To identify a novel susceptibility gene for colorectal cancer (CRC), we conducted a genome-wide linkage analysis of 69 pedigrees segregating colorectal neoplasia in which involvement of known loci had been excluded, using a high-density single nucleotide polymorphism (SNP) array containing 10,204 markers. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of SNPs in strong linkage disequilibrium, we obtained a maximum non-parametric linkage statistic of 3.40 (P=0.0003) at chromosomal region 3q21-q24. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=3.10, genome-wide P=0.038) with 62% of families linked to the locus. We provide evidence for a novel CRC susceptibility gene. Further studies are needed to confirm this localization and to evaluate the contribution of this locus to disease incidence.
\n \n\n \n \nAneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
\n \n\n \n \nThis chapter outlines the contribution of inherited genetic variation to cancer susceptibility and of acquired somatic mutations to cancer growth. The chapter deals with all forms of cancer susceptibility from rare, high-penetrance Mendelian syndromes to common alleles with small effects with importance for population risk. The section on somatic cancer genetics deals with underlying processes, such as genomic instability, and the types of functional change that result in the growth of both benign and malignant tumors. Genetic and epigenetic changes in cancers, from chromosomal scale to small mutations, are discussed. Overall, rather than performing an exhaustive survey in this large field, the chapter outlines the principles of cancer genetics using examples from both common and rare tumor types.
\n \n\n \n \nBACKGROUND: Genomewide association studies have identified 10 low-penetrance loci that confer modestly increased risk for colorectal cancer (CRC). Although they underlie a significant proportion of CRC in the general population, their impact on the familial risk for CRC has yet to be formally enumerated. The aim of this study was to examine the combined contribution of the 10 variants, rs6983267, rs4779584, rs4939827, rs16892766, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, on familial CRC. METHODS: The population-based series of CRC samples included in this study consisted of 97 familial cases and 691 sporadic cases. Genotypes in the 10 loci and clinical data, including family history of cancer verified from the Finnish Cancer Registry, were available. The overall number of risk alleles (0-20) was determined, and its association with familial CRC was analyzed. Excess familial risk was estimated using cancer incidence data from the first-degree relatives of the cases. RESULTS: A linear association between the number of risk alleles and familial CRC was observed (P = 0.006). With each risk-allele addition, the odds of having an affected first-degree relative increased by 1.16 (95% confidence interval, 1.04-1.30). The 10 low-penetrance loci collectively explain approximately 9% of the variance in familial risk for CRC. CONCLUSIONS: This study provides evidence to support the previous indirect estimations that these low-penetrance variants account for a relatively small proportion of the familial aggregation of CRC. IMPACT: Our results emphasize the need to characterize the remaining molecular basis of familial CRC, which should eventually yield in individualized targeting of preventive interventions.
\n \n\n \n \nThe mammalian intestinal epithelium is a rapidly renewing tissue in which tissue homeostasis is regulated by a balance between cell proliferation, differentiation, and apoptosis. Over the last three decades, investigators have described the structure and cell kinetics of the functional unit\u2014the intestinal crypt (known as the crypt of Lieberku\u00a8hn in the small intestine)\u2014and evidence has accumulated to support the concept that there are principally four differentiated intestinal cell types (enterocytes, mucosecreting or goblet cells, enteroendocrine cells, and Paneth cells in the small intestine), derived from a common pluripotent progenitor cell, the intestinal stem cell, located at or just above the bottom of the intestinal crypt. The first half of this chapter will review the evidence behind these prevailing concepts. Until recently, chapters on intestinal stem cells concluded.
\n \n\n \n \nObjective:To screen LKB1 mutation in sporadic colon and ovarian tumors. Methods: Using PCR-SSCP analysis, 72 colon cancer, 45 ovarian cancer, 14 granulosa cell tumor were screened for LKB1 mutation. Results: no mutation was in sporadic colon and ovarian adenocarcinomas. Two mutations were detected in one of the granulosa cell tumors: a mis-sense mutation affecting the putative start codon (ATG\u2192ACG, MIT); and a silent change in erxon 7 (CTT\u2192CTA, leucine). Conclusion: LKB1 mutations in sporadic colon and ovarian cancers are rare event and LKB1 is not the target gene lost on chromosome 19p13.3 in ovarian cancers.
\n \n\n \n \nWhen females choose a mate, they may do so on the basis of some arbitrary character or they may prefer a trait that provides them with some direct or indirect benefit. One class of models of female choice, collectively referred to as the 'handicap principle', states that preferred ornaments act as markers of underlying heritable male fitness. 'Handicap' models have proved to be of great importance in explaining how female mating preferences can coevolve with male ornaments by an augmented form of the 'Fisherian process'. We suggest that differences in heritable female (Darwinian) fitness might affect the evolution of female mating preferences. Although little experimental evidence currently exists, it is entirely plausible that female fitness affects the expression of mating preferences. For example, fitter females might undertake more rigorous searches for rare, preferred males. In order to determine whether differences in female fitness can influence sexual selection by female choice, a model is presented in which mating preferences are more likely to be expressed by females of higher fitness. Results of the model show how specific female preferences for arbitrary, disadvantageous male characters can easily evolve, even if choice itself is costly. In many of these cases, the Fisherian process alone would not be sufficient to cause coevolution of preference and preferred character. Polymorphisms in male characters may also be maintained in the fitter female models. Some of the models show extreme and unusual fluctuations in the frequencies of male characters and female preferences before equilibrium is reached. Differences in female fitness may have important influences on sexual selection by female choice.
\n \n\n \n \nIn some studies of the two-spot ladybird (Adalia bipunctata), melanic males have been found in excess over the typical morph in matings. Data suggest that a genetic female mating preference is responsible. The mating advantage of melanic males may be important in maintaining a polymorphism between melanic and typical ladybirds in many populations in the United Kingdom (U. K.). It has been reported that preference frequency varies linearly with melanic frequency throughout most of the U.K. One particular population of Adalia bipunctata near Aberdare, South Wales, is noted for its high frequency of melanic individuals. It has been suggested that local environmental factors account for the high melanic frequency in this population. It is also possible, however, that a female mating preference may be at least partly responsible for the high frequency of melanics (as has been proposed for the rest of the U.K.). In this study, experiments have been performed to determine the level of female mating preference in the Aberdare population. No evidence was found for any mating advantage to melanic males. There was inconsistent and unexpected evidence that melanic females were overrepresented in matings, but the cause for this was unclear. Female mating preference does not appear, therefore, to be responsible for the high melanic frequency in the population of Adalia bipunctata near Aberdare. There is not a simple association between mating preference and melanic frequency in U.K. populations of the two-spot ladybird.
\n \n\n \n \nTests for non-random mating in laboratory stocks of Adalia bipunctata showed that female two- spot ladybirds from \u2018isofemale lines\u2019, which had formerly mated preferentially with melanic males, now mated at random. In an attempt to obtain new stocks in which females mated preferentially, we isolated \u2018isofemale lines\u2019 from a natural population at Keele, but we found no evidence of females mating preferentially within these stocks. We did, however, observe two interesting phenomena, not previously reported from Keele populations of Adalia bipunctata, or from laboratory stocks derived from the Keele population. Firstly, much of the variation in male mating success, which we observed, could be explained by the date on which the mating tests were carried out. Secondly, there was significant heterogeneity in sex ratios among some of the stocks. We discuss the potential importance of both these phenomena when designing experiments and interpreting data regarding non-random mating in Adalia bipunctata. \u00a9 1992 The Genetical Society of Great Britain.
\n \n\n \n \nThere is contradictory evidence concerning non-random mating among melanic and non-melanic phenotypes of Adalia bipunctata. Although most studies have found a mating advantage in favour of melanic individuals, one found random mating. Furthermore, in some samples the melanic mating advantage was frequency-dependent though not in others. In one population males alone gained a frequency-dependent mating advantage, and it has been argued that this is a result of a female sexual preference. There is no direct evidence for mate choice from any other population. In any case, melanic individuals of both sexes often gain a mating advantage so if mate choice is relevant, then these populations must contain \u201cchoosy\u201d males as well as \u201cchoosy\u201d females. Some of these apparent contradictions are explained by insufficient sampling and/or unsatisfactory statistical analysis. Nevertheless, populations are clearly different from one another and this is important when considering the nature of the melanic mating advantage. \u00a9 1990, The Genetical Society of Great Britain.
\n \n\n \n \nMost models of sexual selection by female choice have considered discrete, homogenous populations. This paper studies the evolution of a female preference along a cline in the frequency of a preferred male trait. Single alleles control both the preference and preferred character. Fisher's process initially causes the preference to spread to some \u2018maximum\u2019 frequency with a corresponding rise in character gene frequency. At this stage, the cline in preference does not necessarily mirror that of the trait. Then, however, preference frequency usually decreases, albeit very slowly, and the preference cline always comes to mirror that of the preferred character. Eventually, preference is completely lost from the cline and the character cline decays to that seen under random mating. This loss can only be prevented if the preference is initially frequent enough to push the character to fixation throughout the cline. Consequently, a preference that arises after the preferred trait may increase very little in frequency itself and have a negligible effect on trait frequency before being lost from the population. Special conditions, such as cyclical natural selection, may be necessary to explain the spread of a preference in a cline from a low initial frequency to frequencies as high as those observed. A preference that predates the preferred trait can enter the population at a high frequency and radically alter a cline in the frequency of a preferred male trait, albeit often transiently. Copyright \u00a9 1989, Wiley Blackwell. All rights reserved
\n \n\n \n \n\"Fisherian\" models of sexual selection by female choice assume that females prefer male characters which are initially advantageous or neutral; character and preference then spread through the population. Once female preference has evolved to a higher frequency, the male character can become more extreme and disadvantageous by the action of some force such as the \"super-normal stimulus\". By contrast, the \"handicap principle\" of sexual selection proposes that females should prefer more extreme, disadvantaged males: males who survive the disadvantage of the \"handicap\" must be fitter in other respects. Previous models of various forms of the \"handicap principle\" have shown that it is very unlikely to work as an alternative to the \"Fisherian process\". However, recent haploid models have shown that a \"condition-dependent handicap\" might evolve. Diploid models show that the \"condition-dependent handicap\" model does not work. Models of \"handicaps\" operating together with the \"Fisherian process\" are also presented. It is inferred that \"Fisherian\" models are more likely than \"handicap\" models to account for the evolution of male sexual ornaments, although a \"handicap\" mechanism may aid the operation of the \"Fisherian process\".
\n \n\n \n \n