The population incidence of cancer

In this thesis stochastic techniques are used in attempts to understand cancer risk, its relationship to patient age and genotype, as well as its distribution in human populations. The starting point for the thesis is the general observation that cancer incidence grows in approximate proportion to an integer power of age. Quasi-mechanistic mathematical models of cancer incidence have suggested that the integer power in a given case is related to the number of crucial cellular events that must occur for a malignant tumour to evolve from a healthy tissue. This idea and its limitations are explored. Further applications of cancer incidence models are then evaluated and developed. Specifically, a critical examination is presented of the notion that increases in risk associated with a particular predisposing germline gene mutation, can provide information about the disease-associated activity of that gene. Finally, there is a discussion of heterogeneity in liability to cancer. Methods for quantifying this heterogeneity and its effect on incidence patterns are investigated.

[1]  N. Day,et al.  Family history and the risk of breast cancer: A systematic review and meta‐analysis , 1997, International journal of cancer.

[2]  S. Tavaré,et al.  Investigating stem cells in human colon by using methylation patterns , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[3]  S. Frank.  Dynamics of Cancer: Incidence, Inheritance, and Evolution , 2007 .

[4]  John Skilling,et al.  Data analysis : a Bayesian tutorial , 1996 .

[5]  E. Furth,et al.  Population risk and physiological rate parameters for colon cancer. The union of an explicit model for carcinogenesis with the public health records of the United States. , 2000, Mutation research.

[6]  Robert DeMars,et al.  The spontaneous azaguanine-resistant mutants of diploid human fibroblasts , 2004, Humangenetik.

[7]  Genes, chromosomes & cancer , 1995 .

[8]  Eric J Kunkel,et al.  Systems biology in drug discovery. , 2006, Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Annual Conference.

[9]  W. Bodmer,et al.  Genetics of colorectal cancer: hereditary aspects and overview of colorectal tumorigenesis. , 2002, British medical bulletin.

[10]  R. Elston.  Segregation analysis. , 1981, Advances in human genetics.

[11]  L. Aaltonen,et al.  Life‐time risk of different cancers in hereditary non‐polyposis colorectal cancer (hnpcc) syndrome , 1995, International journal of cancer.

[12]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[13]  P. Wingo,et al.  Family history and the risk of breast cancer. , 1985, JAMA.

[14]  M. Bisgaard,et al.  Familial adenomatous polyposis (FAP): Frequency, penetrance, and mutation rate , 1994, Human mutation.

[15]  G. Deng,et al.  BRAF Mutation Is Frequently Present in Sporadic Colorectal Cancer with Methylated hMLH1, But Not in Hereditary Nonpolyposis Colorectal Cancer , 2004, Clinical Cancer Research.

[16]  A. Knudson,et al.  Mutation and cancer: neuroblastoma and pheochromocytoma. , 1972, American journal of human genetics.

[17]  B. Leggett,et al.  APC mutation and tumour budding in colorectal cancer , 2003, Journal of clinical pathology.

[18]  八木 オズマール賢次.  Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas , 1999 .

[19]  M. Sanz-Casla,et al.  Role of the BRAF Mutations in the Microsatellite Instability Genetic Pathway in Sporadic Colorectal Cancer , 2007, Annals of Surgical Oncology.

[20]  L. Roncucci,et al.  K‐ras and p53 mutations in hereditary non‐polyposis colorectal cancers , 1997, International journal of cancer.

[21]  C. Ostwald,et al.  Phenotypes of invasion in sporadic colorectal carcinomas related to aberrations of the adenomatous polyposis coli (APC ) gene , 2007, Histopathology.

[22]  A D Carothers,et al.  Cancer risk associated with germline DNA mismatch repair gene mutations. , 1997, Human molecular genetics.

[23]  S. Frank.  Genetic predisposition to cancer — insights from population genetics , 2004, Nature Reviews Genetics.

[24]  T. Sellers,et al.  Epidemiology — identifying the causes and preventability of cancer? , 2006, Nature Reviews Cancer.

[25]  S Srivastava,et al.  A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. , 1998, Cancer research.

[26]  P. Vineis,et al.  Analysis of epidemiological cohort data on smoking effects and lung cancer with a multi-stage cancer model. , 2006, Carcinogenesis.

[27]  J C Reed,et al.  Somatic Frameshift Mutations in the BAX Gene in Colon Cancers of the Microsatellite Mutator Phenotype , 1997, Science.

[28]  S H Moolgavkar,et al.  Two-stage model for carcinogenesis: Epidemiology of breast cancer in females. , 1980, Journal of the National Cancer Institute.

[29]  P. Peltomäki,et al.  Mutations Associated with HNPCC Predisposition — Update of ICG-HNPCC/INSiGHT Mutation Database , 2004, Disease markers.

[30]  A. Fernández-Peralta,et al.  Significance of mutations in TGFBR2 and BAX in neoplastic progression and patient outcome in sporadic colorectal tumors with high-frequency microsatellite instability. , 2005, Cancer genetics and cytogenetics.

[31]  M. Little,et al.  A stochastic carcinogenesis model incorporating genomic instability fitted to colon cancer data. , 2003, Mathematical biosciences.

[32]  A. Morley,et al.  Mutation rate of normal and malignant human lymphocytes. , 1987, Cancer research.

[33]  E Georg Luebeck,et al.  Multistage carcinogenesis and the incidence of colorectal cancer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[34]  O. Aalen,et al.  Frailty modelling of colorectal cancer incidence in Norway: Indications that individual heterogeneity in risk is related to birth cohort , 2006, European Journal of Epidemiology.

[35]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[36]  Martin A. Nowak,et al.  The significance of unstable chromosomes in colorectal cancer , 2003, Nature Reviews Cancer.

[37]  I. Tomlinson,et al.  Colorectal cancer and genetic alterations in the Wnt pathway , 2006, Oncogene.

[38]  J Straub,et al.  APC mutations in sporadic colorectal tumors: A mutational "hotspot" and interdependence of the "two hits". , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[39]  W. Stahel,et al.  Log-normal Distributions across the Sciences: Keys and Clues , 2001 .

[40]  S. Frank.  Age-specific incidence of inherited versus sporadic cancers: a test of the multistage theory of carcinogenesis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[41]  M. Little.  Generalisations of the two-mutation and classical multi-stage models of carcinogenesis fitted to the Japanese atomic bomb survivor data , 1996 .

[42]  P. Babb,et al.  Patterns and trends in prostate cancer incidence, survival, prevalence and mortality. Part II: individual countries , 2002, BJU international.

[43]  D. Thomas,et al.  Bias and efficiency in family-based gene-characterization studies: conditional, prospective, retrospective, and joint likelihoods. , 2000, American journal of human genetics.

[44]  T. Iwama.  Somatic mutation rate of the APC gene. , 2001, Japanese journal of clinical oncology.

[45]  R. Fodde,et al.  Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. , 1996, Gastroenterology.

[46]  I. Tomlinson,et al.  What can we learn from the population incidence of cancer? Armitage and Doll revisited. , 2007, The Lancet. Oncology.

[47]  A. Knudson,et al.  Mutation and cancer: a model for Wilms' tumor of the kidney. , 1972, Journal of the National Cancer Institute.

[48]  T. Turányi.  Sensitivity analysis of complex kinetic systems. Tools and applications , 1990 .

[49]  Lucio Luzzatto,et al.  A quantitative measurement of the human somatic mutation rate. , 2005, Cancer research.

[50]  J. Hopper,et al.  The BOADICEA model of genetic susceptibility to breast and ovarian cancers: updates and extensions , 2008, British Journal of Cancer.

[51]  N. Carter,et al.  Refining molecular analysis in the pathways of colorectal carcinogenesis. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[52]  J Martin,et al.  Exon 3 β-catenin mutations are specifically associated with colorectal carcinomas in hereditary non-polyposis colorectal cancer syndrome , 2005, Gut.

[53]  G. Giles,et al.  Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[54]  R S McCombs,et al.  A HYPOTHESIS ON THE CAUSATION OF CANCER. , 1930, Science.

[55]  I. Tomlinson,et al.  The in vivo rate of somatic adenomatous polyposis coli mutation. , 2008, The American journal of pathology.

[56]  Ian Tomlinson,et al.  The type of somatic mutation at APC in familial adenomatous polyposis is determined by the site of the germline mutation: a new facet to Knudson's 'two-hit' hypothesis , 1999, Nature Medicine.

[57]  M. Ferguson-Smith,et al.  Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. , 1990, Journal of medical genetics.

[58]  H. Campbell,et al.  Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGE review. , 2002, American journal of epidemiology.

[59]  W. Bodmer,et al.  Failure of programmed cell death and differentiation as causes of tumors: some simple mathematical models. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[60]  Xinan Zhang,et al.  Estimating the number of rate limiting genomic changes for human breast cancer , 2005, Breast Cancer Research and Treatment.

[61]  Paul R Burton,et al.  Key concepts in genetic epidemiology , 2005, The Lancet.

[62]  R. Knuechel,et al.  Multicellular spheroids: a three‐dimensional in vitro culture system to study tumour biology , 1998, International journal of experimental pathology.

[63]  F. Pompei,et al.  Cancer suppression at old age. , 2008, Cancer research.

[64]  P. Frost,et al.  Pitfalls and practice of Luria-Delbrück fluctuation analysis: a review. , 1988, Cancer research.

[65]  Adrian E. Raftery,et al.  Bayesian model averaging: a tutorial (with comments by M. Clyde, David Draper and E. I. George, and a rejoinder by the authors , 1999 .

[66]  O. Sieber,et al.  Genomic instability — the engine of tumorigenesis? , 2003, Nature Reviews Cancer.

[67]  P. Armitage,et al.  The Age Distribution of Cancer and a Multi-stage Theory of Carcinogenesis , 1954, British Journal of Cancer.

[68]  C. Potten,et al.  The small intestine as a model for evaluating adult tissue stem cell drug targets 1 , 2003, Cell proliferation.

[69]  D. Ashley.  Colonic cancer arising in polyposis coli. , 1969, Journal of medical genetics.

[70]  A. Yashin,et al.  Correlated individual frailty: an advantageous approach to survival analysis of bivariate data. , 1995, Mathematical population studies.

[71]  B. Hankey,et al.  Temporal patterns in colorectal cancer incidence, survival, and mortality from 1950 through 1990. , 1994, Journal of the National Cancer Institute.

[72]  B. Vogelstein,et al.  Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences. , 1998, The American journal of pathology.

[73]  L. Aaltonen,et al.  Population carrier frequency of hMSH2 and hMLH1 mutations , 2000, British Journal of Cancer.

[74]  J. Peto,et al.  High constant incidence in twins and other relatives of women with breast cancer , 2000, Nature Genetics.

[75]  David R. Anderson,et al.  Model selection and multimodel inference : a practical information-theoretic approach , 2003 .

[76]  I. Tomlinson,et al.  Mutations within Wnt pathway genes in sporadic colorectal cancers and cell lines , 2006, International journal of cancer.

[77]  J. Fraumeni,et al.  Cancer registration in Connecticut and the study of multiple primary cancers, 1935-82. , 1985, National Cancer Institute monograph.

[78]  Steven A Frank,et al.  Age-Specific Acceleration of Cancer , 2004, Current Biology.

[79]  Minoru Toyota,et al.  Integrated genetic and epigenetic analysis identifies three different subclasses of colon cancer , 2007, Proceedings of the National Academy of Sciences.

[80]  R. Houlston,et al.  A systematic review and meta-analysis of familial colorectal cancer risk , 2001, American Journal of Gastroenterology.

[81]  C. Nordling.  A New Theory on the Cancer-inducing Mechanism , 1953, British Journal of Cancer.

[82]  M. Yang.  Introduction to statistical methods in modern genetics , 2019 .

[83]  N. Matsubara,et al.  BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum , 2004, Gut.

[84]  Brinton La,et al.  Second cancer following cancer of the breast in Connecticut, 1935-82. , 1985 .

[85]  R. Keil,et al.  Distance-independence of mitotic intrachromosomal recombination in Saccharomyces cerevisiae. , 1990, Genetics.

[86]  L. Aaltonen,et al.  Cancer risk in mutation carriers of DNA‐mismatch‐repair genes , 1999, International journal of cancer.

[87]  Alejandro Sánchez Alvarado,et al.  Cell turnover and adult tissue homeostasis: from humans to planarians. , 2007, Annual review of genetics.

[88]  Darryl Shibata,et al.  Numbers of mutations to different types of colorectal cancer , 2005, BMC Cancer.

[89]  E. Feuer,et al.  Permutation tests for joinpoint regression with applications to cancer rates. , 2000, Statistics in medicine.

[90]  Konstantin G. Arbeev,et al.  Decline in human cancer incidence rates at old ages: Age-period-cohort considerations , 2005 .

[91]  L. Lipton,et al.  Analysis of somatic molecular changes, clinicopathological features, family history, and germline mutations in colorectal cancer families: evidence for efficient diagnosis of HNPCC and for the existence of distinct groups of non-HNPCC families , 2005, Journal of Medical Genetics.

[92]  W. Haenszel.  Cancer mortality among the foreign-born in the United States. , 1961, Journal of the National Cancer Institute.

[93]  S H Moolgavkar,et al.  A stochastic two-stage model for cancer risk assessment. II. The number and size of premalignant clones. , 1989, Risk analysis : an official publication of the Society for Risk Analysis.

[94]  K. Kinzler,et al.  Genetic instabilities in human cancers , 1998, Nature.

[95]  Nordling Co.  A New Theory on the Cancer-inducing Mechanism , 1953 .

[96]  Brues Am.  Critique of mutational theories of carcinogenesis. , 1960 .

[97]  W. Bodmer,et al.  Genetic pathways in colorectal and other cancers. , 1999, European journal of cancer.

[98]  W F Heidenreich,et al.  Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model , 2001, Radiation research.

[99]  S. Frank,et al.  A multistage theory of age-specific acceleration in human mortality , 2004, BMC Biology.

[100]  H T Lynch,et al.  Hereditary colorectal cancer. , 1991, Seminars in oncology.

[101]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[102]  D L S McElwain,et al.  A history of the study of solid tumour growth: The contribution of mathematical modelling , 2004, Bulletin of mathematical biology.

[103]  P. Laird,et al.  CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer , 2006, Nature Genetics.

[104]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[105]  T. Iwama,et al.  Frequent mutation of beta-catenin and APC genes in primary colorectal tumors from patients with hereditary nonpolyposis colorectal cancer. , 1999, Cancer research.

[106]  B. Leggett,et al.  Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. , 2001, The American journal of pathology.

[107]  Primary bone-forming tumours and their relationship to skeletal growth. , 1959, The Journal of bone and joint surgery. British volume.

[108]  L. Påhlman,et al.  Colorectal cancer with and without microsatellite instability involves different genes , 1999, Genes, chromosomes & cancer.

[109]  Martin A Nowak,et al.  The age incidence of chronic myeloid leukemia can be explained by a one-mutation model , 2006, Proceedings of the National Academy of Sciences.

[110]  Thierry Soussi,et al.  APC gene: database of germline and somatic mutations in human tumors and cell lines , 1996, Nucleic Acids Res..

[111]  A. Yashin,et al.  A correlated frailty model with long‐term survivors for estimating the heritability of breast cancer , 2007, Statistics in medicine.

[112]  Arndt Hartmann,et al.  Distinction of Hereditary Nonpolyposis Colorectal Cancer and Sporadic Microsatellite-Unstable Colorectal Cancer through Quantification of MLH1 Methylation by Real-time PCR , 2007, Clinical Cancer Research.

[113]  D. Parkin,et al.  The evolution of the population-based cancer registry , 2006, Nature Reviews Cancer.

[114]  L. Aaltonen,et al.  Incidence of hereditary nonpolyposis colorectal cancer and the feasibility of molecular screening for the disease. , 1998, The New England journal of medicine.

[115]  H C van Houwelingen,et al.  Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment , 2005, Journal of Medical Genetics.

[116]  T. Kunkel.  DNA Replication Fidelity* , 2004, Journal of Biological Chemistry.

[117]  S. Tavaré,et al.  Pretumor progression: clonal evolution of human stem cell populations. , 2004, The American journal of pathology.

[118]  Douglas F. Easton,et al.  Polygenic susceptibility to breast cancer and implications for prevention , 2002, Nature Genetics.

[119]  Daniel Jones,et al.  Pathways to cancer therapy , 2008, Nature Reviews Drug Discovery.

[120]  K. Czene,et al.  Attributable risks of familial cancer from the Family-Cancer Database. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[121]  H. Yamamoto,et al.  Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer. , 1998, Cancer research.

[122]  Mark S. Clements,et al.  Multistage Carcinogenesis and Lung Cancer Mortality in Three Cohorts , 2005, Cancer Epidemiology Biomarkers & Prevention.

[123]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[124]  D. Freedman,et al.  Multistage models for carcinogenesis. , 1989, Environmental health perspectives.

[125]  Francesco Pompei,et al.  Age Distribution of Cancer: The Incidence Turnover at Old Age , 2001 .

[126]  L. Hayflick.  THE LIMITED IN VITRO LIFETIME OF HUMAN DIPLOID CELL STRAINS. , 1965, Experimental cell research.

[127]  B. Leggett,et al.  Promoter Hypermethylation Frequency and BRAF Mutations Distinguish Hereditary Non-Polyposis Colon Cancer from Sporadic MSI-H Colon Cancer , 2004, Familial Cancer.

[128]  S. Devesa,et al.  Assessing the impact of screening mammography: breast cancer incidence and mortality rates in Connecticut (1943–2002) , 2006, Breast Cancer Research and Treatment.

[129]  J. Stockman,et al.  Mortality in Relation to Smoking: 50 Years' Observations on Male British Doctors , 2006 .

[130]  D. Winn,et al.  Second cancer following cancer of the digestive system in Connecticut, 1935-82. , 1985, National Cancer Institute monograph.

[131]  K. Czene,et al.  Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish family‐cancer database , 2002, International journal of cancer.

[132]  John Durkin,et al.  Tools and applications , 2002 .

[133]  T. Iwama,et al.  Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. , 1996, Gastroenterology.

[134]  Asta Försti,et al.  Opinion: The balance between heritable and environmental aetiology of human disease , 2006, Nature Reviews Genetics.

[135]  T. Iwama,et al.  Frequent Mutation of β-Catenin and APC Genes in Primary Colorectal Tumors from Patients with Hereditary Nonpolyposis Colorectal Cancer , 1999 .

[136]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[137]  R. Sandler,et al.  Influence of target gene mutations on survival, stage and histology in sporadic microsatellite unstable colon cancers , 2006, International journal of cancer.

[138]  W. Foulkes,et al.  Inherited susceptibility to common cancers. , 2008, The New England journal of medicine.

[139]  K. Hemminki,et al.  Cancer risks to spouses and offspring in the family‐cancer database , 2001, Genetic epidemiology.

[140]  D. Schwartz.  Union Internationale Contre le Cancer (UICC) , 2005 .

[141]  J. Haber,et al.  Position effects in ectopic and allelic mitotic recombination in Saccharomyces cerevisiae. , 1989, Genetics.

[142]  C. Bonaïti‐pellié,et al.  Estimating penetrance from family data using a retrospective likelihood when ascertainment depends on genotype and age of onset , 2004, Genetic epidemiology.

[143]  Julian Peto,et al.  Cancer epidemiology in the last century and the next decade , 2001, Nature.

[144]  David Machin,et al.  Survival Analysis: A Practical Approach , 1995 .

[145]  P. Hartge,et al.  The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. , 1997, The New England journal of medicine.

[146]  Jacques Ferlay,et al.  Cancer incidence in five continents. , 1976, IARC scientific publications.

[147]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[148]  J. Waterhouse.  Cancer incidence in five continents, v.3 , 1976 .

[149]  R. Fishel,et al.  The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. , 2001, Cancer research.

[150]  A. Chapelle,et al.  Genetic predisposition to colorectal cancer , 2004, Nature Reviews Cancer.

[151]  R. Simon,et al.  Age-specific incidence of acute lymphoblastic leukemia in U.S. children: in utero initiation model. , 1997, Journal of the National Cancer Institute.

[152]  Julian P T Higgins,et al.  Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. , 2006, European journal of cancer.