A statistical model for the identification of genes governing the incidence of cancer with age

The cancer incidence increases with age. This epidemiological pattern of cancer incidence can be attributed to molecular and cellular processes of individual subjects. Also, the incidence of cancer with ages can be controlled by genes. Here we present a dynamic statistical model for explaining the epidemiological pattern of cancer incidence based on individual genes that regulate cancer formation and progression. We incorporate the mathematical equations of age-specific cancer incidence into a framework for functional mapping aimed at identifying quantitative trait loci (QTLs) for dynamic changes of a complex trait. The mathematical parameters that specify differences in the curve of cancer incidence among QTL genotypes are estimated within the context of maximum likelihood. The model provides testable quantitative hypotheses about the initiation and duration of genetic expression for QTLs involved in cancer progression. Computer simulation was used to examine the statistical behavior of the model. The model can be used as a tool for explaining the epidemiological pattern of cancer incidence.     

Similarities in the Age-Specific Incidence of Colon and Testicular Cancers

Colon cancers are thought to be an inevitable result of aging, while testicular cancers are thought to develop in only a small fraction of men, beginning in utero. These models of carcinogenesis are, in part, based upon age-specific incidence data. The specific incidence for colon cancer appears to monotonically increase with age, while that of testicular cancer increases to a maximum value at about 35 years of age, then declines to nearly zero by the age of 80. We hypothesized that the age-specific incidence for these two cancers is similar; the apparent difference is caused by a longer development time for colon cancer and the lack of age-specific incidence data for people over 84 years of age. Here we show that a single distribution can describe the age-specific incidence of both colon carcinoma and testicular cancer. Furthermore, this distribution predicts that the specific incidence of colon cancer should reach a maximum at about age 90 and then decrease. Data on the incidence of colon carcinoma for women aged 85–99, acquired from SEER and the US Census, is consistent with this prediction. We conclude that the age specific data for testicular cancers and colon cancers is similar, suggesting that the underlying process leading to the development of these two forms of cancer may be similar.     

Parallel Routes of Human Carcinoma Development: Implications of the Age-Specific Incidence Data

Background

The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data.

Methodology/Principal Findings

To test the parallel route hypothesis, I formulated it in terms of a mathematical equation and then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. The age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups.

Conclusions/Significance

I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population, while the multi-stage hypothesis is inconsistent with this data.     

Age-specific incidence data indicate four mutations are required for human testicular cancers

Normal human cells require a series of genetic alterations to undergo malignant transformation. Direct sequencing of human tumors has identified hundreds of mutations in tumors, but many of these are thought to be unnecessary and a result of, rather than a cause of, the tumor. The exact number of mutations to transform a normal human cell into a tumor cell is unknown. Here I show that male gonadal germ cell tumors, the most common form of testicular cancers, occur after four mutations. I infer this by constructing a mathematical model based upon the multi-hit hypothesis and comparing it to the age-specific incidence data. This result is consistent with the multi-hit hypothesis, and implies that these cancers are genetically or epigenetically predetermined at birth or an early age.     

Targeting signal transduction pathways by chemopreventive agents

Cancer is a dynamic process that involves many complex factors, which may explain why a "magic bullet" cure for cancer has not been found. Death rates are still rising for many types of cancers, which possibly contributes to the increased interest in chemoprevention as an alternative approach to the control of cancer. This strategy for cancer control is based on the presumption that because cancer develops through a multi-step process, each step may be a prospective target for reversing or suppressing the process. Thus, the design and development of chemopreventive agents that act on specific and/or multiple molecular and cellular targets is gaining support as a rational approach to control cancer. Nutritional or dietary factors have attracted a great deal of interest because of their perceived ability to act as highly effective chemopreventive agents. They are professed as being generally safe and may have efficacy as chemopreventive agents by preventing or reversing premalignant lesions and/or reducing second primary tumor incidence. Many of these dietary compounds appear to act on multiple target signaling pathways. Some of the most interesting and well documented are resveratrol and components of tea, including EGCG, theaflavins and caffeine. This review will focus on recent work regarding three well-accepted cellular/molecular mechanisms that may at least partially explain the effectiveness of selected food factors, including those indicated above, as chemopreventive anti-promotion agents. These food compounds may act by: (1) inducing apoptosis in cancer cells; (2) inhibiting neoplastic transformation through the inhibition of AP-1 and/or NF-kappaB activation; and/or (3) suppressing COX-2 overexpression in cancer cells.     

A framework for how environment contributes to cancer risk

Evolutionary theory explains why metazoan species are largely protected against the negative fitness effects of cancers. Nevertheless, cancer is often observed at high incidence across a range of species. Although there are many challenges to quantifying cancer epidemiology and assessing its causes, we claim that most modern‐day cancer in animals – and humans in particular – are due to environments deviating from central tendencies of distributions that have prevailed during cancer resistance evolution. Such novel environmental conditions may be natural and/or of anthropogenic origin, and may interface with cancer risk in numerous ways, broadly classifiable as those: increasing organism body size and/or life span, disrupting processes within the organism, and affecting germline. We argue that anthropogenic influences, in particular, explain much of the present‐day cancer risk across life, including in humans. Based on a literature survey of animal species and a parameterised mathematical model for humans, we suggest that combined risks of all cancers in a population beyond c. 5% can be explained to some extent by the influence of novel environments. Our framework provides a basis for understanding how natural environmental variation and human activity impact cancer risk, with potential implications for species ecology.     

The impact of demographic changes on the epidemiology of herpes zoster: Spain as a case study

Varicella zoster virus (VZV) causes varicella upon first exposure and may reactivate later in life into herpes zoster (HZ), with a risk that is thought to be reduced by re-exposures to VZV. Given the decades-long time scales of reactivation and its dependence on the accumulation of re-exposure episodes, adopting a long-term perspective may be useful to correctly interpret current epidemiological trends of VZV. In this study, we investigate the possible impact of demographic changes on varicella and HZ in Spain, using an age-structured mathematical model informed with historical demographic data and calibrated against age-specific profiles of varicella seroprevalence and HZ incidence data. The model qualitatively reproduces the remarkable growth of HZ incidence observed in Spain between 1997 and 2004, before the introduction of varicella vaccination programmes. We demonstrate that this growth may be partially ascribed to the reduction of varicella circulation that followed the overall decline of the birth rate in the twentieth century. Model predictions further suggest that, even under the most optimistic projections, HZ incidence will continue its rise until at least 2040. Considering the effect of demographic changes can help interpreting variations in epidemiological trends of HZ, contributing to a more accurate evaluation of vaccination programmes against VZV.     

Age Distribution of Cancer: The Incidence Turnover at Old Age

In recent years data on cancer incidence in the USA, the Netherlands, and in Hong Kong indicate a flattening and perhaps a turnover at advanced age, but no model has been successful in fitting this data and thus providing clues to the underlying biology. In this work we assume these data are reliable and free from bias. We find that a Beta distribution fits SEER age-specific cancer incidence data for all adult cancers extremely well, and its interpretation as a model leads to the possibility that there is a beneficial cancer extinction process that becomes important at elevated age. Particularly evident from the data is the apparent remarkable uniformity of adult cancers peaking in incidence at about the same age, including cancers in other countries. Possible biological mechanisms include increasing apoptosis and cell senescence with age. Further, the model suggests that cancer is not inevitable at advanced age, but reaches a maximum cumulative probability of affliction with any cancer of about 70% for men and 53% for women in the US, and much smaller values for individual cancers.     

Cells deficient in base-excision repair reveal cancer hallmarks originating from adjustments to genetic instability

Genetic instability, provoked by exogenous mutagens, is well linked to initiation of cancer. However, even in unstressed cells, DNA undergoes a plethora of spontaneous alterations provoked by its inherent chemical instability and the intracellular milieu. Base excision repair (BER) is the major cellular pathway responsible for repair of these lesions, and as deficiency in BER activity results in DNA damage it has been proposed that it may trigger the development of sporadic cancers. Nevertheless, experimental evidence for this model remains inconsistent and elusive. Here, we performed a proteomic analysis of BER deficient human cells using stable isotope labelling with amino acids in cell culture (SILAC), and demonstrate that BER deficiency, which induces genetic instability, results in dramatic changes in gene expression, resembling changes found in many cancers. We observed profound alterations in tissue homeostasis, serine biosynthesis, and one-carbon- and amino acid metabolism, all of which have been identified as cancer cell ‘hallmarks’. For the first time, this study describes gene expression changes characteristic for cells deficient in repair of endogenous DNA lesions by BER. These expression changes resemble those observed in cancer cells, suggesting that genetically unstable BER deficient cells may be a source of pre-cancerous cells.     

Cancer and aging: a model for the cancer promoting effects of the aging stroma

The incidence of cancer rises exponentially with age in humans and many other mammalian species. Malignant tumors are caused by an accumulation of oncogenic mutations. In addition, malignant tumorigenesis requires a permissive tissue environment in which mutant cells can survive, proliferate, and express their neoplastic phenotype. We propose that the age-related increase in cancer results from a synergy between the accumulation of mutations and age-related, pro-oncogenic changes in the tissue milieu. Most age-related cancers derive from the epithelial cells of renewable tissues. An important element of epithelial tissues is the stroma, the sub-epithelial layer composed of extracellular matrix and several cell types. The stroma is maintained, remodeled and repaired by resident fibroblasts, supports and instructs the epithelium, and is essential for epithelial function. One change that occurs in tissues during aging is the accumulation of epithelial cells and fibroblasts that have undergone cellular senescence. Cellular senescence irreversibly arrests proliferation in response to damage or stimuli that put cells at risk for neoplastic transformation. Senescent cells secrete factors that can disrupt tissue architecture and/or stimulate nearby cells to proliferate. We therefore speculate that their presence may create a pro-oncogenic tissue environment that synergizes with oncogenic mutations to drive the rise in cancer incidence with age. Recent evidence lends support to this idea, and suggests that senescent stromal fibroblasts may be particularly adept at creating a tissue environment that can promote the development of age-related epithelial cancers.     

Nutrition, insulin, insulin-like growth factors and cancer.

The incidence of colon, pancreatic, and kidney cancers, as well as aggressive prostate cancer in men, and breast and endometrial cancer in women is invariably high in Western countries. Nutritional and related factors have been typically implicated. This review presents a model integrating nutrition, insulin and IGF-1 physiology ("bioactive" IGF-1), and carcinogenesis based on the following: (1) insulin and the IGF-1 axis function in an integrated fashion to promote cell growth and survival; (2) chronic exposure to these growth properties enhances carcinogenesis; (3) factors that influence bioactive IGF-1 will affect cancer risk. The model presented here summarizes the data that chronic exposure to high levels of insulin and IGF-1 may mediate many of the risk factors for some cancers that are high in Western populations. This hypothesis may help explain some of the epidemiologic patterns observed for these cancers, both from a cross-national perspective and within populations. Of particular importance is that some of relevant factors are modifiable through nutritional and lifestyle interventions. Out of a variety of perspectives presented, nutritional manipulation through the insulin pathway may be more feasible than attempting to influence total IGF-1 concentrations, which are determined largely by growth hormone. Further study is required to test these conclusions.     

Testing and characterizing the two-stage model of carcinogenesis for a wide range of human cancers

The age dependence of incidence for 45 cancer types in three populations is analyzed on a two-stage kinetic model containing three determinable parameters: (i) the fraction of population at risk for a cancer; (ii) the product of the frequencies of cancer-producing mutations, and (iii) the growth rate of the transformed clone from which a cancer ultimately evolves. The model, simplifying that proposed by others, fits many cancers. Data are easily handled in terms of the derived parameters, providing the basis for epidemiological analysis, here applied in detail to liver, cervix and testis cancers for nearly 50 world-wide populations. We identify 12 cancers for which only a limited fraction of the population is at risk. We argue that the appearance of most cancers requires at least three mutational events. For child, youth, or early adult cancers, one mutation may be congenital. We arrange the various cancers in a descending scale, defining six groups that differ in the derived mutation frequencies. A cancer appearing later in life, for which the whole population can be at risk, shows a low mutation frequency, consistent with background spontaneous mutation. The other cancers require increases in mutation frequency, arising from an increased rate of cell division and/or mutation rate.     

Is the Initial Event in Carcinogenesis An Enhancement of the Mutation Rate?

The age-specific incidence rates of adult cancer indicate that the carcinogenic process is a power function of elapsed time. If the malignant clone arises by a series of mutations, and each mutation is regarded as an independent event with a small instantaneous probability of occurrence, then the slope of the age-specific incidence gives an indication of the number of genes involved. In most cases, the epidemiological data exhibit an age-specific incidence the slope of which is between a fourth and a seventh power of age. Assuming that the mutations involved are deletions and must occur in otherwise viable and proliferative cells, the mutation rate required to generate enough mutant cells to fit the cancer incidence data must be remarkably high in the pre-malignant cell population. The initiation process may thus be an event that results in a raised mutation rate in the affected cell and its progeny. It is proposed that the process of induction involves one or more mutations that induce a metabolic lesion that has the effect of increasing the subsequent mutation rate in the affected clone. A possible mechanism involving free radical generation is suggested and some of the biological implications of the proposal examined.     

Is the Initial Event in Carcinogenesis An Enhancement of the Mutation Rate?

The age-specific incidence rates of adult cancer indicate that the carcinogenic process is a power function of elapsed time. If the malignant clone arises by a series of mutations, and each mutation is regarded as an independent event with a small instantaneous probability of occurrence, then the slope of the age-specific incidence gives an indication of the number of genes involved. In most cases, the epidemiological data exhibit an age-specific incidence the slope of which is between a fourth and a seventh power of age. Assuming that the mutations involved are deletions and must occur in otherwise viable and proliferative cells, the mutation rate required to generate enough mutant cells to fit the cancer incidence data must be remarkably high in the pre-malignant cell population. The initiation process may thus be an event that results in a raised mutation rate in the affected cell and its progeny. It is proposed that the process of induction involves one or more mutations that induce a metabolic lesion that has the effect of increasing the subsequent mutation rate in the affected clone. A possible mechanism involving free radical generation is suggested and some of the biological implications of the proposal examined.     

HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story

Human leukocyte antigen (HLA) class I molecule downregulation occurs frequently in many cancers, and this abnormality might adversely affect the clinical course of cancer and the outcome of T-cell-based immunotherapy. Mutations in the HLA class I genes themselves, abnormalities in their regulation and/or defects in HLA class I-dependent antigen processing can underlie HLA class I downregulation. These mutations modulate the susceptibility of tumor cells to in vitro lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Immune selection of CTL- and NK-cell-resistant tumor cells might explain the rapid progression and poor prognosis of cancers that exhibit HLA class I downregulation. These findings provide compelling evidence that HLA class I downregulation represents a significant challenge for the successful application of T-cell-based immunotherapy of cancer.     

The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer

Short-chain fatty acids are the major by-products of bacterial fermentation of undigested fibers in the colon. SCFAs, mostly propionate and butyrate, induce differentiation, growth arrest, and apoptosis in colon cancer cells. The anticancer effect of SCFAs is also supported by epidemiological studies suggesting an inverse relationship between the level of dietary fibers and the incidence of human colon cancer. Dietary components influence the risk of human colon cancer including colon cancer through diverse mechanisms, which include the activation or inhibition of autophagy (type II programmed cell death (PCD)). Herein we demonstrate that propionate and butyrate induce autophagy in human colon cancer cells to dampen apoptosis, whereas inhibition of autophagy potentiates SCFA-induced apoptosis. The propionate-induced autophagy originates from mitochondria defects associated with cellular ATP depletion and ROS generation, both of which contribute to AMPK activation and consequential mTOR inhibition. Remarkably, when autophagy is suppressed through either pharmacological or genetic approaches, the colon cancer cells become sensitized toward propionate-induced apoptotic cell death (type I PCD). Our study is the first report characterizing this novel role of SCFAs in orchestrating two types of programmed cell death. The observed pro-survival effects of autophagy in retarding mitochondria-mediated apoptosis suggest that application of an autophagy inhibitor might improve the therapeutic efficacy of SCFAs in inducing colon cancer suppression.     

From humans to hydra: patterns of cancer across the tree of life

Cancer is a disease of multicellularity; it originates when cells become dysregulated due to mutations and grow out of control, invading other tissues and provoking discomfort, disability, and eventually death. Human life expectancy has greatly increased in the last two centuries, and consequently so has the incidence of cancer. However, how cancer patterns in humans compare to those of other species remains largely unknown. In this review, we search for clues about cancer and its evolutionary underpinnings across the tree of life. We discuss data from a wide range of species, drawing comparisons with humans when adequate, and interpret our findings from an evolutionary perspective. We conclude that certain cancers are uniquely common in humans, such as lung, prostate, and testicular cancer; while others are common across many species. Lymphomas appear in almost every animal analysed, including in young animals, which may be related to pathogens imposing selection on the immune system. Cancers unique to humans may be due to our modern environment or may be evolutionary accidents: random events in the evolution of our species. Finally, we find that cancer‐resistant animals such as whales and mole‐rats have evolved cellular mechanisms that help them avoid neoplasia, and we argue that there are multiple natural routes to cancer resistance.     

Under-diagnosis and under-ascertainment of cases may be the reasons for low childhood cancer incidence in rural India

Cancer statistics from India revealed that childhood cancer incidence is lesser in rural than urban India. This might be due to under-diagnosis or under-ascertainment of cases or could even be true. With registries able to explicitly measure and appropriately streamline the ascertainment of cases to comply with acceptable standards, it is under-diagnosis that is variable and highly influenced by development of or accessibility to specialized centres in or around the registry area. This is reflected implicitly by marked variation in incidence between different populations in India: weighted age standardized rates of all childhood cancers together was the highest (108 per million) in metropolitan areas, followed by other urban (86) and rural (53) areas in that order. A childhood cancer registry focusing on pertinent data collection and specific epidemiological studies is desirable to explain the variations in incidence and outcome of childhood cancers in India.     

Abortive autophagy induces endoplasmic reticulum stress and cell death in cancer cells

Autophagic cell death or abortive autophagy has been proposed to eliminate damaged as well as cancer cells, but there remains a critical gap in our knowledge in how this process is regulated. The goal of this study was to identify modulators of the autophagic cell death pathway and elucidate their effects on cellular signaling and function. The result of our siRNA library screenings show that an intact coatomer complex I (COPI) is obligatory for productive autophagy. Depletion of COPI complex members decreased cell survival and impaired productive autophagy which preceded endoplasmic reticulum stress. Further, abortive autophagy provoked by COPI depletion significantly altered growth factor signaling in multiple cancer cell lines. Finally, we show that COPI complex members are overexpressed in an array of cancer cell lines and several types of cancer tissues as compared to normal cell lines or tissues. In cancer tissues, overexpression of COPI members is associated with poor prognosis. Our results demonstrate that the coatomer complex is essential for productive autophagy and cellular survival, and thus inhibition of COPI members may promote cell death of cancer cells when apoptosis is compromised.