Principles Of Cancer Genetics Pdf

[Idara Viengxay]

Thisis the second edition of a widely used textbook that consolidates the basic concepts of the cancer gene theory and provides a framework for understanding the genetic basis of cancer. Particular attention is devoted to the origins of the mutations that cause cancer, and the application of evolutionary theory to explain how the cell clones that harbor cancer genes tend to expand. Focused on the altered genes and pathways that cause the growth of the most common tumors, Principles of Cancer Genetics is aimed at advanced undergraduates who have completed introductory coursework in genetics, biology and biochemistry, medical students and medical house staff. For students with a general interest in cancer, this book provides a highly accessible and readable overview. For more advanced students contemplating future study in the field of oncology and cancer research, this concise book will be useful as a primer.

Fred Bunz, M.D., Ph.D is a native of Long Beach, New York. He attended Stony Brook University and graduated from its Medical Scientist Training Program. His doctoral research in the enzymology of human DNA replication was conducted at Cold Spring Harbor Laboratory. Dr. Bunz completed a postdoctoral fellowship in Cancer Genetics at The Johns Hopkins University and the Howard Hughes Medical Institute, and now heads a laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins that is focused on understanding the effects of DNA damage on cancer cells and normal cells. He lives in Baltimore with his wife, two children, a cat, and an Old English Sheepdog.

Particular attention is devoted to the origins of cancer and the application of evolutionary theory to explain how mutant cell populations tend to expand and spread. Focused on the genes and signaling pathways involved in the most common tumors, Principles of Cancer Genetics is a highly readable account that will be of interest to anyone who would like to attain a basic understanding of cancer biology. Students who have completed introductory coursework in genetics, biology and biochemistry, medical students and medical house staff will find this book to be a useful starting point toward mastery of this complex but fascinating topic. This updated edition delves into the critical interactions between growing tumors and the immune system, and introduces the concepts of T cell activation, immunoediting and immune evasion. Novel strategies for cancer diagnosis and prognosis, including new roles for next-generation sequencing and liquid biopsies, as well as established and emerging therapeutic modalities are now described in detail.

For laypersons, students and researchers in other fields with a general interest in cancer, this book provides an accessible overview, enriched with many easy-to-understand illustrations. For advanced students considering future study in the field of oncology and cancer research, this concise book is a useful guide to the basic principles that underlie our understanding of cancer.

Fred Bunz, M.D., Ph.D is a research scientist, lecturer and author at the Johns Hopkins School of Medicine. A native of Long Beach, New York, Dr. Bunz attended Stony Brook University and received training in cancer genetics at Cold Spring Harbor Laboratory and Johns Hopkins University, which he joined as a fellow of the Howard Hughes Medical Institute. Dr. Bunz currently heads a laboratory at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins that investigates the effects of DNA damage and pathogens on cancer cells and normal cells. He lives in Baltimore with his family.

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Metastasis is the hallmark of cancer that is responsible for the greatest number of cancer-related deaths. Yet, it remains poorly understood. The continuous evolution of cancer biology research and the emergence of new paradigms in the study of metastasis have revealed some of the molecular underpinnings of this dissemination process. The invading tumor cell, on its way to the target site, interacts with other proteins and cells. Recognition of these interactions improved the understanding of some of the biological principles of the metastatic cell that govern its mobility and plasticity. Communication with the tumor microenvironment allows invading cancer cells to overcome stromal challenges, settle, and colonize. These characteristics of cancer cells are driven by genetic and epigenetic modifications within the tumor cell itself and its microenvironment. Establishing the biological mechanisms of the metastatic process is crucial in finding open therapeutic windows for successful interventions. In this review, the authors explore the recent advancements in the field of metastasis and highlight the latest insights that contribute to shaping this hallmark of cancer.

Recently, it has become broadly understood that the EMT program is a spectrum of transitional stages between the epithelial and mesenchymal phenotypes, in contrast to a progression that involves a binary choice between full-epithelial and full-mesenchymal phenotypes.15 The transition of one state to another is governed by a number of growth factors16 and signaling pathways.17 Spontaneous EMT in primary tumor cells shifts between different intermediate stages with different invasive, metastatic, and differentiation characteristics.18 Tumor cells that express a mix of epithelial and mesenchymal phenotypes are more effective in circulation, colonization at the secondary site, and the development of metastasis.18 Moreover, transcriptional, chromatin, and single-cell RNA sequencing show that the various stages possess diverse cellular characteristics, chromatin landscapes, and gene expression signatures that are regulated by common and distinct transcription factors and signaling pathways. Moreover, the various EMT stages are situated in diverse microenvironments and are in contact with diverse stromal cells.18 For example, metastatic cells with the most pronounced mesenchymal phenotype proliferate near endothelial and inflammatory cells. These tumor cells release large quantities of chemokines and proteins to attract immune cells and stimulate angiogenesis, thus promoting the development of a unique inflammatory and highly vascularized niche.18 Cancer-associated fibroblasts have also been shown to drive and direct cancer cell migration through fibronectin alignment.19 In addition, hypoxia,20 metabolic stressors, and matrix stiffness21 trigger the EMT program in cancer cells. Transitioning is often driven by transcription factors that are programmed to repress epithelial genes and activate mesenchymal genes.22 Epigenetic and posttranslational modulators also play a vital role in controlling the EMT process.15

In recent years, there has been an important debate on whether EMT has a central role in cancer metastasis and resistance to chemotherapy.17,23,24,25 Research in lung and pancreatic cancers shows that even though EMT might not be essential for metastasis, it does contribute to chemoresistance.23,24 Nevertheless, more evidence is needed to completely and clearly elucidate the role of EMT in cancer progression and the metastatic process.

Markers that predict metastatic progression showed that advanced cancers arise from diverse cell types, which deeply affects the eventual genetic and epigenetic alterations that promote metastatic progression.33 Metastatic small cell lung cancer (SCLC) cells differed in the genes that they expressed.33 This might explain why some cancer cells respond to treatment, whereas others do not. As such, understanding intertumoral heterogeneity among different cancers can reveal the mechanisms of metastatic progression and how the cell type of origin contributes to tumor development. In colorectal cancer, cells expressing L1 cell adhesion molecule (L1CAM) confer metastasis-initiating abilities and chemoresistance. L1CAM hijacks the regenerative capacity of intestinal cells to promote metastasis.34 In addition, the cytotoxic immune signature and the presence of lymphatic vessels play an important role in the generation of distant metastases, regardless of genomic instability.35

Metabolic differences among cancer cells lead to differences in metastatic potential. Metastatic cancer cells depend on monocarboxylate transporter 1 (MCT1) to deal with oxidative stress. MCT1 plays a major role in circulating lactate, which is a prominent energy source for metastasizing cells.46 As such, highly metastatic cells have increased levels of MCT1, whereas the inhibition of MCT1 decreases lactate uptake by metastatic cells and, thus, reduces their metastatic capability.46

Changes in ATP/ADP and ATP/AMP ratios also promote metastatic behavior. In pancreatic ductal adenocarcinoma, ECM remodeling through cellular adhesion and compression affects these ratios.47 Metabolomics shows that such alterations increase phosphocreatine production, which has a role in the invasive migration, chemotaxis, and liver metastasis of cancer cells.47

Secondary sites do not receive invading cancer cells passively. In fact, the host microenvironment, termed the premetastatic niche (PMN), is selectively primed by the primary tumor even before the initiation of metastasis.48 The development of a PMN is a multistep process involving secretory factors and extracellular vesicles that induce vascular leakage, ECM remodeling, and immunosuppression.48 High-definition microscopes have obtained images of cancer cells sharing biological material with less malignant cells, making these cells more cancerous.49 Cancer cells release vesicles that carry messenger RNA transcribed from genes that are involved in cell migration and metastasis, which are then accepted by other cells.49,50 After host cells engulf these vesicles, human cells that did not express a malignant phenotype start to migrate faster. The transferred genes also enhance the ability of cells to invade other organs.49 As such, metastatic characteristics can be transferred through extracellular vesicle exchange.49

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