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PubMed1995

Is detrusor instability in elderly males related to the grade of obstruction?

Analysis of 185 consecutive patients with BPH revealed concomitant detrusor instability in 20% of the patients. Of all patients 30.9% were not obstructed, 51.8% were moderately obstructed and 17.3% were severely obstructed. Patients with detrusor instability during filling cystometry revealed no differences in average age, prostate volume or symptoms. Mean filling cystometry parameters revealed earlier sense of urge correlating with higher pressures at lower volumes in patients with detrusor instability. Pressure-flow analysis showed no differences between the patients with and without detrusor instability in bladder outflow obstruction parameters. Further analysis, however, revealed that the prevalence of patients with detrusor instability reaches a "steady state" at a moderate level of obstruction. On clinical epidemiological grounds, the conclusion is made that detrusor instability is developing in the early phase of obstruction. Probably detrusor instability and bladder outflow obstruction are concomitant, due to the aging process in many of these patients.

Aged↗
PubMed1991

Urethral morphology and bladder instability.

In order to calculate the relationship between Spinning top urethra (STU) and bladder instability 160 voiding cystourethrogramms (VCU), performed in 102 girls, have been analysed retrospectively. 28 girls had STU, 16 of those had bladder instability as well (57%). We could not find the highly positive correlation between unstable bladder and STU as reported by other authors, although there was a statistically positive correlation between STU and bladder instability. However the confidence interval was very broad (38%-75%). We conclude that bladder instability may contribute to STU but cannot render the etiological explanation for all cases. STU seems to be a polyetiological sign. In our opinion only the combination of STU and bladder instability has a diagnostic impact, since several therapeutical concepts are available in cases of bladder instability. The finding of STU in the VCU should alert the examiner's attention to functional disorders of the lower urinary tract. If no instability can be found, STU should be considered to be a normal variant.

Child↗
PubMed2000

Relationship between microsatellite instability and telomere shortening in colorectal cancer.

PURPOSE: Two pathways have been proposed for the development of colorectal cancers: loss of heterozygosity and replication error. Colorectal cancers arising through the replication error pathway, like most hereditary nonpolyposis colorectal cancers, show microsatellite instability. It has been also reported that telomere shortening frequently occurs in colorectal cancers and that telomerase is often activated strongly in them. The aim of this study was to examine whether any relationships can be found among microsatellite instability, telomere length, and telomerase activity in colorectal cancers. METHODS: Genomic DNA was extracted from 55 invasive cancers and corresponding normal mucosas. Five microsatellite loci were analyzed by polymerase chain reaction. Telomere length was examined by Southern blot analysis. Telomerase activity was assayed by telomeric repeat amplification protocol with minor modifications. RESULTS: Microsatellite instability was found in 8 (14.5 percent) of 55 tumors, and all of them showed short telomeres. Furthermore, four high-frequency microsatellite instability tumors that showed microsatellite instability at more than two loci exhibited remarkably short telomeres. The microsatellite instability correlated significantly with frequency of telomere shortening (P = 0.0183; Fisher's exact probability test), but not with strength of telomerase activity. CONCLUSION: The relationship identified by this study between microsatellite instability and telomere shortening might suggest some association between the DNA mismatch repair system and the telomere maintenance mechanism in colorectal cancers.

Aged↗
PubMed2003

Early-age-at-onset colorectal cancer and microsatellite instability as markers of hereditary nonpolyposis colorectal cancer.

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites (> or = 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Microsatellite instability and mutations in DNA mismatch repair genes in sporadic colorectal cancers.

PURPOSE: This study was designed to investigate the frequency of mutations in DNA mismatch repair genes in sporadic colorectal cancers. METHODS: Genomic DNAs procured from paraffin blocks of the pathologic specimens from 230 consecutive patients with colorectal cancer were examined for their microsatellite instability status using a mononucleotide microsatellite marker, BAT-26, and also evaluated expressions of hMLH1, hMSH2, and hMSH6 proteins by immunohistochemical staining. Any of these 230 patients did not have family histories of hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, colorectal cancer, or hereditary nonpolyposis colorectal-related cancers, such as endometrial, small bowel, and ureteral and renal pelvic cancers. When microsatellite instability was positive, mutations in the simple repeated sequences of TGF-betaRII, BAX, IGF IIR, hMSH3, and hMSH6 genes were examined. In microsatellite instability-positive or staining-negative cases, polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing detected mutations of hMLH1, hMSH2, and hMSH6 genes. If mutations were found in tumor tissue samples, we tested for a germline mutation with a microdissected corresponding normal tissue. RESULTS: Among 230 cases of sporadic colorectal cancer, 21 (9.1 percent) manifested microsatellite instability. In the immunohistochemical staining, 20 (8.6 percent) showed loss of expressions. All 20 staining-negative cases were microsatellite instability-positive. Only 1 of 21 (4.8 percent) microsatellite instability-positive cases showed intact staining for three proteins. The frame-shift mutations of the simple repetitive sequences were found in 17 cases (81.0 percent) in TGF-betaRII, 11 (52.4 percent) in BAX, 5 (23.8 percent) in IGF IIR, 7 (33.3 percent) in hMSH3, and 8 (38.1 percent) in hMSH6 genes. Germline mutation was observed in only one case, which accounts for 4.8 percent among positive microsatellite instability and 0.4 percent of total patients, and was found in hMSH2. Five somatic mutations (2 in hMLH1, 2 in hMSH2, and 1 in hMSH6) also were found. CONCLUSION: The results indicated that a germline mutation of DNA mismatch repair gene was a rare event in sporadic colorectal cancers.

Base Pair Mismatch↗
PubMed2005

Mechanisms of microsatellite instability in colorectal cancer patients in different age groups.

PURPOSE: The proportion of colorectal cancers located proximal to the splenic flexure increases with age. Colorectal cancers of the microsatellite instability phenotype are preferentially located in the proximal colon. We investigated the location of colorectal cancer with this phenotype in different age groups to determine whether different molecular mechanisms could account for the changes in distribution of colorectal cancers. METHODS: A representative sample of 230 colorectal cancers from three age groups (<45 years, 60-70 years, >87 years) was selected from a subset of The Upper Midwest Oncology Medical Registries database. Microsatellite instability was determined by polymerase chain reaction using a panel of five microsatellite markers. The presence of new microsatellite alleles at two or more loci was scored as microsatellite instability. Tumors were otherwise considered microsatellite stable. MLH1 and MSH2 expression was determined by immunohistochemistry. Methylation of the MLH1 gene promotor was determined by methylation-specific polymerase chain reaction assay. RESULTS: The proportion of tumors of the microsatellite instability phenotype was 21 percent in the young group, 15 percent in the middle group, and 33 percent in the old group. More tumors of the microsatellite instability phenotype were proximal compared with microsatellite-stable tumors in all three age groups, but the differences were significant only for the old group. Tumors of the microsatellite instability phenotype in the older group were associated with MLH1 inactivation (24/29 or 83 percent), MLH1 promoter methylation (18/29 or 62 percent), and proximal location (25/29 or 86 percent), while tumors in the young group were associated with MSH2 inactivation (8/18 or 44 percent) and distal location (11/18 or 62 percent). CONCLUSION: The age-related proximal shift of colorectal cancers is associated with the microsatellite instability phenotype, MLH1 inactivation, and MLH1 promoter hypermethylation.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Drug insurance instability and its correlates: results from the 2000 Medical Expenditure Panel Survey.

BACKGROUND: Health insurance instability (ie, temporal gaps in health insurance coverage) is a prevalent phenomenon in the United States. To date, most studies have focused on the factors that affect the intermittent lack of health insurance coverage. However, no studies known to the authors have examined the factors associated with prescription drug insurance instability (ie, temporal gaps in drug insurance coverage) among working-age adults. Developing an accurate profile of persons with unstable drug insurance is essential to formulate rational policy to address this problem. OBJECTIVES: The objectives of this study were to (1) document the prevalence of prescription insurance instability among working-age adults and (2) describe the association between prescription drug insurance instability and demographic, socioeconomic status, and employment characteristics. METHODS: The data source used in this study was the 2000 Medical Expenditure Panel Survey. This study used a cross-sectional design using data provided by respondents at each of the 3 interviews conducted during the year 2000. Chi-square and hierarchical multinomial logistic regression analyses were used to describe the associations among (1) demographics, (2) socioeconomic status, and (3) employment characteristics and drug insurance status (classified as continuous, absent, or unstable). RESULTS: During the year 2000, 12.5% (21.1 million) of the working-age adults in the United States had unstable prescription drug coverage. Persons aged 35-54 years had lower rates of drug insurance instability compared with those aged 18-24 [adjusted odds ratio 0.66 (95% confidence interval 0.54-0.80)]. The least educated (12 or fewer years of education) were more likely than those with more education (13-16 years) to experience at least one period without drug coverage (62% vs 32%, P<0.01). The poorest respondents (those at less than 200% of the federal poverty level) were more likely than the wealthiest respondents (those at more than 400% of the poverty level) to report at least some time without drug coverage (37% vs 28%, P<0.01). Those experiencing a divorce or death of a spouse were more than twice as likely as stably married persons to experience at least one period without drug insurance [adjusted odds ratio 2.23 (95% confidence interval 1.68-2.96)]. Adults who were unstably employed during the year and/or who worked for small firms generally experienced higher rates of drug insurance instability. CONCLUSIONS: Prescription drug insurance instability is a prevalent phenomenon among working-age adults in the United States, with approximately 1 in 8 experiencing this problem during 2000. Our results suggest that demographics, socioeconomic status, and employment characteristics all play important roles in predicting prescription drug insurance status, with the least educated and poorest being particularly vulnerable to interruptions in drug coverage. Premium assistance programs providing subsidies to small firms' low-income employees and permitting small firms to form insurance pools may help to decrease the number of drug coverage uninsurance spells in this population.

Adolescent↗
PubMed1999

Origin of microsatellite instability in gastric cancer.

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma.

Adaptor Proteins, Signal Transducing↗
PubMed2002

In memoriam Bernard Strehler--genomic instability in ageing: a persistent challenge.

Genomic instability comprises a broad spectrum of mutational alterations in the genome, such as point mutations in DNA, microsatellite expansions or contractions, amplifications and deletions of DNA sequences, gene rearrangements and structural or numerical chromosomal aberrations. A substantial body of data demonstrates an increase of genomic instability during normal ageing. This includes cytogenetic changes; loss of rDNA; formation of extrachromosomal circular DNA species; loss of telomeric repeats; increased microsatellite instability; as well as point mutations and deletions in global nuclear and mitochondrial DNA. Evidence has accumulated supporting a causative role of genomic instability in ageing. Genomic instability can be counteracted by a number of proteins including antioxidant enzymes, the WRN protein (deficient in Werner syndrome), telomerase, poly(ADP-ribose) polymerase-1 and a range other others, as well as by multi-protein systems such as DNA mismatch repair, base-excision repair and nucleotide-excision repair. Important research tasks for the future will be to elucidate how and what extent the various expressions of genomic instability contribute to the ageing process and to understand the molecular mechanisms and regulation of the above factors and pathways involved in limiting the induction of ageing-associated genomic instability.

Aging↗
PubMed1998

Microsatellite instability is uncommon in young patients with renal cell carcinoma.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited syndrome which predisposes to the development of colorectal cancer and, to a lesser extent, other extracolonic neoplasms. Widespread microsatellite instability is a feature of nearly all tumors from patients with hereditary non-polyposis colorectal cancer. It was recently found that most patients under age 35 with colorectal cancer also have widespread microsatellite instability in their tumors and that many of these patients have the germline mutations of mismatch repair genes that characterize hereditary non-polyposis colorectal cancer. Renal cell carcinoma has occasionally been reported in patients with hereditary non-polyposis colorectal cancer, and some renal cell carcinomas have been shown to have microsatellite instability at multiple loci. For this reason, we sought to address the possibility that some young patients with renal cell carcinoma may have hereditary non-polyposis colorectal cancer by screening their tumors for microsatellite instability. Thirty-two patients under the age of 45 with renal cell carcinoma were examined for the presence of microsatellite instability in their tumor tissue. Microsatellite instability was not observed in any of the tumors. The absence of microsatellite instability in renal cell carcinomas from young patients suggests that these patients are unlikely to have hereditary non-polyposis colorectal cancer and would generally not benefit from genetic screening for this syndrome.

Adult↗
PubMed1996

Diagnosis of knee instability using sonography.

OBJECTIVE: A sonographic method has been developed to diagnose knee joint instabilities and to gain exactly quantifiable and reproducible measurements. DESIGN: Based on biomechanical considerations, a new positioning device to analyse knee instabilities sonographically has been developed and tested in in vivo studies. BACKGROUND: Common instrumental testing techniques are difficult to reproduce and show a lack of reliability. METHOD: Using sonography the cortical line of the femur and tibia are observed. At the same time a translation of these two partners at the knee joint is provoked in a defined position using the special holding device and under a defined amount of stress. Using this method 142 healthy people, placed in different age groups, were tested to establish standard values for the physiological knee joint translation. A prearthroscopic stability analysis was performed on 101 patients. RESULTS: This study proves that the special device developed, together with the technique used, provides reliable and exact measurements for knee instability in different translation directions. In healthy subjects the lateral compartment always showed a larger translation than the medial compartment. A gradual increase in translation was determined in the age groups over 30 years. A significant difference of 0.0001 was shown between knee stability and instabilities. Moreover, a further differentiation between partial and total ACL ruptures and chronic instabilities was determined. This provides an important advantage not offered by usual instrumental testing techniques. CONCLUSIONS: The ability to diagnose even a very low extent of instability and to differentiate between different kinds of instabilities enables exact controls to be carried out for both conservative and operative treatment.

Journal Article↗
PubMed2000

Microsatellite instability is associated with genetic alteration but not with low levels of expression of the human mismatch repair proteins hMSH2 and hMLH1.

Mutational inactivation of hMSH2 or hMLH1 has been known to be responsible for microsatellite instability and cellular resistance to DNA-damaging alkylating agents. However, the effects of altered expression of hMSH2 or hMLH1 on microsatellite stability and cellular response to alkylating agents has not been well investigated. Previously, we have reported that downregulation of the hMLH1 protein was a frequent event and was closely associated with cellular resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in human gastric carcinoma cell lines. Therefore, to investigate the relationship between microsatellite instability and quantitative changes in hMSH2 and hMLH1, we compared the genetic status and expression levels of hMSH2 and hMLH1 with microsatellite instability in 11 human gastric carcinoma cell lines. Five cell lines contained wild-type hMSH2 and hMLH1 and expressed adequate levels of hMSH2 and hMLH1 proteins. In three cell lines, genetic alterations such as mutation in the hMLH1 gene (SNU-1) or the hMSH2 gene (SNU-638), or hypermethylation in the promoter region of the hMLH1 gene (SNU-520) were observed. Microsatellite instability assays revealed that only these three cell lines exhibited microsatellite instability. Three cell lines (SNU-216, -484, and -668) containing wild-type hMSH2 and hMLH1 genes produced significantly downregulated hMSH2 and/or hMLH1 proteins. In spite of the substantial decrease in the protein levels, these cell lines did not show microsatellite instability. Together with our previous report, this study suggests that: microsatellite instability of cells is associated only with genetic alteration of the mismatch repair genes; relatively low levels of the hMSH2 and hMLH1 proteins may be sufficient to retain the microsatellite stable phenotype; and the cellular response to alkylating agents is associated with genetic alteration and decreased expression of the mismatch repair genes in human gastric carcinoma cell lines.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Instability, dynamics, and morphology of thin slipping films.

Based on the linear stability and nonlinear simulations, we show that the surface instability, dynamics, and morphology of supported thin liquid films are profoundly altered by the presence of slippage on the substrate. A general dispersion equation for flow in slipping thin films is derived and simplified to identify three different regimes of slippage (weak, moderate, and strong) and obtain the length and time scales of instability in them. For illustration, the ubiquitous van der Waals interactions have been employed. Different regimes of slip-flow can be predicted based on a nondimensional parameter, xi, which is a function of slip length, film thickness, intermolecular potential, and interfacial tension. Two distinct transitions from weak to moderate slip and from moderate to strong slip occur at xiT1 approximately 0.01 and xiT2 approximately 500, respectively. More specifically, a decrease in film thickness causes transitions from weak to moderate to strong slip regime. Even a weak slippage causes faster breakup of a thin film, whereas slippage beyond a transition value (slip length, bT1) increases the length scale of instability and reduces the number density of holes compared to the nonslipping case. Strong slippage produces holes faster, and the holes are fewer in number and have less developed rims. The exponents for the length scale (lambdam infinity h0n; h0 is film thickness) and time scale of instability (tr infinity h0m) change nonmonotonically with slippage (for nonretarded van der Waals instability, n E (1.25, 2), m E (3, 6)). Retardation in van der Waals potential increases the exponents (n E (1.5, 2.5), m E (5, 8)). The initial stage of evolution of a slipping film, simulated based on nonlinear equations, follows the length scale and time scale of instability, close to the prediction of linear analysis. It is hoped that the present analysis will help in better interpretation of thin film experiments, in estimation of slippage, and in the determination of intermolecular forces from the length and time scales of the instability.

Computer Simulation↗
PubMed2001

Mutations in the APC tumour suppressor gene cause chromosomal instability.

Two forms of genetic instability have been described in colorectal cancer: microsatellite instability and chromosomal instability. Microsatellite instability results from mutations in mismatch repair genes; chromosomal instability is the hallmark of many colorectal cancers, although it is not completely understood at the molecular level. As truncations of the Adenomatous Polyposis Coli (APC) gene are found in most colorectal tumours, we thought that mutations in APC might be responsible for chromosomal instability. To test this hypothesis, we examined mouse embryonic stem (ES) cells homozygous for Min (multiple intestinal neoplasia) or Apc1638T alleles. Here we show that Apc mutant ES cells display extensive chromosome and spindle aberrations, providing genetic evidence for a role of APC in chromosome segregation. Consistent with this, APC accumulates at the kinetochore during mitosis. Apc mutant cells form mitotic spindles with an abundance of microtubules that inefficiently connect with kinetochores. This phenotype is recapitulated by the induced expression of a 253-amino-acid carboxy-terminal fragment of APC in microsatellite unstable colorectal cancer cells. We conclude that loss of APC sequences that lie C-terminal to the beta-catenin regulatory domain contributes to chromosomal instability in colorectal cancer.

Adenomatous Polyposis Coli Protein↗
PubMed1998

Prevalence of minisatellite and microsatellite instability in radiation-induced post-Chernobyl pediatric thyroid carcinomas.

Exposure to ionizing radiation induces different forms of genomic instability in cultured cells and experimental animals. A higher rate of germline mutations at human hypervariable minisatellite loci was reported in children born from parents exposed to radiation after Chernobyl, implicating genome destabilization as a possible mechanism responsible for late radiation effects in humans. To test if radiation-induced carcinogenesis in the thyroid gland may be associated with somatic minisatellite instability or microsatellite instability, we utilized a PCR-based approach to study normal and tumor DNA from 17 pediatric post-Chernobyl papillary thyroid carcinomas for mutations at three different minisatellite loci (D1S80, D17S30, ApoB), and 27 microsatellite loci of di-, tri-, or tetranucleotide repeats. Minisatellite instability was found in three (18%) tumors, with one of them exhibiting mutations in all three minisatellite loci, whereas two others showed mutations in one of two informative markers. By contrast, none of 20 sporadic thyroid cancers from patients with no history of radiation exposure was positive for minisatellite instability. Microsatellite analysis of post-Chernobyl tumors revealed a mutation in one (6%) tumor only at the locus of D10S1412, whereas all other 26 microsatellite markers showed identical patterns in each normal/tumor pair. Our results suggest that somatic cell microsatellite instability does not contribute to radiation-induced thyroid carcinogenesis. However, somatic minisatellite mutation events are present in a subset of radiation-induced, but not sporadic, thyroid cancers, suggesting that this type of genomic instability may play a role in radiation-induced tumorigenesis in the thyroid gland.

Adolescent↗
PubMed2003

Radiation-induced genomic instability and its implications for radiation carcinogenesis.

Radiation-induced genomic instability is characterized by an increased rate of genetic alterations including cytogenetic rearrangements, mutations, gene amplifications, transformation and cell death in the progeny of irradiated cells multiple generations after the initial insult. Chromosomal rearrangements are the best-characterized end point of radiation-induced genomic instability, and many of the rearrangements described are similar to those found in human cancers. Chromosome breakage syndromes are defined by chromosome instability, and individuals with these diseases are cancer prone. Consequently, chromosomal instability as a phenotype may underlie some fraction of those changes leading to cancer. Here we attempt to relate current knowledge regarding radiation-induced chromosome instability with the emerging molecular information on the chromosome breakage syndromes. The goal is to understand how genetic and epigenetic factors might influence the onset of chromosome instability and the role of chromosomal instability in carcinogenesis.

Chromosome Breakage↗
PubMed1999

Genetic instability in incidentally discovered and advanced prostate cancer.

OBJECTIVE: To investigate the frequency of microsatellite instability, a marker for genetic instability, in incidental and advanced prostate cancers, and to determine the role and prognostic importance of genetic instability in prostate carcinogenesis. PATIENTS AND METHODS: Microsatellite analysis was performed on 72 prostate cancers, of which 26 were incidentally discovered at transurethral prostatectomy (TURP) for benign disease. They were staged and graded 1-3 according to glandular differentiation. Fresh prostatic tissue was obtained at TURP performed for bladder outlet obstruction, from 43 patients (median age 73 years, range 55-88), with tissue from the remaining 29 (median age 75, range 53-83) patients obtained from pathology archives, having been originally collected at TURP between 1969 and 1986. RESULTS: Instability was detected in 14 (19%) cancers overall, in eight (31%) of 26 incidental tumours and in six (13%) of 46 clinically apparent tumours. These differences were not statistically different (2P=0.1). The time to progression and survival were similar between men with tumours showing instability and those with no instability. CONCLUSION: These data suggest that genetic instability is an early event in prostate carcinogenesis, but does not appear to influence prognosis.

Aged↗
PubMed2001

An association between sebaceous carcinoma and microsatellite instability in immunosuppressed organ transplant recipients.

Sebaceous carcinomas are rare cutaneous appendageal tumors that may occur sporadically or in association with an internal malignancy in Muir-Torre syndrome. In Muir-Torre syndrome microsatellite instability can often be demonstrated in tumor DNA as a result of an inherited mutation in one of several known mismatch repair genes; however, the role of microsatellite instability in sporadic sebaceous carcinomas has not been previously studied. In this report we describe the clinicopathologic characteristics of a series of unselected sebaceous carcinomas and examine them for the presence of microsatellite instability. Of 10 consecutive tumors identified over a 10 y period, only one was from a patient known to have Muir-Torre syndrome. Of the nine presumed sporadic cases, five were from four renal transplant recipients and four from otherwise healthy individuals. Microsatellite instability was demonstrable in three cases: in the Muir-Torre syndrome-associated tumor and in two tumors from transplant patients. Microsatellite instability was subsequently also found in a sebaceous carcinoma from a further transplant patient prospectively sought from another institution. The presence of microsatellite instability in post-transplant sebaceous carcinomas was associated with loss of expression of the mismatch repair protein hMSH2. In summary, sebaceous gland carcinomas, while characteristic of Muir-Torre syndrome, are commonly found outside this context. Among presumed sporadic cases, our data suggest they may be over-represented in immunosuppressed renal transplant recipients. The presence of microsatellite instability in transplant-associated lesions, together with loss of hMSH2 expression suggests that immunosuppression might unmask a previously silent Muir-Torre syndrome phenotype in some cases. Alternatively, there is experimental evidence to suggest that immunosuppressive drugs, most plausibly azathioprine, could select for the emergence of a mutator phenotype and thus predispose to the development of sebaceous carcinomas. The role of mismatch repair defects in other post-transplant skin malignancies remains to be established.

Aged↗