Accumulation Of Chromosomal Aberrations Research Articles

Stability analysis of mixtures of mutagenetic trees

BackgroundMixture models of mutagenetic trees are evolutionary models that capture several pathways of ordered accumulation of genetic events observed in different subsets of patients. They were used to model HIV progression by accumulation of resistance mutations in the viral genome under drug pressure and cancer progression by accumulation of chromosomal aberrations in tumor cells. From the mixture models a genetic progression score (GPS) can be derived that estimates the genetic status of single patients according to the corresponding progression along the tree models. GPS values were shown to have predictive power for estimating drug resistance in HIV or the survival time in cancer. Still, the reliability of the exact values of such complex markers derived from graphical models can be questioned.ResultsIn a simulation study, we analyzed various aspects of the stability of estimated mutagenetic trees mixture models. It turned out that the induced probabilistic distributions and the tree topologies are recovered with high precision by an EM-like learning algorithm. However, only for models with just one major model component, also GPS values of single patients can be reliably estimated.ConclusionIt is encouraging that the estimation process of mutagenetic trees mixture models can be performed with high confidence regarding induced probability distributions and the general shape of the tree topologies. For a model with only one major disease progression process, even genetic progression scores for single patients can be reliably estimated. However, for models with more than one relevant component, alternative measures should be introduced for estimating the stage of disease progression.

Chromosomal Biomarkers for Detection of Human Papillomavirus Associated Genomic Instability in Epithelial Cells of Cervical Cytology Specimens

The goal of this study was to compare how accumulation of chromosomal aberrations in human papillomavirus (HPV)-infected cells correlates with the severity of cervical dysplastic lesions. We assessed the frequency of genomic alterations for 35 different loci in a pilot biopsy study and selected two loci (3q26 and 8q24) with the highest frequency of copy number gains found in high-grade dysplasia and cancer. These probes were labeled with gold and red fluorophores and combined with HPV biotin-labeled probes for subsequent detection using a tyramide signal amplification system with a green fluorophore. Cells that were both HPV positive and chromosomally abnormal were designated as "double-positive cells." Cervical cytology specimens from 235 patients were used for this blinded study. The average number of double-positive cells increased from two cells in patients with a cytological interpretation of atypical squamous cells of undetermined significance to 22 cells in low-grade squamous intraepithelial lesion and 99 cells in high-grade squamous intraepithelial lesion, reflecting an accumulation of chromosomal abnormality with disease progression. Using a cutoff of four or more double-positive cells as the criterion for the presence of a cervical intraepithelial neoplasia 2 or 3 lesion, we demonstrated that low-grade squamous intraepithelial lesion and high-grade squamous intraepithelial lesion cytology specimens with underlying cervical intraepithelial neoplasia 2/3 histology showed positive test results in more than 80% of cases. Correlation of 3q26 and 8q24 aneusomy with concurrent HPV infection may thus serve as a biomarker of genetic instability in HPV-infected cells.

Amplificación del oncogén ccnd1 y contenido celular de adn en los carcinomas epidermoides de cabeza y cuello

Cyclin d1 protein (encoded by the ccnd1 gene) contributes to the progression of the cell cycle in the g1/s checkpoint. Cyclin d1 overexpression (for instance as a consequence of ccnd1 amplification) might result in loss of control over genetic damage at this point and in an accumulation of chromosomal aberrations. In this work we analyze whether ccnd1 amplification is associated with a higher incidence of alterations in cellular Dna content. 31 squamous cell carcinomas of the head and neck were studied. ccnd1 amplification was determined by polymerase chain reaction. Cellular Dna content was determined by flow cytometry. ccnd1 amplification was found in 6 (19%) cases. Thirteen (42%) cases were diploid and 18 (58%) were aneuploid. Two (33%) of the 6 cases with ccnd1 amplification were aneuploid compared with 16 (64%) of the cases without ccnd1 amplification (P=0.36). We conclude that ccnd1 amplification is not associated to a higher incidence of chromosomal aberrations in squamous cell carcinomas of the head and neck.

Distribution of Non-Diploid Flow-Cytometric DNA Indices and Their Relation to the Nodal Metastasis in Squamous Cell Carcinomas of the Head and Neck

Squamous cell carcinomas of the head and neck (HNSCC) evolve from diploid epithelial cells of the mucosa. At the time of diagnosis about two thirds of clinically diagnosed HNSCC are non-diploid according to flow-cytometric (FCM) analysis, indicating that during tumour progression there must be an acquisition and accumulation of chromosomal aberrations. At diagnosis one third to one half of HNSCC have clinically positive neck nodes. The objective of the present study was to see whether the progression to a metastatic phenotype is reflected in the distribution of FCM DNA ploidy in node-negative and node-positive HNSCC. The series comprised 200 patients with HNSCC. Tumour samples were obtained from diagnostic biopsies or primary surgery. A multistep preparation method and propidium iodide staining of nuclear DNA content was used for FCM. One hundred and forty one (71%) of the tumours were non-diploid. Only two tumours were hypodiploid (DNA index 0.73 and 0.93, respectively). Ten of the tumours exhibited two non-diploid stem cell lines. The frequency of non-diploidy in node-negative tumours was 65% and in node-positive ones about 80%. The frequency distribution of non-diploid DNA indices clustered in the hypotetraploid region (with a modal value of 1.71–1.74) and did not differ between node-negative and node-positive tumours. The hypothesis that the disposition to metastasis is reflected in the frequency distribution of non-diploid DNA indices could thus not be verified.

Defects in transforming growth factor-β signaling cooperate with a Ras oncogene to cause rapid aneuploidy and malignant transformation of mouse keratinocytes

Genetic inactivation of the transforming growth factor-beta (TGF-beta) signaling pathway can accelerate tumor progression in the mouse epidermal model of multistage carcinogenesis. By using an in vitro model of keratinocyte transformation that parallels in vivo malignant conversion to squamous cell carcinoma, we show that v-ras(Ha) transduced primary TGF-beta1-/- keratinocytes and keratinocytes expressing a TGF-beta type II dominant-negative receptor transgene have significantly higher frequencies of spontaneous transformation than control genotypes. Malignant transformation in the TGF-beta1-/- keratinocytes is preceded by aneuploidy and accumulation of chromosomal aberrations. Similarly, transient inactivation of TGF-beta signaling with a type II dominant-negative receptor adenovirus causes rapid changes in ploidy. Exogenous TGF-beta1 can suppress aneuploidy, chromosome breaks, and malignant transformation of the TGF-beta1-/- keratinocytes at concentrations that do not significantly arrest cell proliferation. These results point to genomic instability as a mechanism by which defects in TGF-beta signaling could accelerate tumor progression in mouse multistage carcinogenesis.

Parental Age and Risk of Sporadic and Familial Cancer in Offspring

We used the nationwide Swedish Family-Cancer Database to analyze the effect of parental age on cancer in offspring at ages 15-53 years. We studied 13 cancer sites, including 37,877 people. Data on familial and sporadic cancers were analyzed separately. We adjusted for age of spouse, year of diagnosis, and birth order. Rate ratios (RRs) were calculated by Poisson regression. Maternal age was associated with sporadic melanoma and leukemia, causing a 30% excess if mothers were more than 40 years vs. less than 20 years of age. A marginal effect of about 10% of both maternal and paternal age was observed for sporadic breast cancer. Paternal age increased the RR of sporadic nervous system cancer by about 15%. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells may be a mechanism for these findings. In familial cancers of colon, melanoma, and thyroid, higher age showed an apparent protective effect, which was also noted for sporadic cervical cancer and melanoma. The results argue against major age-induced mutagenic/carcinogenic effects on germ cells as well as against age-induced adverse cancer-related hormonal effects during pregnancy. Because two or more mutations are required for adult cancers, however, these cancers may be an insensitive indicator of germ cell mutagenesis.

Parental Age As a Risk Factor of Childhood Leukemia and Brain Cancer in Offspring

We use here the Swedish Family-Cancer Database to analyze the time trends in childhood leukemia and brain cancer between 1960 and 1994 and the effect of parental age on childhood leukemia and brain cancer of some 1500 cases each. The database includes all persons born in Sweden after 1940 with their biological parents, over 6 million individuals, whose cancers were retrieved from the Swedish Cancer Registry from years 1958-1994. Incidence in cancer increased from 1960 to 1994; low grade astrocytoma accounted for most of the increase, whereas high grade astrocytoma has not increased in incidence. There has been a moderate increase in leukemia to about 1980. We found a parental age effect for both leukemia and brain cancer, with the former (of about 50% excess in those over 35 years) being mediated by maternal age and the latter (of about 25% excess) by paternal age. Accumulation of chromosomal aberrations and mutations during the maturation of germ cells is a likely mechanism for these findings. They can help to explain partially the secular trends of these malignancies and the excess risks in offspring of the well educated.

The accumulation of chromosome aberrations and Dlb-1 mutations in mice with highly fractionated exposure to gamma radiation

The dichotomy between the doses at which experimental measurements of genetic effects can be made and the doses to which people are exposed is often different by two or more orders of magnitude. This presents a significant problem when determining the effects of low doses of radiation or chemicals. The solution has usually involved extrapolating the data by curve-fitting or by applying theoretical considerations. Both approaches are unsatisfactory due to uncertainties of the assumptions used in each process. The alternative solution has been to increase the sample size enormously at the lower doses. This is impractical beyond a certain point due to the variation in the spontaneous frequency and the need to quadruple the sample size for a doubling of precision. The development of new methods for measuring stable genetic effects, however, permits a simple and effective approach to this problem: if the genetic events being detected have no effect on survival, i.e., are selectively neutral, then the effects of multiple independent treatments will be additive. If the independent treatments are identical, then the effect of each is easily calculated by dividing the total effect by the number of treatments. Here we report a limited test of this approach using mice. Chromosome aberrations induced in lymphocytes and Dlb-1 mutations induced in the small intestine were measured after daily doses of 0.64, 1.85 or 5.5 cGy 137Cs gamma rays administered for 21, 42 or 63 days. The dose response curve for chromosome translocations obtained in this way, combined with the data from single larger acute doses, shows no evidence for a threshold over a 500-fold dose range. Dlb-1 mutations were increased at each dose and time but the results do not permit reliable extrapolations. The results suggest that translocations might be useful for quantifying the effect of doses below 0.05 cGy and that the effect of dose rate and dose fractionation at much lower doses than reported here could be investigated.

A Comparison of the Quantitative Effects of Seed Moisture Content and Temperature on the Accumulation of Chromosome Damage and Loss of Seed Viability in Lettuce

The rate of accumulation of cells containing chromosome aberrations in lettuce (Lactuca sativa L.) seeds is a positive function of temperature and moisture content. It may be described by an equation similar to that for loss of seed viability. The relative effect of temperature on the rates of loss of viability and accumulation of chromosome aberrations is the same. In contrast, the relative effect of moisture on the rate of loss of viability is greater than that for the rate of accumulation of aberrations. Hence considerably more chromosome damage accumulates before death in drier lettuce seeds

Inbreeding Depression in Diploid and Induced‐Autotetraploid Crested Wheatgrass1

Forage and seed yields of diploid crested wheatgrass, Agropyron cristatum (L.) Gaertu., were reduced sharply by selling. Some progenies were much more sensitive to selfing than others. Vigor and fertility reductions averaged 44.9 and 43.4%, respectively, in 15 S1 progenies. Inbreeding depression of induced‐autotetraploid crested wheatgrass was much less than that of comparable diploids. Forage yields of seven induced‐tetraploid S1 progenies declined 17.3%, compared with a 54.9% reduction for their exact diploid counterparts.Possible causes of rapid loss of vigor in natural autotetraploids are discussed. Newly synthesized autotetraploids—includiug crested wheatgrass; corn, Zea mays L.; Italian ryegrass, Lolium multillorum Lam.; and alsike clover, Trifolium hybridnm L.—show a much lower degree of inbreeding depression than old natural autotetraploids such as alfalfa, Medicago sativa L.; orchardgrass, Dactylis glomerata L.; and crested wheatgrass, Agropyron desertorum (Fisch. ex. Link) Schult. An accumulation of chromosome aberrations and unfavorable gene combinations in species buffered by autoploidy is offered as a major cause of excessive inbreeding depression in natural autotctraploids. The degree of inbreeding depression in natural autotetraploid species may give an indication of their relative ages.