Breast cancer family history and allele-specific DNA methylation in the legacy girls study

Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6–13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.     

Most lung and colon cancer susceptibility genes are pair-wise linked in mice, humans and rats

Genetic predisposition controlled by susceptibility quantitative trait loci (QTLs) contributes to a large proportion of common cancers. Studies of genetics of cancer susceptibility, however, did not address systematically the relationship between susceptibility to cancers in different organs. We present five sets of data on genetic architecture of colon and lung cancer susceptibility in mice, humans and rats. They collectively show that the majority of genes for colon and lung cancer susceptibility are linked pair-wise and are likely identical or related. Four CcS/Dem recombinant congenic strains, each differing from strain BALB/cHeA by a different small random subset of ±12.5% of genes received from strain STS/A, suggestively show either extreme susceptibility or extreme resistance for both colon and lung tumors, which is unlikely if the two tumors were controlled by independent susceptibility genes. Indeed, susceptibility to lung cancer (Sluc) loci underlying the extreme susceptibility or resistance of such CcS/Dem strains, mapped in 226 (CcS-10 x CcS-19)F2 mice, co-localize with susceptibility to colon cancer (Scc) loci. Analysis of additional Sluc loci that were mapped in OcB/Dem strains and Scc loci in CcS/Dem strains, respectively, shows their widespread pair-wise co-localization (P = 0.0036). Finally, the majority of published human and rat colon cancer susceptibility genes map to chromosomal regions homologous to mouse Sluc loci. 12/12 mouse Scc loci, 9/11 human and 5/7 rat colon cancer susceptibility loci are close to a Sluc locus or its homologous site, forming 21 clusters of lung and colon cancer susceptibility genes from one, two or three species. Our data shows that cancer susceptibility QTLs can have much broader biological effects than presently appreciated. It also demonstrates the power of mouse genetics to predict human susceptibility genes. Comparison of molecular mechanisms of susceptibility genes that are organ-specific and those with trans-organ effects can provide a new dimension in understanding individual cancer susceptibility.     

Quantitative trait locus mapping for atherosclerosis susceptibility

PURPOSE OF REVIEW: Atherosclerosis is a complex trait with both environmental and genetic aspects. Although some progress has been made in defining genes associated with atherosclerosis in humans, animal models have been useful in learning about pathways and genes involved in atherogenesis. This review describes an unbiased genetic mapping method called quantitative trait locus mapping and progress in using this method to identify genes that alter atherosclerosis susceptibility in mice. RECENT FINDINGS: Approximately 10 well defined genetic loci have been described that are associated with lesion severity in diet-induced or gene knockout mouse models of atherosclerosis. Recently, two of these genetic loci were narrowed considerably by analysis of genetic recombinants within these loci. In addition, a computational method to discover quantitative trait loci has been applied to atherosclerosis. However, none of the genes responsible for these atherosclerosis quantitative trait loci has been definitively identified. The recent completion of the mouse draft genome should facilitate the task of identifying these genes. SUMMARY: Quantitative trait locus mapping studies in mouse models of atherosclerosis have defined genetic regions that alter lesion severity. The identification of the responsible genes may lead to insights into the pathogenesis of atherosclerosis as well as to candidates for human genetic association studies.     

Genetic control of polyamine-dependent susceptibility to skin tumorigenesis

Overexpression of an ornithine decarboxylase (ODC) transgene greatly increases the susceptibility of mouse skin to carcinogen-induced tumor development. Like many phenotypes in transgenic models, this enhanced susceptibility phenotype is strongly influenced by genetic background. We have mapped tumor-modifier genes in intraspecific crosses between transgenic K6/ODC mice on a susceptible strain background (C57Bl/6J), a moderately resistant background (FVB), or a highly resistant background (C3H/HeJ). We identified several quantitative trait loci that influenced either tumor multiplicity or predisposition to the development of squamous cell carcinoma, but not both phenotypes. Because we did not use a tumor-promotion protocol to induce tumors, most of the quantitative trait loci mapped in this study are distinct from skin tumor-susceptibility loci identified previously. The use of a combined transgenic-standard strain approach to genetic analysis has resulted in detection of previously unknown genetic loci affecting skin tumor susceptibility.     

An algorithm for molecular dissection of tumor progression

The volumetric growth of tumor cells as a function of time is most often likely to be a complex trait, controlled by the combined influences of multiple genes and environmental influences. Genetic mapping has proven to be a powerful tool for detecting and identifying specific genes affecting complex traits, i.e., quantitative trait loci (QTL), based on polymorphic markers. In this article, we present a novel statistical model for genetic mapping of QTL governing tumor growth trajectories in humans. In principle, this model is a combination of functional mapping proposed to map function-valued traits and linkage disequilibrium mapping designed to provide high resolution mapping of QTL by making use of recombination events created at a historic time. We implement an EM-simplex hybrid algorithm for parameter estimation, in which a closed-form solution for the EM algorithm is derived to estimate the population genetic parameters of QTL including the allele frequencies and the coefficient of linkage disequilibrium, and the simplex algorithm incorporated to estimate the curve parameters describing the dynamic changes of cancer cells for different QTL genotypes. Extensive simulations are performed to investigate the statistical properties of our model. Through a number of hypothesis tests, our model allows for cutting-edge studies aimed to decipher the genetic mechanisms underlying cancer growth, development and differentiation. The implications of our model in gene therapy for cancer research are discussed.     

Y-a-t-il des gènes du cancer du testicule?

The reply to this question depends on a precise definition of the question. Does one mean genes that cause tumor formation, genes that are responsible for susceptibility to testicular cancer or genes that are associated with tumor progression? There is little evidence to support gene mutation as a cause of testicular cancer. Cancer formation is probably the result of a complex interaction between environmental factors and gene variants that may give a susceptiblity to cancer. Testicular cancer susceptibility genes are now being mapped. Recently a locus on Xq has been defined that is associated with some familial cases of germ cell tumors. Most of these cases have a history of cryptorchidism, so the locus may be responsible for a susceptibility t undecended testis. Other chromosomal rearrangements are associated with testicular cancer. These include interstitial deletions of 5q and 12q, and isochromosome 12p. The relationship between these changes and tumor formation or progression has yet to be established. Increasing evidence suggests that the isochromosome 12p may play an important role in testicular cancer, because this chromosomal rearrangment can be detected in carcinoma in situ cells which are considered to be the common ancestor of all types of testicular cancer. Multiple copies of a gene on 12p may influence cancer formation or development. A candidate factor is cyclin D2. This cyclin plays a key role in the progression of the cell cycle. Dysregulation of the cell cycle caused by the presence of an increased dose of cyclin D2 may play an important contribution in testicular cancer.     

The candidate gene approach in plant genetics: a review

The candidate gene (CG) approach has been applied in plant genetics in the past decade for the characterisation and cloning of Mendelian and quantitative trait loci (QTLs). It constitutes a complementary strategy to map-based cloning and insertional mutagenesis. The goal of this paper is to present an overview of CG analyses in plant genetics. CG analysis is based on the hypothesis that known-function genes (the candidate genes) could correspond to loci controlling traits of interest. CGs refer either to cloned genes presumed to affect a given trait (`functional CGs') or to genes suggested by their close proximity on linkage maps to loci controlling the trait (`positional CGs'). In plant genetics, the most common way to identify a CG is to look for map co-segregation between CGs and loci affecting the trait. Statistical association analyses between molecular polymorphisms of the CG and variation in the trait of interest have also been carried out in a few studies. The final validation of a CG will be provided through physiological analyses, genetic transformation and/or sexual complementation. Theoretical and practical applications of validated CGs in plant genetics and breeding are discussed.     

Genotype × diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F₂ mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F₂ mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL × diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL × diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.     

A wild-derived inbred mouse strain,MSM/Ms,provides insights into novel skin tumor susceptibility genes

Cancer is one of the most catastrophic human genetic diseases. Experimental animal cancer models are essential for gaining insights into the complex interactions of different cells and genes in tumor initiation, promotion, and progression. Mouse models have been extensively used to analyze the genetic basis of cancer susceptibility. They have led to the identification of multiple loci that confer, either alone or in specific combinations, an increased susceptibility to cancer, some of which have direct translatability to human cancer. Additionally, wild-derived inbred mouse strains are an advantageous reservoir of novel genetic polymorphisms of cancer susceptibility genes, because of the evolutionary divergence between wild and classical inbred strains. Here, we review mapped Stmm (skin tumor modifier of MSM) loci using a Japanese wild-derived inbred mouse strain, MSM/Ms, and describe recent advances in our knowledge of the genes responsible for Stmm loci in the 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) two-stage skin carcinogenesis model.     

Molecular genetics of atherosclerosis

Atherosclerosis is a complex multifocal arterial disease involving interactions of multiple genetic and environmental factors. Advances in techniques of molecular genetics have revealed that genetic polymorphisms significantly influence susceptibility to atherosclerotic vascular diseases. A large number of candidate genes, genetic polymorphisms and susceptibility loci associated with atherosclerotic diseases have been identified in recent years and their number is rapidly increasing. In this review we focus on some of the major candidate genes and genetic polymorphisms associated with human atherosclerotic vascular diseases.     

Genetic identification of multiple loci that control breast cancer susceptibility in the rat.

We have used a rat model of induced mammary carcinomas in an effort to identify breast cancer susceptibility genes. Using genetic crosses between the carcinoma-resistant Copenhagen (COP) and carcinoma-sensitive Wistar-Furth rats, we have confirmed the identification of the Mcs1 locus that modulates tumor number. We have now also identified two additional loci, Mcs2 and Mcs3. These three loci map to chromosomes 2, 7, and 1, respectively, and interact additively to suppress mammary carcinoma development in the COP strain. They are responsible for a major portion of the tumor-resistant phenotype of the COP rat. No loss of heterozygosity was observed surrounding the three loci. A fourth COP locus, Mcs4, has also been identified on chromosome 8 and acts in contrast to increase the number of carcinomas. These results show that mammary carcinoma susceptibility in the COP rat is a polygenic trait. Interestingly, a polymorphism in the human genomic region homologous to the rat Mcs4 region is associated with an increased breast cancer risk in African-American women. The isolation of the Mcs genes may help elucidate novel mechanisms of carcinogenesis, provide information important for human breast cancer risk estimation, and also provide unique drug discovery targets for breast cancer prevention.     

Mammary cancer susceptibility: human genes and rodent models

Breast cancer is a complex disease, showing a strong genetic component. Several human susceptibility genes have been identified, especially in the last few months. Most of these genes are low-penetrance genes and it is clear that numerous other susceptibility genes remain to be identified. The function of several susceptibility genes indicates that one critical biological pathway is the DNA damage response. However, other pathways certainly play a significant role in breast cancer susceptibility. Rodent models of breast cancer are useful models in two respects. They can help identify new mammary susceptibility genes by taking advantage of the very divergent susceptibilities exhibited by different mouse or rat strains and carrying out relevant genetic analyses. They also provide investigators with experimental systems that can help decipher the mechanism(s) of resistance to mammary cancer. Recent genetic and biological results obtained with mouse and especially with rat strains indicate that (1) numerous quantitative trait loci control mammary cancer susceptibility or resistance, with distinct loci acting in different strains, and (2) distinct resistance mechanisms operate in different rat resistant strains, precocious mammary differentiation being one of these mechanisms.     

Genetic Approaches to the Study of Gene Variants and Their Impact on the Pathophysiology of Type 2 Diabetes

Diabetes mellitus is an incurable progressive disease, characterized by elevated blood glucose levels, which lead to the development of micro- and macrovascular complications. Although the etiopathology of the disease remains unclear, it seems to be multifactorial, with an important interaction between genetics and environmental causes. Currently, the genetics of type 2 diabetes (T2D) is poorly understood. The recent advance of the genetic technologies and with a better understanding of genetics, more than 120 distinct genetic loci, with more than 150 variants, have been identified that may be involved in the pathogenesis of T2D. However, as these variants can account for only approximately 20% of the heritability of T2D, there is an obvious need for additional approaches to identify susceptibility genes or genetic mechanisms involved in the development of this disease. There is a growing number of genes found to be related to T2D; however, their individual impact on the pathogenesis of the disease appears to be low, while silencing of protective genes may also contribute to the development of this disease. The present review attempts to summarize our current knowledge in the field of genetics of T2D, highlighting the possible practical applications for each approach.     

Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature

Some cases of pancreatic cancer (PC) are described to cluster within families. With the exception of PALLD gene mutations, which explain only a very modest fraction of familial cases, the genetic basis of familial PC is still obscure. Here the literature was reviewed in order to list the known genes, environmental factors, and health conditions associated with PC or involved in the carcinogenesis of the pancreas. Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast–ovarian familial cancer), where PC is part of the cancer spectrum of the disease. In addition, in this review I ranked known/possible risk factors extending the analysis to the hereditary pancreatitis (HP), diabetes, or to specific environmental exposures such as smoking. It appears that these factors contribute strongly to only a small proportion of PC cases. Recent work has revealed new genes somatically mutated in PC, including alterations within the pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to reveal new candidate genes for the susceptibility to this disease and to better ascertain the actual contribution of the familial forms.     

高血压易感基因的分子进化

利用家系连锁分析、候选基因法及全基因组关联研究均未能有效发现普通人群的高血压易感基因或位点。遗传学研究表明, 人类许多疾病易感性的形成与走出非洲时的环境适应性进化密切相关, 这为高血压遗传学研究提供了新思路。文章系统综述了高血压易感基因分子进化研究的理论基础和最新进展, 介绍了本研究小组运用分子进化思路在中国汉族人群高血压遗传学研究中的发现, 对未来的研究方向进行了展望, 以期为高血压和其他疾病的遗传学研究提供参考。     

Genomic approaches to identification of tumour-susceptibility genes using mouse models

Individual susceptibility to cancer in humans is determined by complex interactions between germline genetic variation and levels of exposure to environmental carcinogens or tumour promoters. Only a small fraction of cancer susceptibility is inherited in a Mendelian manner (high-penetrance familial cancer), and most tumours result from the combined effects of many gene-gene and gene-environment interactions. The sequencing of the mouse genome provides new approaches to one of the most challenging tasks of cancer genetics today.     

Systemic Regulation of RAS/MAPK Signaling by the Serotonin Metabolite 5-HIAA

Human cancer is caused by the interplay of mutations in oncogenes and tumor suppressor genes and inherited variations in cancer susceptibility genes. While many of the tumor initiating mutations are well characterized, the effect of genetic background variation on disease onset and progression is less understood. We have used C. elegans genetics to identify genetic modifiers of the oncogenic RAS/MAPK signaling pathway. Quantitative trait locus analysis of two highly diverged C. elegans isolates combined with allele swapping experiments identified the polymorphic monoamine oxidase A (MAOA) gene amx-2 as a negative regulator of RAS/MAPK signaling. We further show that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), which is a product of MAOA catalysis, systemically inhibits RAS/MAPK signaling in different organs of C. elegans. Thus, MAOA activity sets a global threshold for MAPK activation by controlling 5-HIAA levels. To our knowledge, 5-HIAA is the first endogenous small molecule that acts as a systemic inhibitor of RAS/MAPK signaling.     

Gene-Expression Profiling of Experimental Autoimmune Encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a mouse model that serves as an experimental tool for studying the etiology, pathogenesis, as well as new therapeutic approaches of multiple sclerosis (MS). EAE is a polygenic chronic inflammatory demyelinating disease of the nervous system that involves the interaction between genetic and environmental factors. Previous studies have identified multiple quantitative trait loci (QTL) controlling different aspects of disease pathogenesis. However, progress in identifying new susceptibility genes outside the MHC locus has been slow. With the advent of new global methods for genetic analysis such as large-scale sequencing, gene expression profiling combined with classic linkage analysis and congenic and physical mapping progress is considerably accelerating. Here we review our preliminary work on the use of gene expression mapping to identify new putative genetic pathways contributing to the pathogenesis of EAE.     

Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice

Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human.