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The landscape of viral associations in human cancers
Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and—for a subset—whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein–Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
The World Health Organization estimates that 15.4% of all cancers are attributable to infections and 9.9% are linked to viruses 1,2 . Cancers that are attributable to infections have a greater incidence than any individual type of cancer worldwide. Eleven pathogens have been classified as carcinogenic agents in humans by the International Agency for Research on Cancer (IARC) 3 . After Helicobacter pylori (associated with 770,000 cases worldwide), the four most prominent infection-related causes of cancer are estimated to be viral 2 : HPV 4 (associated with 640,000 cases), HBV 5 (420,000 cases), hepatitis C virus (HCV) 6 (170,000 cases) and EBV 7 (120,000 cases). It has been shown that viruses can contribute to the biology of multistep oncogenesis and are implicated in many of the hallmarks of cancer 8 . Notably, the discovery of links between infection and cancer types has provided actionable opportunities, such as the use of HPV vaccines as a preventive measure, to reduce the global impact of cancer. The following characteristics have been proposed to define human viruses that cause cancer through direct or indirect carcinogenesis 9 : (1) presence and persistence of viral DNA in tumor biopsies (2) growth-promoting activity of viral genes in model systems (3) dependence of a malignant phenotype on continuous viral oncogene expression or modification of host genes and (4) epidemiological evidence that a virus infection represents a major risk for the development of cancer.
The worldwide efforts of comprehensive genome and whole-transcriptome analyses of tissue samples from patients with cancer have generated appropriate facilities for capturing information not only from human cells but also from other—potentially pathogenic—organisms or viruses that are present in the tissue. A comprehensive collection of whole-genome and whole-transcriptome data from cancer tissues has been generated within the International Cancer Genome Consortium (ICGC) project PCAWG 10 , providing a unique opportunity for a systematic search for tumor-associated viruses.
The PCAWG Consortium aggregated whole-genome sequencing (WGS) data from 2,658 cancers across 38 tumor types that have been generated by the ICGC and The Cancer Genome Atlas (TCGA) projects. These sequencing data were reanalyzed with standardized, high-accuracy pipelines to align to the human genome (build hs37d5) and identify germline variants and somatically acquired mutations 10 . The PCAWG working group ‘Pathogens’ analyzed the WGS and whole-transcriptome sequencing (RNA-sequencing (RNA-seq)) data of the PCAWG consensus cohort (2,656 donors). Focusing on viral pathogens, we applied three independently developed pathogen-detection pipelines ‘Computational Pathogen Sequence Identification’ (CaPSID) 11 , ‘Pathogen Discovery Pipeline’ (P-DiP) and ‘Searching for Pathogens’ (SEPATH) to generate a large compendium of viral associations across 38 cancer types. We extensively characterized the known and novel viral associations by integrating driver mutations, mutational signatures, gene expression profiles and patient survival data of the same set of tumors analyzed by the PCAWG Consortium.
Eukaryotic Cell Cycle
The diagram in Figure 4.12.2 represents the cell cycle of a eukaryotic cell. As you can see, the eukaryotic cell cycle has several phases. The mitotic phase (M) actually includes both mitosis and cytokinesis. This is when the nucleus and then the cytoplasm divide. The other three phases (G1, S, and G2) are generally grouped together as interphase . During interphase, the cell grows, performs routine life processes, and prepares to divide. These phases are discussed below.
Figure 4.12.2 Eukaryotic Cell Cycle. This diagram represents the cell cycle in eukaryotes. The First Gap (G1), Synthesis, and Second Gap (G2) phases make up interphase (I). The mitotic phase includes mitosis and cytokinesis. After the mitotic phase, two cells result.
Incidence of Cancer by Geographic Regions
Of the 21 regions listed in the GLOBOCAN 2002 database, East Asia had the largest number of incident cancer cases (all ages, all sites except skin) in 2002 (n = 2,890,311) North America and South Central Asia were second (n = 1,570,520) and third (n = 1,261,527) on the list, respectively [ Figure 1 ]. The pattern of cancer sites varied substantially from region to region. For example, the three most common cancer sites among individuals 15 years or older in East Asia were stomach (18.9 percent), lung (17.1 percent), and liver (14.3 percent), whereas those in North America were prostate (16.5 percent), breast (14.7 percent), and lung (14.5 percent) [ Figure 2 and Figure 3 ].
Number of Incident Cancer Cases in 2002 (all ages, all sites but skin). No bars are shown for Melanesia, Micronesia, and Polynesia because the numbers of incidence cancer cases in these three regions were very small.
Type of Incident Cancer in Eastern Asia (male and female, age 15-65+, 2002). Cases: 2,864,408.
Types of Incident Cancer in North America (male and female, age 15-65+, 2002). Cases: 1,561,046.
For both males and females, the incidence rate of cancer increased substantially with age. For example, the annual male cancer incidence in the age group of 0 to 14 years was 6.45 per 100,000 in Western Africa, 9.07 per 100,000 in Eastern Asia, 14.10 per 100,000 in Western Europe, and 15.12 per 100,000 in North America the rates in the same regions for those who were 65 years or older were 385.44, 1461.59, 2327.87 and 2958.14 per 100,000, respectively (Table 1). North America, Australia/New Zealand, and Europe had the highest overall incidence rates in 2002, while Northern and Western Africa had the lowest incidence rates (Tables 1-2). The geographic variation was rather substantial. For example, the age-standardized rate in North American males (398.4 per 100,000 person-years) was four times of the age-standardized rate in North African males (99 per 100,000 person-years).
The geographic disparity in cancer incidence is largely attributable to the various socioeconomic, environmental, and lifestyle factors in different regions of the world. Compared with developed countries, developing countries in general may lack the resources to ascertain incident cancer cases. For example, in developed countries, many cases of breast, prostate, colon, and cervical cancers are identified through screening (e.g. mammography, prostate-specific antigen test, colonoscopy, and Pap smear), whereas in developing countries, large-scale screening efforts are usually uncommon. Genetic factors also play a role, but the dominant effect of genetics is only observed in a relatively small percentage of the population. It is believed that the majority of cancer cases (over 90 percent) are due to the joint effect of genetic variations, environmental factors, and lifestyle choices . Geographic factor per se probably has little influence on cancer risk except sunlight exposure and vitamin D metabolism, both of which have been linked to cancer risk. The major categories of cancer risk factors include tobacco use, occupational exposures, environmental contamination, infectious agents, and lifestyle factors.
Knowledge about the role of tobacco smoking in the etiology of cancer has accumulated for many years . In 2004, the IARC published a monograph on tobacco use and cancer, which concluded that tobacco contributed, to a greater or lesser extent, to cancer in 15 different sites, including lung, urinary tract, upper respiratory tract, pancreas, stomach, and liver.
Although the prevalence of smoking has declined in many developed countries, it is increasing in developing countries . Currently, approximately 5 million people are killed annually by tobacco use by 2030, estimates based on current trends indicate that this number will increase to 10 million, with 70 percent of deaths occurring in developing countries . It is important to adopt policies such as tobacco tax increases, dissemination of information about health risks from smoking, restrictions on smoking in public places and in workplaces, comprehensive bans on advertising and promotion, and increased access to cessation therapies to reduce the incidence of cancer and other diseases related to tobacco use .
Occupational exposures have long been linked to the risk of cancer. A recent publication listed 28 definitive human occupational carcinogens ranging from ionizing radiation, asbestos, silica, wood dust, and arsenic to benzene . Generally speaking, developed countries went through the industrialization process earlier than the developing countries, and individuals living in developed countries often had a higher chance of being exposed to various occupational exposures. However, as many developing countries go through an economic transition from primarily agricultural activities to more industrial development and manufacturing, there may be concerns about the lack of resources in monitoring occupational exposures and developing or reinforcing occupational standards, which is usually an ongoing process. For example, the current United States’ occupational standard for benzene, one of the most widely used industrial chemicals and a known human carcinogen, is 1 part per million (ppm) or 3.26 mg/m³. This is considerably lower than the occupational standard for benzene in China between 1979 and 2002, which was 40 mg/m³ (area breathing zone concentration) . In 2002, the occupational standard for benzene in China was modified and significantly lowered, but the current standards (10 mg/m³ for short-term exposure limit and 6 mg/m³ for time-weighted average) are still higher than the U.S. standard . Given that hematological toxicity is observed in workers with benzene exposures below the level of 1 ppm , the current occupational standards for benzene may still need to be reviewed and evaluated.
Exposure to environmental contamination, such as indoor air pollution and pesticides, is known to increase the risk of cancer. More than half of the world’s populations rely on dung, wood, crop waste, or coal to meet their most basic energy needs . Cooking and heating with such solid fuels on open fires or stoves without chimneys lead to indoor air pollution. This indoor smoke contains a range of health-damaging pollutants, including small soot or dust particles, that are able to penetrate the lungs, increasing the risk of lung cancer and other diseases of the respiratory tract. In poorly ventilated dwellings, indoor smoke can exceed acceptable levels for small particles in outdoor air 100-fold. Exposure is particularly high among women and children, who spend the most time near the domestic hearth. The use of polluting fuels thus poses a major burden on the health of poor families in developing countries . As for pesticides, the global market value is estimated at $32 billion in 2000, with the share of developing countries around $3 billion . Around 30 percent of pesticides marketed in developing countries do not meet internationally accepted quality standards, and the problem is particularly widespread in sub-Saharan Africa. These poor-quality pesticides frequently contain hazardous substances and impurities that already have been banned or severely restricted elsewhere and, therefore, pose a serious threat to human health and the environment .
In 2002, an estimated total of 1.9 million cancer cases, or 17.8 percent of the global cancer burden, were attributed to various infections . Several infectious agents are considered to be causes of cancer . For example, Helicobacter pylori infection is known to increase the risk of stomach cancer , whereas infection with hepatitis B and C viruses can lead to liver cancer . The relationship between socioeconomic status and the acquisition of Helicobacter pylori infection has been confirmed in a number of studies the prevalence of infection varies from 8.9 percent to 72.8 percent among children from developed and developing countries, respectively the re-infection rate is also significantly higher in the latter . Similarly, the prevalence of infection with hepatitis B and C viruses is higher in developing countries than in developed countries . The higher incidences of stomach and liver cancers in developing countries are largely due to the higher prevalence of related infections. Other infections considered to be important in cancer include human papilloma virus, Epstein-Barr virus, and human immunodeficiency virus .
Diet and physical activity
Excessive weight and obesity, resulting from excess calorie intake and physical inactivity, have become a serious health issue in many developed countries. In the United States, for example, it is estimated that nearly a third of the adult population is obese and two-thirds are overweight . Obesity and excessive weight have been linked to many types of cancers, including those of the colon, breast, and prostate . The higher incidences of colon, breast, and prostate cancers in developed countries are attributed in part to a lifestyle of high-calorie diet and physical inactivity. This lifestyle results in positive energy imbalance that further leads to insulin resistance (or metabolic syndrome) characterized by hyperinsulinemia, dyslipidemia, hypertension, and glucose intolerance . Insulin resistance has been linked to a number of health problems including cancer, type 2 diabetes, and cardiovascular diseases . These lifestyle-related health issues have begun to spread to certain developing countries where there has been steady economic growth. This spread also results in changes in regional cancer patterns. For example, dramatic increases in the incidences of breast, prostate, and colon cancers have been observed in the major cities of China .
4.12: 9. 12- Viruses and Cancer - Biology
Describe structural and functional similarities between mitochondria and chloroplasts that provide evidence of common ancestry.
Explain how the structural and functional differences between mitochondria and chloroplasts provide evidence of adaptations among common ancestral organisms.
Examine the differences and similarities in the structural features of animal and plant cells. Justify the claim that both animals and plants have common ancestors based on your observations.
What conserved core processes are common to both animals and plants? Construct an explanation of the differences based on the selective advantages provided in different environments.
Louis Sullivan described architectural design as “form follows function.” For example, a window is designed to add light to a space without heat transport. A door is designed to allow access to a space. Windows and doors have different functions and so take different forms. Biological systems are not designed, but selected from random trials by interaction with the environment. Apply Sullivan’s principle to explain the relationship of function and form for each pair of cellular structures below.
- Plasma membrane and endoplasmic reticulum
- Mitochondrion and chloroplast
- Rough endoplasmic reticulum and smooth endoplasmic reticulum
- Flagella and cilia
- Muscle cells and secretory cells
Complex multicellular organisms share nutrients and resources, and their cells communicate with each other. A society may encourage cooperation among individuals while discouraging selfish behavior to increase the overall success of the social system, sometimes at the expense of the individual. Scientific questions are testable and often attempt to reveal a mechanism responsible for a phenomenon. Pose three questions that can be used to examine the ways in which a social system regulates itself. Be prepared to share these in small group discussions with your classmates about the similarities between these regulatory strategies and the analogous roles of plasmodesmata and gap junctions in cell communication.
Plasmodesmata in vascular plants and gap junctions in animals are examples of specialized features of cells. Mechanisms by which transport occurs between cells evolved independently within several eukaryotic clades. Explain, in terms of cellular cooperation, the selective advantages provided by such structures.
Mammalian red blood cells have no nuclei, must originate in other tissue systems, are relatively long-lived, are small with shapes that actively respond to their environment, and are metabolic anaerobes. Other vertebrates have red blood cells that are usually nucleated and are often relatively large, aerobic, self-replicating, and short-lived.
To connect these facts to biology, questions need to be asked. The questions that you pose will depend on the path your class is taking through the curriculum. Begin by summarizing what you know:
- What are the functions of a eukaryotic cell nucleus?
- What is the approximate average size of a human red blood cell?
- What is the range of blood vessel diameters in adult humans?
- What is the range of red blood cell size in vertebrates?
- What is the average lifetime of a human red blood cell?
- How can you show how cell production is stimulated using examples from particular systems?
- How is cell death controlled?
- What biochemical cycles are associated with anaerobic and aerobic respiration, and what are the important differences between these?
- What process is involved in the transport of oxygen and carbon dioxide into and out of red blood cells?
- What behaviors and dynamic homeostatic processes might be associated with the properties of red blood cells in mammalian and nonmammalian organisms?
- What do you know about the evolutionary divergences among vertebrates?
Your summary has revealed some similarities and differences among vertebrate erythrocyte and circulatory system structures. Scientific questions are testable. They can be addressed by making observations and measurements and analyzing the resulting data.
- Pose three scientific questions that arise from your summaries of what you know about erythrocytes and capillary size.
- For each question you pose, predict what you believe would be the answer and provide reasoning for your prediction.
- Describe an approach you think can be used to obtain data to test your prediction.
- In the production of mammalian red blood cells, erythrocytes that have not yet matured and are still synthesizing heme proteins are surrounded by a macrophage. Predict the role of the macrophage in the maturation of a red blood cell.
Mitochondria have DNA that encode proteins related to the structures and functions of the organelles. The replication appears to occur continuously, however, many questions about control of replication rate and segregation during mitosis are yet unanswered. Many diseases are caused by mitochondrial dysfunction. Mitophagy, as the name suggests, leads to the destruction of mitochondria. Predict whether or not cellular control mechanisms involving the regulation of mitochondrial DNA by the nucleus exist. Make use of what you know about selection and homeostasis as they apply to both the organism and to the organelle.