Male breast cancer, age and sex chromosome aneuploidy.

BACKGROUND: In cultured, dividing transformed T lymphocytes and in dividing bone marrow cells from normal men and those with a haematological malignancy, sex chromosome aneuploidy has been found to increase in prevalence and degree with age. This has rarely been investigated in non-dividing uncultured blood samples. The loss and gain of the X chromosome in dividing transformed lymphocytes in women with age is much more frequent than that of the Y chromosome in males. However, paradoxically X chromosome aneuploidy is rarely seen in the dividing cells of bone marrow of females. METHODS: In blood samples from 565 men with breast cancer and 54 control men from the England and Wales general population, 80 cell nuclei per sample were scored for presence of X and Y chromosomes using fluorescent centromeric probes. RESULTS: Sex chromosome aneuploidy, largely Y chromosome loss, was present in 63% of cases and 57% of controls, with the prevalence and degree of aneuploidy increasingly sharply and highly significantly with age. At ages 65-80 years, 71% of cases and 85% of controls showed aneuploidy and 15% and 25%, respectively, had ≥ 10% of cells aneuploid. Allowing for age, aneuploidy was less prevalent (P=0.03) in cases than controls. CONCLUSION: Sex chromosome aneuploidy in non-dividing nuclei of peripheral blood cells is frequent in adult men, the prevalence and degree increasing sharply with age. The possible relation of sex chromosome aneuploidy to breast cancer risk in men, and to cancer risk generally, needs further investigation, ideally in cohort studies.

Self-mixing flow sensor using a monolithic VCSEL array with parallel readout.

The self-mixing sensing technique is a compact, interferometric sensing technique that can be used for measuring fluid flows. In this work, we demonstrate a parallel readout self-mixing flow velocity sensing system based on a monolithic Vertical-Cavity Surface-Emitting Laser (VCSEL) array. The parallel sensing scheme enables high-resolution full-field imaging systems employing electronic scanning with faster acquisition rates than mechanical scanning systems. The self-mixing signal is acquired from the variation in VCSEL junction voltage, thus markedly reducing the system complexity. The system was validated by measuring velocity distribution of fluid in a custom built diverging-converging planar flow channel. The results obtained agree well with simulation and demonstrate the feasibility of high frame-rate and resolution parallel self-mixing sensors.

Cancer risk in patients with constitutional chromosome deletions: a nationwide British cohort study.

The finding of increased risks of specific cancers in individuals with constitutional deletions of chromosomes 11p and 13q led to the discovery of cancer predisposition genes at these locations, but there have been no systematic studies of cancer risks in patients with constitutional deletions, across the chromosome complement. Therefore, we assessed cancer incidence in comparison with national cancer incidence rates in a follow-up of 2561 patients with constitutional autosomal chromosome deletions diagnosed by microscopy or fluorescence in situ hybridisation in Britain during the period 1965-2002. Thirty cancers other than non-melanoma skin cancer occurred in the cohort (standardised incidence ratio (SIR)=2.4, 95% confidence interval (CI) 1.6-3.5). There were significantly increased risks of renal cancer in persons with 11p deletions (SIR=1869, 95% CI 751-3850; P=4 x 10(-21)), eye cancer with 13q deletions (SIR=1084, 95% CI 295-2775; P=2 x 10(-11)), and anogenital cancer with 11q deletions (SIR=305, 95% CI 63-890; P=3 x 10(-7)); all the three latter cancers were in the 11 subjects with 11q24 deletions. The results strongly suggest that in addition to suppressor genes relating to Wilms' tumour risk on 11p and retinoblastoma on 13q, there are suppressor genes around 11q24 that greatly affect anogenital cancer risk.

Closely linked cis-acting modifier of expansion of the CGG repeat in high risk FMR1 haplotypes.

In its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis-acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a approximately 50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (chi(1)(2)=17.84, p=0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples.

X chromosome loss and ageing.

The detection of a low level 45,X cell line during routine cytogenetic analysis in an adult female can be difficult to interpret. In the absence of recent information regarding loss of the X chromosome and ageing, we undertook a prospective study. A total of 19,650 cells from 655 females aged from birth to 80 years were screened cytogenetically. The frequency of X chromosome loss ranged from 0.07% at age <16 years to 7.3% at >65 years of age and showed a highly significant quadratic relationship between X chromosome loss and ageing (P < or = 0.00001). We have produced a graphic representation that provides a minimum baseline age-related rate of X chromosome loss. This should assist diagnostic cytogenetics laboratories to determine the significance of 45,X cell lines detected in women of all ages. We also compared the frequency of 45,X cells in women referred with at least one spontaneous abortion with those referred for other reasons and found no significant difference. Thus, in our population, an excess of 45,X cells is not associated with pregnancy loss.

Polysulfone-ZrO(2) surface interactions. The influence on formation, morphology and properties of zirfon-membranes.

The interaction between polysulfone and ZrO(2) particles is studied as a function of the particle sintering temperature in order to understand the role of ZrO(2) on the formation, morphology, and properties of organo-mineral composite membranes. The adsorption between the sintered ZrO(2) and the constituents of polysulfone, 2,2-diphenylpropane and diphenyl sulfone, is investigated using high-pressure liquid chromatography. The influence of the polymer-ZrO(2) interaction on the flow behavior of the casting suspension is registered via viscoelastic measurements. The organo-mineral composite membranes are formed by immersion precipitation in water, and the resulting membrane morphology is analyzed using high-resolution SEM. The zirconia concentration in the top-layer of the composite structure is determined by XPS. Finally, the link between the polymer-filler interactions, the membrane formation process, and the resulting membrane structure and properties is established.

The complex nature of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes.

OBJECTIVE: To describe the systematic analysis of constitutional de novo apparently balanced translocations in patients presenting with abnormal phenotypes, characterise the structural chromosome rearrangements, map the translocation breakpoints, and report detectable genomic imbalances. METHODS: DNA microarrays were used with a resolution of 1 Mb for the detailed genome-wide analysis of the patients. Array CGH was used to screen for genomic imbalance and array painting to map chromosome breakpoints rapidly. These two methods facilitate rapid analysis of translocation breakpoints and screening for cryptic chromosome imbalance. Breakpoints of rearrangements were further refined (to the level of spanning clones) using fluorescence in situ hybridisation where appropriate. RESULTS: Unexpected additional complexity or genome imbalance was found in six of 10 patients studied. The patients could be grouped according to the general nature of the karyotype rearrangement as follows: (A) three cases with complex multiple rearrangements including deletions, inversions, and insertions at or near one or both breakpoints; (B) three cases in which, while the translocations appeared to be balanced, microarray analysis identified previously unrecognised imbalance on chromosomes unrelated to the translocation; (C) four cases in which the translocation breakpoints appeared simple and balanced at the resolution used. CONCLUSIONS: This high level of unexpected rearrangement complexity, if generally confirmed in the study of further patients, will have an impact on current diagnostic investigations of this type and provides an argument for the more widespread adoption of microarray analysis or other high resolution genome-wide screens for chromosome imbalance and rearrangement.

Segmental aneuploidy and the genetic gross structure of the Drosophila genome.

By combining elements of two Y-autosome translocations with displaced autosomal breakpoints, it is possible to produce zygotes heterozygous for a deficiency for the region between the breakpoints, and also, as a complementary product, zygotes carrying a duplication for precisely the same region. A set of Y-autosome translocations with appropriately positioned breakpoints, therefore, can in principle be used to generate a non-overlapping set of deficiencies and duplications for the entire autosomal complement.-Using this method, we have succeeded in examining segmental aneuploids for 85% of chromosomes 2 and 3 in order to assess the effects of aneuploidy and to determine the number and location of dosage-sensitive loci in the Drosophila genome (Figure 5). Combining our data with previously reported results on the synthesis of Drosophila aneuploids (see Lindsley and Grell 1968), the following generalities emerge.-1. The X chromosome contains no triplo-lethal loci, few or no haplo-lethal loci, at least seven Minute loci, one hyperploid-sensitive locus, and one locus that is both triplo-abnormal and haplo-abnormal. 2. Chromosome 2 contains no triplo-lethal loci, few or no haplo-lethal loci, at least 17 Minute loci, and at least four other haplo-abnormal loci. 3. Chromosome 3 contains one triplo-lethal locus that is also haplo-lethal, few or no other haplo-lethal loci, at least 16 Minute loci, and at least six other haplo-abnormal loci. 4. Chromosome 4 contains no triplo-lethal loci, no haplo-lethal loci, one Minute locus, and no other haplo-abnormal loci.-Thus, the Drosophila genome contains 57 loci, aneuploidy for which leads to a recognizable effect on the organism: one of these is triplo-lethal and haplo-lethal, one is triplo-abnormal and haplo-abnormal, one is hyperploid-sensitive, ten are haplo-abnormal, 41 are Minutes, and three are either haplo-lethals or Minutes. Because of the paucity of aneuploid-lethal loci, it may be concluded that the deleterious effects of aneuploidy are mostly the consequence of the additive effects of genes that are slightly sensitive to abnormal dosage. Moreover, except for the single triplo-lethal locus, the effects of hyperploidy are much less pronounced than those of the corresponding hypoploidy.

Cytogenetic and molecular study of four couples with multiple trisomy 21 pregnancies.

We studied four families each with three trisomy 21 conceptions. In two of the families the trisomy 21 conceptions all occurred when the mothers were under 35 years of age and in the other two families they all occurred when the mothers were over 35 years of age. Cytogenetic studies showed low level mosaic trisomy 21 in the two younger mothers, but not in the two older. In the three families tested using molecular techniques the results were consistent with the additional chromosome 21 in the trisomic conceptuses being maternally derived. Novel alleles were detected in the trisomic offspring of one of the younger mothers, demonstrating that the mother had been conceived as a trisomy with three different chromosomes 21. Therefore the multiple trisomy 21 pregnancies in the two younger mothers resulted from maternal trisomy 21 mosaicism, but may have been due to chance in the older mothers.

A systematic search for uniparental disomy in carriers of chromosome translocations.

A systematic search was made for uniparental disomy in carriers of apparently balanced chromosome translocations who also had unexplained abnormalities of mental or physical development. Of 65 families studied, biparental origin of both translocated chromosomes was demonstrated in 64, and only 1 case of maternal uniparental disomy of chromosome 14 was detected in the carrier of a Robertsonian t(13q14q). We conclude that uniparental disomy is a rare occurrence in this population.

A reinvestigation of non-disjunction resulting in 47, XXY males of paternal origin.

We have used polymorphisms within the Xp/Yp pseudoautosomal region (PAR 1) to determine the frequency and location of recombination in 80 paternally derived 47, XXY males. Of 64 informative results, there were 10 single cross-overs, one double cross-over and 53 without a cross-over. Therefore 2/3 of 47, XXY males of paternal origin result from meiosis in which the X and Y chromosomes fail to recombine. This failure was not associated with the presence of an increase in recombination in the smaller Xq/Yq pseudoautosomal region (PAR 2) or with the presence of microdeletions within PAR 1.

Stability and haplotype analysis of the FRAXE region.

FRAXE full mutations are rare and appear to be associated with mild mental retardation. As part of a screening survey of boys with learning difficulties to determine the frequency of full and premutations, we have collected data on the frequency of instability at FRAXE for about 4000 transmissions and the haplotype for over 7000 chromosomes. The distribution of FRAXE repeats was similar to other English populations but differed from two North American Caucasian series. Observed instability at FRAXE was rare but increased with increasing repeat number, and there were no expansions into the full mutation range, except in pedigrees ascertained through a full mutation. Haplotype analysis suggested division into five groups with each group having a characteristic distribution of FRAXE repeats. Fourteen of the 15 full mutations occurred on a single haplotype and this haplotype also had a significant excess of intermediate-sized alleles, suggesting that full mutations originate from large normal alleles. However, a related haplotype also had a significant excess of intermediates but we observed no full mutations on this haplotype, suggesting either loss or gain of stability determinants on it. We suggest that whilst triplet repeat size is a significant predisposing factor for expansion at FRAXE other genetic determinants are also likely to be important.

Distinctive patterns of memory function in subgroups of females with Turner syndrome: evidence for imprinted loci on the X-chromosome affecting neurodevelopment.

X-monosomy is a form of Turner syndrome (TS) in which an entire X chromosome is missing. It is usually assumed that neuropsychological deficits in females with TS result from insufficient dosage of gene products from alleles on the sex chromosomes. If so, then parental origin of the single X chromosome should be immaterial. However, if there are imprinted genes on the X chromosome affecting brain development, neuropsychological development will depend on the parental origin of the single X chromosome. We contrasted verbal and visuospatial memory in females with a single paternal X chromosome (45,X(p)) and those with a single maternal X (45,X(m)). Neither group showed any impairment on immediate story recall; if anything, performance was above control levels. Groups did not differ on a measure of delayed recall. However, when delayed recall was considered after adjusting for level of immediate recall, 45,X(m) females showed enhanced verbal forgetting relative to controls over a delay. On the Rey figure, both groups were poor at copying the figure, but, after adjusting scores for initial copy score and strategy, only the 45,X(p) females showed disproportionate forgetting relative to controls. We propose there may be one or more imprinted genes on the X chromosome that affect the development of lateralised brain regions important for memory function.

Studies of the fragile (X) syndrome in populations of mentally retarded individuals in Hawaii.

Three populations of retarded individuals were surveyed and the frequency of the fra (X) was found to be 1.9% in males and 0.3% in females.

The fragile (X) syndrome: the mutation problem.

In an attempt to understand the nature of the mutational event leading to the fra(X) syndrome, we have searched for sporadic cases in 3 populations: affected males, affected females, and non-affected transmitting females. In all 3 populations there was a dearth of isolated cases, and the reasons for this are discussed.

Two families with Xq27.3 fragility, no detectable insert in the FMR-1 gene, mild mental impairment, and absence of the Martin-Bell phenotype.

In 2 families, propositi were investigated because of mild developmental delay and, in one case, behavior disorders. Seven males in the 2 families were found to have a fragile site at Xq27.3 but the usual insert in the FMR-1 gene was absent. The affected males had mild, or in some cases, no clear intellectual impairment and did not have the Martin-Bell phenotype. Carrier females in one family tended to show a high level of cytogenetic expression of the fragile site but were clinically normal. It is not yet clear whether these families have unusual mutations in the FMR-1 gene or whether their fragile sites are different, but cytogenetically indistinguishable from, that associated with inserts in the FMR-1 gene.

Marker X syndrome in an oriental family with probable transmission by a normal male.

We report an oriental family with sex-linked mental retardation, macroorchidism, and a marker or fragile site on the X chromosome--mar(X)(q28). The three affected males resemble clinically most previously reported affected Caucasians. The marker was present in four female 40-70 years old, including one with normal intelligence. Transmission of the disorder appears to have taken place through a clinically normal male to his grandson.

Chromosome anomalies as predictors of recurrence risk for spontaneous abortion.

Reproductive histories and chromosomes of spontaneous abortions were studied by segregation analysis in 1890 sibships ascertained through a cytogenetically studied abortion. Normal karyotypes are associated with recurrent abortion. Among abnormal karyotypes, trisomy has an elevated recurrence risk even after adjustment through a liability indicator for maternal age. Possible mechanisms and conflicting evidence in the literature on trisomy are discussed. None of these differences in recurrence risk is large enough to play a significant numerical role in genetic counseling.

X-linked mental retardation: a study of 7 families.

Seven families with X-linked mental retardation (MR) have been studied clinically and cytogenetically. All affected males in six of the families were found to have a fragile site on Xq in a number of their peripheral lymphocytes. The fragile site was not seen in any of the affected males in the seventh family. The affected males in the six families with the fragile X had a syndrome characterized by a variable degree of MR, macro-orchidism, a characteristic repetitive, jocular speech, normal body proportions, and large jaws and ears. The fragile X chromosome could only be detected in a proportion of female carriers and its frequency in females was found to be correlated with their mental status to be inversely correlated with their age.