerful translational research platform for pre-clinical and co-clinical studies. The number of mouse models and the volume and heterogeneity of data related to the characterization of these models has increased dramatically in recent years, making integrated searches of these data and identifying relevant models a significant barrier to their effective use. The Mouse Tumor Biology database (MTB) (http://tumor.informatics.jax.org) provides on-line query tools to facilitate cohesive searches and visualization of these varied data, thus enabling the identification of novel mouse models of human cancer and potential therapeutic treatments. The Mouse Tumor Biology database is an expertly curated resource for information and data about genetically modified mouse strains and PDX models of human cancer. Enforcement of standard gene and strain nomenclature and use of controlled vocabularies within MTB enables complete and accurate searching of the published literature for relevant mouse models. MTB contains data from spontaneous or endogenously induced tumors from genetically defined mice including tumor classification, incidence and latency, tumor associated QTLs, pathology reports, images and genetic changes in the tumor (somatic) and background strain (germline) genomes. The PDX resource enables searches based on tumor type, cancer diagnosis, and genomic properties of the engrafted tumors. Information in MTB is obtained from curation of peer-reviewed scientific publications and from direct data submissions from individual investigators and large-scale programs. MTB contains over 71,000 Tumor Frequencies, and over 2,080 Pathology Reports with over 5,800 images from over 3,600 references. MTB also provides access to detailed clinical, pathological, expression and genomics data from over 450 PDX models. Information in MTB is integrated with cancer models data from other bioinformatics resources including PathBase, the Gene Expression Omnibus (GEO), and ArrayExpress. MTB is supported by NCI grant CA089713. Citation Format: Dale A. Begley, Debbie M. Krupke, Steven B. Neuhauser, Joel E. Richardson, John P. Sundberg, Janan T. Eppig, Carol J. Bult. The mouse tumor biology database (MTB): An integrated data resource for mouse and patient derived xenograft (PDX) models of human cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 631.

The heritability of cancers is usually affected by complex interactions between carcinogens and the host's genome. New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and micro RNAs are increasingly recognized as important events. Chemotherapeutic drugs interfere with cell division in different ways, e.g. with the duplication of DNA or the separation of newly formed chromosomes. Most forms of chemotherapy target rapidly dividing cells and are not specific for cancer cells, although some degree of specificity may come from the inability of many cancer cells to repair DNA damage. Hence, chemotherapy has the potential to harm healthy tissues, especially those tissues that have a high replacement rate (e.g. intestinal lining). These cells usually repair themselves after chemotherapy.[1] DNA has long been considered a favored target for cancer chemotherapeutic agents. Indeed many of the most effective clinical agents, such as alkylating and interactive agents, are DNA interactive. Achieving the desired sequence specificity with DNA-interactive agents is considered to be one of the most formidable hurdles in the development of new agents to achieve therapeutic invention.[2]

In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual's relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone into identifying the genes that are mutated in tumorigenesis with the over-whelming majority of genetically-modified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of ‘resisting’ cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM mice that show some form of ‘resistance’ to cancer. Identification of mice with increased resistance to cancer is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In this review we describe the different mouse lines that display a ‘cancer resistance’ phenotype and discuss the molecular basis of their resistance.

Cancer is a large group of diseases that result when cells divide out of control and acquire the ability to spread beyond their prescribed borders. Cancer is a genetic disease because it is caused by mutations, but it is rarely inherited because these mutations occur, in most cases, in somatic cells rather than in germ cells. Cancer affects one in three people during their lifetime and is the second leading cause of death in the United States. In women, the most common and most lethal cancers originate in the lung, breast, and colon. In men, cancers of the lung, prostate, and colon predominate. In sharp contrast to cancer, also called a malignant tumor, a benign tumor is defined as a collection of cells that grows out of control but does not spread into surrounding tissues.

Lung cancer and head and neck cancer have similar genotoxic risk factors. While the vast majority of lung cancers are caused by cigarette smoking alone, smoking together with heavy drinking are the major etiological agents of head and neck cancer. In addition, human papilloma virus (HPV) has been identified as an important causative factor of tonsillar carcinomas. In contrast, chromosomal instability and aneuploidy identifiable by DNA measurement are predominately associated with cancer progression. This selective review summarizes our studies that aimed to gain a better understanding of the biology and pathology of lung cancer and head and neck cancer. In particular, it was attempted (a) to develop a microscopy-based tumor classification system that provides insight into the genetics of cancer cells and in particular their DNA ploidy, (b) to apply this classification system to lung cancer and head and neck cancer and to correlate it with clinicopathological parameters and molecular biomarkers, and (c) to analyze molecular characteristics and in particular the presence of human papilloma virus in lung cancer and head and neck cancer. Therefore, we developed a core classification based on the semi-quantitative assessment of the size and type of tumor cell nuclei and mitoses. It was found that (1) nuclear and mitosis size correlated with the DNA content of the tumor cells, (2) tripolar mitoses were indicative of cancer with near-triploid DNA content, (3) morphological and DNA parameters indicating variability of the cancer genome were associated with poor prognosis of lung cancer patients, (4) HPV-positive head and neck squamous cell carcinomas were characterized by smaller tumor nuclei and reduced DNA amount compared to HPV-negative carcinomas, and (5) HPV is associated with lung cancer in certain geographical regions of the world.

The development of human cancer is generally considered to be the result of genetic mutations that cause a progressively more malignant phenotype. We propose that such genetic changes can be observed in a small number of lymphocytic metaphase plates. We have identified a specific chromosome marker formation in a primary endometrial adenocarcinoma obtained from a 74-year-old woman. After observing an isochromosome for 1q in the tumor cells, we predicted that in her lymphocytes this particular chromosome must show susceptibility to breakage. After 6 months, when lymphocytes were available from this patient, 4.0% of her metaphases exhibited chromatid breaks in the pericentromeric region of one homolog of chromosome 1, thus confirming our prediction. Since then, the primary endometrial tumor cell line has been passaged through nude mice and has become highly metastatic. Examination of tumors obtained from different organ sites of these mice has revealed that the same altered homolog 1 underwent various types of chromosome and chromatid aberrations, thereby confirming the presence of instability in this particular chromosome in this particular cancer. A detailed karyotypic evolution from normal lymphocyte cultures --> primary endometrial tumor --> highly metastatic endometrial tumor was therefore possible to construct. Our results further support the idea that peripheral blood lymphocytes can be used as the tissue for studying genetics of cancer predisposition.

Two of three humans never get cancer. Even the majority of heavy smokers remain cancer free. Is this a matter of chance, or are there cancer-resistant genotypes? Based on the evidence discussed, it would appear that evolution has favored a limited number of relatively common resistance genes that may nip incipient cancerous foci in the bud, i.e., to stop them at their inception. It is further suggested that resistance genes may act at the level of tissue organization in a dominant fashion.

The concept that cancer is a multi-step process caused by genetically- and epigenetically-determined abnormal gene function is now well established. Gain-of-function or loss-of-function changes affect a number of genes that control cellular processes such as cell cycle, apoptosis and differentiation and that consequently behave as oncogenes or tumor suppressors, respectively. It is also well established that several genetic hits are required to trigger cell transformation and malignant progression of cancer, in which the altered functions of each oncogene or tumor suppressor contribute, in a coordinated way, to compose the complex network of the cancer phenotypic traits [1, 2]. Elucidating how such gene function diversity is generated during the tumorigenic events is an unanswered question. Although tremendous advances in knowledge have occurred in recent years, there is still no clear understanding in this field.

This study extends our previous work on the genetics of recurrent spontaneous abortion and of gestational trophoblastic tumors in an ethnically homogeneous population of Chinese in Taiwan by comparing the prevalence of recurrent spontaneous abortions, cancer, and congenital anomalies in the first-, second-, and third-degree relatives of the index couples to that of normally fertile couples from the same population. The rationale for this study was to provide another test for our hypothesis that genes linked to the major histocompatibility complex are responsible for the diseases in the index couples. If they are, these genes should segregate with a higher frequency in the relatives of the index couples than in the relatives of normally fertile couples and lead to a higher prevalence of these diseases in the extended families. Such a difference was found and adds support to our hypothesis that major histocompatibility complex-linked genes affect growth, development, and susceptibility to cancer.

Biologists have tracked the origins and evolution of a type of childhood leukaemia that is deadliest when it recurs.

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 high- level 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. The approach to studying the genetic basis of cancer is undergoing a revolution. Rather than focusing on individual genes, scientists are now exploring substantial components of the expressed genome. The wealth of molecular information being generated from the laboratory as well as the volume of data being stored in the patient record is continuing to increase at an astounding rate. Finding new ways to integrate these data has been crucial to developing novel insights into the genetics of cancer. Thus bioinformatics, which is the convergence of biology, information science, and computation is continuing to emerge as a crucial component of cancer biology research.

Research in the ISG group is supported partially by FEDER and by MEC (SAF2006-03, 726 and PETRI N◦ 95–0913.OP), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), and CDTEAM project. C.C. is a “Ramon y Cajal” investigator from Ministerio de Educacion y Ciencia, Spain. Research in C.C.’s laboratory is supported partially by FIS (PI04/0261), Junta de Castilla y León (SA087A06), and Fundación de Investigación MMA.

The cancer is global and undoubtedly one of the major causes of mortality and morbidity irrespective of geographic and ethnic origin. It equally applies to people living across the Indian subcontinent and as well as among those originating from various countries of the subcontinent (Kamath et al., 1999; Winter et al.,1999). It is estimated that 75,000 new breast cancer cases occur in Indian women every year (Chopra, 2001). However, its full appreciation and implications on health and living are underestimated due to overwhelming burden of environmentally related diseases in the Indian subcontinent, such as malnutrition, infection and pollution (Chopra, 2001). Smoking and chronic exposure to toxic substances is attributed to some cancers. An alarming excess of oral cancer is a good example, probably related to the social habit of tobacco chewing.

Cancer is characterized by unrestrained proliferation and loss of organization, a process that is intimately linked to, and controlled by, reciprocal signaling between the genetically altered tumor epithelium, the stroma, the components of the basement membrane and inflammatory mediators. Much work has been done to characterize the genetics of cancer cells. In this review, we describe the experiments that have been performed, which point to the significant role of the tissue microenvironment in the developmental regulation of normal and neoplastic cells. Using a variety of model systems, the works of a number of laboratories have converged on a hypothesis where the correction of 1 or 2 signaling defects can revert tumor cells to a normal phenotype, both in vivo and in culture, even when the tumor cells possess multiple genetic and epigenetic lesions. This paradigm has been successfully used to treat acute promyelocytic leukemia, and it remains the task of biomedical researchers to identify additional targets for the reversion of other human malignancies.

Genetically-engineered mouse models offer controlled and reproducible systems in which to study the genetics of cancer development. We have used massively-parallel sequencing to provide a comprehensive analysis of the step-wise progression of cancer in the highly tractable Eμ-Myc mouse model. The Eμ-Myc mouse has been engineered to harbor a t(8;14) translocation juxtaposing the IgH enhancer to the proto-oncogene Myc, a lesion frequently observed in mature B-cell malignancies. Eμ-Myc mice develop spontaneous Burkitt-like B-cell leukemia/lymphoma with 100% penetrance through predicable premalignant to malignant progression phases. Malignant progression ostensibly occurs as a result of secondary somatic mutations that co-operate with Myc. Despite common perception that the majority of tumors can be explained by disruption of the archetypal Cdkn2a and Trp53 tumor suppressor axis, in more than half of spontaneous Eμ-Myc tumors harbor secondary mutations that remain unknown. We hypothesize that the identification of genes that cooperate with Myc could therefore yield not only new biological insight into oncogenic pathways involved in B-cell lymphomagenesis but also improve therapy for patients in the future. We applied exome-sequencing to a cohort of 18 spontaneous murine Eμ-Myc lymphomas to determine novel somatic driver mutations capable of cooperating with Myc. In addition to exome-sequencing, we harvested blood samples at 2-week intervals throughout the premalignant to malignant phases to allow a temporal analysis of mutations that were detected at end-stage. End-stage tumors were found to be heterogeneous in nature, ranging from 11 to 36 single-base mutations, deletions or insertions. The screen identified genes previously described to be mutated in Eμ-Myc lymphoma (Trp53, Cdkn2a, Kras and Nras). Interestingly, concurrent mutations in known cancer genes were evident in clonal tumors from the sequenced cohort with, for example, a Cdkn2a deletion co-occurring with an activating Kras mutation. In addition to these mutations, we identified novel protein-truncating mutations in Bcl6 co-repressor (Bcor), which has not previously been described in Eμ-Myc lymphoma. Bcor truncating mutations were present at a high frequency, occurring in 3 out of 18 samples. RNAi mediated knockdown of Bcor in Eμ-Myc fetal liver hematopoietic stem cells reconstituted into lethally irradiated congenic recipient mice accelerated lymphomagenesis, validating Bcor as a tumor suppressor gene in this model. BCOR loss-of-function mutations have recently been identified in human cancers suggesting that BCOR acts as a tumor-suppressor in a wide range of malignancies. Given that Bcor mutations frequently occur in the Eμ-Myc lymphoma, we hypothesize that Bcor is critically important for B-cell development and that its disruption can induce malignancy in co-operation with other potent oncogenes such as Myc. Citation Format: Marcus P. Lefebure, Richard Tothill, Jason Li, Geoff Matthews, Jake Shortt, Edwin Hawkins, Elizabeth Kruse, Maria Doyle, Gretchen Poortinga, Ross Hannan, Vivian Bardwell, Micah Gearhart, Ricky W. Johnstone. Exome sequencing reveals Bcl6 co-repressor (Bcor) as a frequently mutated tumor suppressor gene in Eμ-Myc lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 449. doi:10.1158/1538-7445.AM2014-449

Despite advances in our knowledge of genetics of cancer and some progress in cancer treatment over the last few decades, lung cancer remains the leading cause of cancer mortality worldwide. Recently cancer metabolomics have been widely applied into cancer research, including of cancer diagnosis and therapy. Our recent work has identified tumor initiating cells (TICs) derived from non-small cell lung cancer (NSCLC) patients and shown that metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in NSCLC. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients. Those findings provide potential diagnostic markers and/or therapeutic target for NSCLC. Locked nucleic acids (LNAs) are novel high-affinity DNA analogs that can be used as genotype-specific drugs. In this study we tested NSCLC patient-derived xenograft tumor growth inhibition by GLDC LNAs antisense oligonucleotides. These LNAs antisense oligonucleotides strongly reduce GLDC protein levels. The osmotic minipumps were filled with GLDC LNAs antisense oligonucleotides at 0.5,1 and 5 mg/kg/day dose and implanted dorsally into tumor-bearing NOD/SCID Il2rγ-/- mice. Tumor growth was inhibited at dosages from 1 mg/kg/day. LNAs antisense oligonucleotides appeared to be non-toxic at dosages of 5 mg/kg/day. Furthermore, we found significant changes of serum metabolomics in lung cancer patients compared to normal donors. Our data show that GLDC LNAs antisense oligonucleotides are potent genotype-specific drugs that can inhibit lung tumor growth in vivo. Note: This abstract was not presented at the meeting. Citation Format: Wen Cai Zhang, Bing Lim. Targeting metabolic enzyme with locked nucleic acids in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1438. doi:10.1158/1538-7445.AM2014-1438

Cellular responses to anti-cancer agents result from the interaction between drugs, cellular targets and mechanisms of damage repair. Despite the pharmacological advances in the treatment of cancer, the clinical efficacy of chemotherapy is unpredictable in most patients. However, new information on the genetics of cancer delineates strategies by which the genetic background of tumour cells and patients might be profiled to select anti-cancer agents with improved efficacy and tolerability. This article focuses on the application of pharmacogenetics in the characterization of differences in the pharmacokinetics and pharmacodynamics of anti-cancer agents among individuals to define the likelihood of response and reduce the incidence of adverse effects.

Cancer development is a multistep process that involves both the activation of protooncogenes and the inactivation of tumor suppressor genes. Furthermore, both epidemiological and experimental data indicate that a third class of genes, tumor susceptibility genes, control the propensity to develop carcinogen-induced tumors. Recent studies suggest that tumor susceptibility is determined by the combined effect of both sensitivity and resistance genes. The mouse skin model of multistage carcinogenesis is an excellent paradigm in which to study the genetics of cancer susceptibility. This is particularly true with regard to tumor promotion, a process that occurs in other organs and species including humans. We have studied the genetics of tumor promotion susceptibility in the mouse two-stage skin tumor model using crosses between sensitive DBA/2 or C3H and resistant C57BL/6 mice. Our results suggest that TPA promotion susceptibility is a multigenic trait. We have tentatively mapped one tumor susceptibility locus, Psl1, to mouse chromosome 9 and are currently identifying and characterizing candidate tumor susceptibility genes that map to this chromosomal region. The multistage model of carcinogenesis in mouse skin has, for more than 50 years, provided a conceptual framework from which to study the carcinogenesis process. Many concepts now currently applied to other tissues and model systems were originally derived from the mouse skin model. Because tumor promotion is an important component of carcinogenesis in humans, the identification of genes that modify response to tumor-promoting stimuli would be a significant advancement in our understanding of the genetic basis of susceptibility to cancer.

The genetic basis of many hereditary cancer susceptibility syndromes is now well established. In contrast to the diseases that exhibit classic mendelian inheritance and are caused by alterations in single genes, hereditary cancer is more complex. Besides a germline mutation in a cancer-predisposing gene, additional somatic mutations in cancer related genes are required to develop the disease phenotype. The rate at which they are acquired is influenced by environmental factors and the efficiency of cellular protective activities. The inheritance of a single altered cancer-predisposing allele is sufficient to place the carrier at much higher risk of the disease compared with the general population. Thus, cancers with hereditary background are characterized by a much earlier average age of onset, usually occurring 15 to 20 years earlier than sporadic cancers. It is anticipated that most forms of cancer have a hereditary subgroup, which can be as high as 40% in hereditary retinoblastoma. In most adult tumours the estimated hereditary fraction is much smaller, about 10% or less. Inherited cancers give, however, valuable information about genetics of cancer in general.

Despite considerable efforts in understanding the biology and genetics of cancer, most currently available treatments fail to achieve tumor eradication in the majority of patients. Key to more effective therapies is adequate disease classification and subsequent patient stratification. In addition, it is important to understand the mechanisms of drug-response or resistance and identify novel targets amenable to therapeutic intervention. It is increasingly recognized that at the preclinical stage, testing therapeutic strategies and validating target relevance in more predictive models closely mimicking clinical disease such as patient derived xenografts (PDXs), may translate into improved clinical efficacy and lower rate of drug attrition. XenTech collection of over 120 runing PDX models is one of the largest in the world. PDX models were established by grafting post-surgery human tumor fragments in the interscapular region of immunodeficient mice. These deeply characterized PDX models can be used for in vivo preclinical assays. Such preclinical platform is a reliable surrogate of patient cohorts and can address several aims: 1. Evaluate tumor response to treatment. PDXs can be subjected to parallel evaluation of tumor response to various treatment protocols. Drug-response profile is linked to tumor histotype and molecular features in order to identify predictive markers of drug response to assist treatment choice. 2. Assess treatment-driven tumor eradication. The ability of a treatment to induce complete tumor response is assessed by monitoring tumor regression over a long period. Most tumors, despite complete macroscopic regression, are still present as latent microscopic nodular islands that may give rise to tumor recurrence. Molecular characterization of tumor foci responsible for tumor relapse may be performed to identify genes/pathways involved in residual tumor cell survival, which may provide new diagnostic and/or therapeutic targets for designing novel adjuvant treatment strategies. 3. Development of bioluminescent metastatic models to study the mechanisms of tumor invasion and to test anti-metastatic therapy. 4. Non-invasive molecular imaging technology to monitor tumor metabolism, vascularization and apoptosis. 5. Constitution of preclinical panels of rare malignancies to obtain phase II-like tumor cohorts. Development of new therapies for rare tumors is rendered difficult by the unavailability of patient cohorts wide enough to set up robust clinical trials. To assist the clinical need, these panels would allow the evaluation of new and more efficient therapies. We describe here in detail our PDX collection and illustrate how it represents a powerful tool to identify preferential therapeutic options for patients by exploring and improving anti-cancer therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5273. doi:1538-7445.AM2012-5273

The development of human cancer is a multistep process that entails a progressively more malignant phenotype through the evolution of cellular subsets with increasing numbers of genetic alterations. Here we review the molecular genetics of human cancer predisposition and progression and describe paradigmatic cancer types and cancer syndromes. We also briefly consider the future impact of molecular biology on cancer diagnosis and treatment.

Cancer is considered to be a multifactorial disease in which a host cell is transformed from normal to malignant as a result of complex interactions of external (environmental) stimuli and cancer-predisposing or cancer-suppressing genes. Although certain chemical carcinogens and ionizing radiation are known to cause specific alterations at the level of the gene, other correlations are less clear. Not infrequently, cancer is found to aggregate in families in an apparently nonrandom fashion. It has been through the study of such families that our understanding of the genetic events leading to cancer has developed. Both common and rare tumors may occur together in familial-cancer families. Frequently, tumors occur at an earlier age than one would expect in the general population; often, multiple tumors of different organs develop in a particular affected family member. Recent advances in the genetics of familial cancer syndromes have led to the possibility to perform genetic testing on unaffected relatives who might carry a genetic defect that predisposes them to cancer. Complex ethical, social, and legal implications arise from these new technical advances.

RECENT advances in the genetics of cancer have raised the possibility of widespread DNA testing for the detection of predisposition to cancer. This may allow individuals at high risk to avail themselves of preventive measures and potentially avoid early death. At least one company has already announced plans to begin offering testing for genetic cancer risk. While much alleviation of human suffering may eventually result from these advances in cancer genetics, a number of important questions must be addressed before widespread testing of this sort can be recommended. Two relatively common heritable cancer risk genes have recently been located. Among people with colon cancer, it appears that as many as 10% carry an altered germline copy of a gene called MSH2 . 1-3 Individuals with an altered MSH2 gene face an approximately 80% risk of colon cancer; women also have an elevated risk of endometrial and ovarian cancer. Intense medical surveillance

While the incidence of cancer is increasing among both children and adults, mortality rates have decreased for children, while they have increased for adults. Of children diagnosed with cancer today, 80% are predicted to be long-term survivors. Although there are differences between children and adults with respect to the tumor types, biology, and outcome, there are common lessons which we can learn from our children regarding the genetics of cancer, its management and treatment, and the importance of longitudinal studies of the survivors. Specific pediatric cancers, such as retinoblastoma, have led to the recognition of tumor suppressor genes, now also observed among adult tumors including sarcomas, breast, lung, and bladder cancer. The presence of the tumor suppressor gene provides an understanding for the incidence of second malignant tumors among patients with heritable diseases. Furthermore, cancer prone families, such as those with the Li-Fraumeni syndrome, also carry the p 53 tumor suppressor gene; the presence of which greatly increases the risk of developing invasive cancer. Childhood cancer is rare; it represents only 1% of the total US cancer problem. However, 53% of all children with cancer, but only 2% of all adults, are studied via the NCI cooperative group mechanism. For some specific childhood tumors such as rhabdomyosarcoma and Wilms' tumor, as many as 70-85% of all cases are managed via NCI sponsored trials. Essentially all pediatric cancer is treated by interdigitating radiation with surgical resection and systemic chemotherapy. This approach has contributed to high cure rates. Finally, our understanding of the late effects of being a cancer survivor have come from longitudinal studies of children. The most severe long-term effects related to radiation in childhood pertain to growth and development, infertility, and second malignant tumor induction. Here the children treated for Hodgkin's disease have taught us the dose and volume effects on axial skeletal and soft tissue growth. Infertility issues are also treatment-related and may often be obviated by using gonadal shielding. The risk of secondary leukemia is related to dose and class of specific chemotherapeutic agents administered; it is 5.5% among children receiving 6 cycles of MOPP. There is a 22-fold risk at 30 years of age of solid tumor induction following radiotherapy for children with Hodgkin's disease. These serious concerns have been offset by current therapeutic approaches of using lower doses and smaller volumes of radiation with fewer cycles of less toxic chemotherapeutic agents. Childhood cancer ranks high among number of person-years of potential life saved annually.(ABSTRACT TRUNCATED AT 400 WORDS)

As the process of tumor progression proceeds from the normal cellular state to a preneoplastic condition and finally to the fully invasive form, the molecular characteristics of the cell change as well. These characteristics can be considered a molecular fingerprint of the cell at each stage of progression and, analogous to fingerprinting a criminal, can be used as markers of the progression process. Based on this premise, the Cancer Genome Anatomy Project was initiated with the broad goal of determining the comprehensive molecular characterization of normal, premalignant, and malignant tumor cells, thus making a reality the identification of all major cellular mechanisms leading to tumor initiation and progression ([Strausberg, R.L., Dahl, C.A., and Klausner, R.D. (1997). “New opportunities for uncovering the molecular basis of cancer.” Nat. Genet., 16: 415-516.], www.ncbi.nlm.nih.gov/ncicgap/ ). The expectation of determining the genetic fingerprints of cancer progression will allow for 1) correlation of disease progression with therapeutic outcome; 2) improved evaluation of disease treatment; 3) stimulation of novel approaches to prevention, detection, and therapy; and 4) enhanced diagnostic tools for clinical applications. Whereas acquiring the comprehensive molecular analysis of cancer progression may take years, results from initial, short-term goals are currently being realized and are proving very fruitful.