world cancer report - iarc

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GEOGRAPHIC VARIATION IN MUTATION PATTERNS Mutations in cancer genes are the direct consequence of attack on DNA by exogenous or endogenous agents or of errors in DNA repair systems. By analysing the type and the sequence context of such mutations, it is possible to form hypotheses regarding the nature of the mutagenic mechanism involved. The most interesting genes in this respect are those altered by missense point mutations, such as members of the RAS family, CDKN2A/ INK4A, and, in particular, the p53 gene. The p53 gene is the most frequently mutated gene in human cancer, with over 16,000 mutations reported and compiled in a database maintained at IARC (http://www.iarc.fr/p53). The diversity of these mutations allows the identification of patterns which vary depending on the tumour type, the geographic origin and the risk factors involved. These are often specific for particular agents that have caused these mutations. Thus p53 gene mutations in cancers may be seen as “fingerprints” left by carcinogens in the human genome, which may help to identify the particular carcinogen involved. A typical example of such a “fingerprint” is the mutation at codon 249 observed in liver cancers of patients from sub- Saharan Africa and Eastern Asia. In these regions, liver cancer is a consequence of chronic infection by hepatitis viruses and of dietary poisoning with aflatoxins, a Lesions in the p16 INK4A-cyclin D, CDK4-pRb and p14 ARF-Mdm2-p53 pathways occur so frequently in cancer, regardless of patient age or tumour type, that they appear to be fundamental to malignancy [24]. Prospects for the molecular analysis of cancer More than 200 genes that are altered at variable proportions in different human 102 Mechanisms of tumour development Fig. 3.24 Geographic variations in the prevalence of p53 gene mutations in breast cancers. class of mycotoxins which contaminates traditional diets (groundnuts) (Food contaminants, p43). Experiments in animals and in cell culture have shown that aflatoxins can directly induce the mutation at codon 249. This particular mutation is not found in liver cancers in areas of the world, such as the USA, where exposure to aflatoxins is low. Specific mutations have also been observed in lung cancers from smokers (due to tobacco carcinogens). In skin cancers, the mutations bear typical chemical signatures of the damage inflicted to DNA by exposure to solar ultraviolet radiation. In other instances, exemplified by patterns of mutation in breast cancer, marked differ- cancer types have been characterized. Most of these have a powerful impact on tumour growth. However, it is very likely that many critical genes with less penetrant phenotypes remain to be identified. In particular, the genes involved in stress reponses, in the control of oxygen metabolism and in the detoxification of xenobiotics are all candidates for a role as cofactors in the ences have been observed between geographical areas, which may provide information on the nature of risk factors involved. In many other cancers, mutation patterns also vary from one region of the world to another. This variability may give clues about the genetic heterogeneity of populations, as well as about the diversity of agents involved in causing cancers. For example, in oesophageal cancers, mutation types widely differ between high-incidence and low-incidence regions, suggesting that specific mutagens are at work in causing the excess incidence seen in some parts of the world, such as Northern Iran and Central China. cancer process. Moreover, many biological alterations leading to cancer may not be detectable at the DNA level. Cancer-causing changes may result from modification of RNA levels or processing, and of protein structure and function through a variety of epigenetic phenomena. The systematic profiling of gene expression in cancer cells will probably reveal a whole new set of
potential cancer genes altered through less conspicuous mechanisms. Apart from expression studies, the whole terri- REFERENCES 1. Fearon ER, Vogelstein B (1990) A genetic model for colorectal tumorigenesis. Cell, 61: 759-767. 2. Weinberg RA (1995) The molecular basis of oncogenes and tumor suppressor genes. Ann N Y Acad Sci, 758: 331- 338. 3. Savelyeva L, Schwab M (2001) Amplification of oncogenes revisited: from expression profiling to clinical application. Cancer Lett, 167: 115-123. 4. Kinzler KW, Vogelstein B (1997) Cancer-susceptibility genes. Gatekeepers and caretakers. Nature, 386: 761, 763. 5. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell, 100: 57-70. 6. Hunter T (1991) Cooperation between oncogenes. Cell, 64: 249-270. 7. Hung MC, Lau YK (1999) Basic science of HER-2/neu: a review. Semin Oncol, 26: 51-59. 8. Wiesmuller L, Wittinghofer F (1994) Signal transduction pathways involving Ras. Mini review. Cell Signal, 6: 247- 267. 9. Henriksson M, Luscher B (1996) Proteins of the Myc network: essential regulators of cell growth and differentiation. Adv Cancer Res, 68: 109-182. 10. Antonsson B, Martinou JC (2000) The Bcl-2 protein family. Exp Cell Res, 256: 50-57. 11. Knudson AG (1996) Hereditary cancer: two hits revisited. J Cancer Res Clin Oncol, 122: 135-140. 12. Knudson AG, Jr. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A, 68: 820-823. 13. Bartek J, Bartkova J, Lukas J (1997) The retinoblastoma protein pathway in cell cycle control and cancer. Exp Cell Res, 237: 1-6. 14. Lukas J, Muller H, Bartkova J, Spitkovsky D, Kjerulff AA, Jansen-Durr P, Strauss M, Bartek J (1994) DNA tumor virus oncoproteins and retinoblastoma gene mutations tory of protein structure, dynamics and interactions is still largely unexplored. An understanding of such processes will share the ability to relieve the cell's requirement for cyclin D1 function in G1. J Cell Biol, 125: 625-638. 15. Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science, 244: 217-221. 16. Birch JM (1994) Li-Fraumeni syndrome. Eur J Cancer, 30A: 1935-1941. 17. Bresalier RS (1997) The gatekeeper has many keys: dissecting the function of the APC gene. Gastroenterology, 113: 2009-2010. 18. Zheng L, Li S, Boyer TG, Lee WH (2000) Lessons learned from BRCA1 and BRCA2. Oncogene, 19: 6159- 6175. 19. Shiloh Y, Rotman G (1996) Ataxia-telangiectasia and the ATM gene: linking neurodegeneration, immunodeficiency, and cancer to cell cycle checkpoints. J Clin Immunol, 16: 254-260. 20. Lane DP (1992) Cancer. p53, guardian of the genome. Nature, 358: 15-16. 21. Hainaut P, Hollstein M (2000) p53 and human cancer: the first ten thousand mutations. Adv Cancer Res, 77: 81-137. 22. Momand J, Jung D, Wilczynski S, Niland J (1998) The MDM2 gene amplification database. Nucleic Acids Res, 26: 3453-3459. 23. Chin L, Pomerantz J, DePinho RA (1998) The INK4a/ARF tumor suppressor: one gene--two productstwo pathways. Trends Biochem Sci, 23: 291-296. 24. Sherr CJ (2000) The Pezcoller lecture: cancer cell cycles revisited. Cancer Res, 60: 3689-3695. provide a basis for the development of new means for treatment and diagnosis. WEBSITES American Tissue Type Collection: http://www.atcc.org/ Centers for Disease Control and Prevention, Atlanta: http://www.cdc.gov/ Cancer Genome Anatomy Project: http://www.ncbi.nlm.nih.gov/ncicgap/ European Bioinformatics Institute: http://www.ebi.ac.uk/ HotMolecBase (Weizmann Institute, Israel): http://bioinformatics.weizmann.ac.il/hotmolecbase/ IARC p53 database: http://www.iarc.fr/p53/ Kyoto encyclopedia of genes and genomes: http://www.genome.ad.jp/kegg/kegg.html OMIM (Online Mendelian Inheritance in Man): http://www3.ncbi.nlm.nih.gov/omim/ Protein Data Bank (a protein structure database): http://www.rcsb.org/pdb/ Oncogenes and tumour suppressor genes 103
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WORLD HEALTH ORGANIZATION WHO OMS I
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WORLD CANCER REPORT Editors Bernard
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CONTENTS Foreword 9 1 The global bu
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The global burden of cancer Cancer
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Fig. 1.2 Incidence and mortality of
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Central and Southern Europe differ
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Incidence of cancer in South Centra
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from documentation of disease to a
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TOBACCO SUMMARY >In addition to lun
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Fig. 2.3 Smoking by children is inc
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Cancers positively Sex Standardized
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PHARMACOLOGICAL APPROACHES TO SMOKI
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level the dose—response relations
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lipoprotein-associated cholesterol,
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Agent Cancer site/cancer Main indus
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Industry, occupation Cancer site/ca
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to occupational exposures in develo
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Air pollutant WHO Air Quality Guide
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der cancer of the order of 50% is p
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AFLATOXIN B 1 HEPATITIS VIRUS (chro
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Fig. 2.30 Correlation between regio
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MEDICINAL DRUGS SUMMARY > Certain d
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Drug or drug combination Cancer IAR
Page 48 and 49: Agent or substance Cancer site/canc
Page 50 and 51: sources of electromagnetic fields [
Page 52 and 53: CHRONIC INFECTIONS SUMMARY > Infect
Page 54 and 55: Infection Subclinical Mutagenic fac
Page 56 and 57: TUMOURS ASSOCIATED WITH HIV/AIDS Ap
Page 58 and 59: DIET AND NUTRITION SUMMARY > Up to
Page 60 and 61: Fig. 2.54 The age-adjusted mortalit
Page 62 and 63: OVERWEIGHT, OBESITY AND PHYSICAL AC
Page 64 and 65: IMMUNOSUPPRESSION SUMMARY >Persiste
Page 66 and 67: Fig. 2.64 Cancer following immunosu
Page 68 and 69: Syndrome Gene Location Cancer site/
Page 70 and 71: viduals, confirmation of a gene def
Page 72 and 73: REPRODUCTIVE FACTORS AND HORMONES S
Page 74 and 75: PHYTO-ESTROGENS AND CANCER PEVENTIO
Page 76 and 77: Indicator Number of oral contracept
Page 79 and 80: Mechanisms of tumour development Th
Page 81 and 82: The stages in tumorigenesis have be
Page 83 and 84: PRECURSOR LESIONS IN CHEMOPREVENTIO
Page 85 and 86: CARCINOGEN ACTIVATION AND DNA REPAI
Page 87 and 88: adducts, a few weeks or months for
Page 89 and 90: I Reactive oxygen species Methylati
Page 91 and 92: which remove the mismatched bases,
Page 93 and 94: Common human oncogenes Many common
Page 95 and 96: product of the RB1 gene (pRb) and a
Page 97: ates a molecular bridge between p53
Page 101 and 102: One of the earliest genes to be ide
Page 103 and 104: Regulation of the cell cycle and co
Page 105 and 106: CELL-CELL COMMUNICATION SUMMARY > C
Page 107 and 108: Connexin genes and tumour suppressi
Page 109 and 110: APOPTOSIS SUMMARY > The term apopto
Page 111 and 112: Caspase-8 Caspase-3 c-FLIP Procaspa
Page 113 and 114: ways. Several options are under inv
Page 115 and 116: INVASION AND METASTASIS SUMMARY > T
Page 117 and 118: laminin, entactin and also heparan
Page 119 and 120: Target Example of agent Comments Ad
Page 121 and 122: organs, and to respond to local gro
Page 123 and 124: TOBACCO CONTROL SUMMARY > Tobacco-i
Page 125 and 126: Region Deaths due to % of total dea
Page 127 and 128: ipated, is primarily attributable t
Page 129 and 130: smoke. This may be achieved in part
Page 131 and 132: there is no evidence for the effica
Page 133 and 134: industries, processes and occupatio
Page 135 and 136: stoves arises in rural areas of dev
Page 137 and 138: Climbing plants on trellis at end r
Page 139 and 140: HEPATITIS B VACCINATION SUMMARY > P
Page 141 and 142: Fig. 4.17 Chronic active HBV-associ
Page 143 and 144: HUMAN PAPILLOMAVIRUS VACCINATION SU
Page 145 and 146: Vaccine Site of trial Number of pat
Page 147 and 148: prolonged use. Similar drugs, that
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aspirin and other non-steroidal ant
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SCREENING FOR BREAST CANCER SUMMARY
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Fig. 4.35 Cumulative mortality from
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SCREENING FOR PROSTATE CANCER SUMMA
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Fig. 4.39 Poster designed for an an
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is around 10% for cancer (out of ev
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45 with one positive rehydrated FOB
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eing based on (i) time trends in th
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Fig. 4.48 Women at a clinic in Indi
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SCREENING FOR ORAL CANCER SUMMARY >
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India will provide useful informati
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cer incidence following cure of inf
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100 50 25 10 5 2.5 1 Japan Males Fe
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Human cancers by organ site Maligna
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tobacco smoking: age at start, aver
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diagnosis is usually confirmed by h
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is frequent and survival rates are
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Fig. 5.14 Physician reading digital
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Markers of prognosis in breast canc
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cer in the contralateral breast (Ch
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100 50 25 10 5 2.5 1 Japan Chile Po
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depends on staging. Small intramuco
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Fig. 5.30 A diet rich in fresh frui
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ane protein involved in cell adhesi
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LIVER CANCER SUMMARY > About 560,00
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Fig. 5.39 A woman in the Gambia pre
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REFERENCES 1. Ferlay J, Bray F, Par
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Certain Possible Uncertain Age Andr
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Management The dramatic division be
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TUMOUR NORMAL Gastrula PGC 2n Impri
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CANCERS OF THE FEMALE REPRODUCTIVE
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Fig. 5.62 Five-year relative surviv
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Inheritance of high-penetrance gene
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invasive malignant. Malignant germ
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OESOPHAGEAL CANCER SUMMARY >Cancer
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Fig. 5.76 A radiographic view of an
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with a stent; laser recannulation,
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Fig. 5.82 Risk of bladder cancer am
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Partial cystectomy is appropriate f
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poorly known since hypopharyngeal c
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Fig. 5.92 Oral leukoplakia with mil
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LYMPHOMA SUMMARY > Malignant lympho
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T Fig. 5.101 Nuclear magnetic reson
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Fig. 5.106 Five-year relative survi
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Fig. 5.109 The immediate aftermath
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A B Fig. 5.113 Acute myeloid leukae
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Fig. 5.118 Five-year relative survi
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Fig. 5.120 Age-specific incidence a
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Hereditary condition Mode of inheri
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MELANOMA SUMMARY > Approximately 13
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Fig. 5.131 Primary melanoma with a
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THYROID CANCER SUMMARY > Cancer of
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Papillary carcinoma RET/PTC TRK BRA
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KIDNEY CANCER SUMMARY > Cancer of t
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Stage Clear cell carcinoma Papillar
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TUMOURS OF THE NERVOUS SYSTEM SUMMA
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ing the optic tract, brain stem and
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mut = mutant p53 wt = wildtype p53
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SURGICAL ONCOLOGY SUMMARY > Surgica
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Year Radical mastectomy (%) Modifie
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TELEMEDICINE The prospects for tele
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Equipment Energy 50% depth dose App
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CANCER EDUCATION IN MEDICAL COURSES
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Fig. 6.10 Crystals of cisplatin: mo
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Responsiveness Cancer (in decreasin
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Most of the world’s most common c
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treatment of cancer. The problems l
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duction. It is clear that tumour ce
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REHABILITATION SUMMARY > Rehabilita
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cer and its associated disability.
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REFERENCES 1. Garden FH, Gillis TA
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Cancer pain relief varies and in so
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EMERGING ISSUES IN PALLIATIVE CARE
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Cancer control The negative impact
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priority to cancer control activiti
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Prevention of cancer Every country
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- Assessing the magnitude of the ca
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high-risk women. Further details on
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ecords departments are either rudim
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THE INTERNATIONAL AGENCY FOR RESEAR
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in the capitals/urban areas of four
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in the overall cancer strategy. WHO
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68% 1955 1975 1995 2025 32% 40% by
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Fig. 7.15 A grandfather at work in
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Fig. 7.17 Main causes of death in d
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Contributors and Reviewers Sources
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Dr Vera Luiz da Costa e Silva Tobac
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Georgia Moore Centers for Disease C
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REVIEWERS Dr Sandra E. Brooks 405 W
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2.53 T. Norat and E. Riboli, IARC 2
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Gastroenterology, 118(2 Suppl 1): S
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5.106 & 5.107 IARC/SEER/Osaka Cance
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4.17 R. Lambert, IARC/Adapted from
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Brain cancer, see nervous system tu
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Fibroblast growth factor (FGF), 117
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Microarray, 240 Micronutrients, 65,
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S Saccharin, 64, 85 Salicin, 153 Sa
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