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PubMedDate not supplied

Genetic instability and the evolution of angiogenic tumor cell lines (review).

Advanced tumor growth requires the formation of new blood vessels (angiogenesis). Whether new blood vessels are formed or not depends on a balance between angiogenesis inhibitors and promoters. Host tissue, as well as tumor cells, express inhibitory factors preventing angiogenesis. During cancer progression, tumor cell lines evolve which produce factors promoting the angiogenic switch. We use mathematical models in order to examine the conditions required for angiogenic cell lines to emerge and hence for the disease to progress. We find that genetic instability, defined as a much elevated mutation rate of somatic cells, is required for the emergence of angiogenic tumor cells. This is because a high mutation rate ensures that within a short period of time, a sufficiently high number of angiogenic cells are generated. This founder population of mutant cells is large enough to overcome the inhibitory factors produced by the tissue thereby inducing the angiogenic switch through the production of promoters. In the absence of genetic instability, angiogenic cells cannot fix, even if the relevant mutations are generated at low levels in the tumor cell population. This is because angiogenic promoters will not be sufficiently abundant to counter the influence of inhibitory factors. In this context, the inhibition of angiogenesis can be viewed as a host defense ensuring that the tumor need be genetically unstable if it is to grow and progress beyond a certain size limit. We observe that genetic instability is of value early in tumorigenesis but becomes a liability later. This is because instability decreases the fitness of the angiogenic tumor once it has become established.

Animals↗
PubMedDate not supplied

Exploring and exploiting instability.

Genetic instability was postulated to be essential for tumor development almost three decades ago, and yet its exact nature in and relationship with cancer continue to be ill-understood and hotly debated subjects. In this article, we review and discuss current knowledge and thinking about the existence, characteristics, reasons for and mechanisms of genetic instability in human cancers, as well as how its study can help us better understand and fight cancer. Particular emphasis is given to chromosomal instability, the most common and least understood of the types of genetic instability found in human tumors.

Aneuploidy↗
PubMed1993

Carpal Instability: Evaluation and Treatment.

Carpal instability is a common cause of wrist pain, motion loss, and disability. Diagnosis and treatment of carpal instability are dependent on a clear understanding of wrist anatomy and carpal kinematics, both normal and pathologic, as well as their relation to the current concepts regarding management. A brief review of anatomy and normal kinematics is presented, followed by a detailed discussion of specific instability patterns, including pathomechanics. A treatment algorithm is provided, detailing the authors' preferred treatment for the most common instability patterns.

Journal Article↗
PubMed1993

Glenohumeral Instability: Evaluation and Treatment.

Glenohumeral instability encompasses a spectrum of disorders of varying degree, direction, and etiology. The keys to accurate diagnosis are a thorough history and physical examination. Plain radiographs are frequently negative, especially in subtle forms of instability. Computed tomography (CT), CT arthrography, magnetic resonance imaging, arthroscopy, and examination under anesthesia may occasionally yield important diagnostic information. Nonoperative treatment of shoulder instability consists of reduction of the joint (when necessary), followed by immobilization and rehabilitative exercises. The length and the value of immobilization remain controversial. Rehabilitative programs emphasize strengthening f the dynamic stabilizers of the shoulder, particularly the rotator cuff muscles. Both arthroscopic and open techniques can be used for operative stabilization of the glenohumeral joint. Results of these repairs are assessed not only in terms of recurrence rate, but also in terms of functional criteria, including return to athletics. Some standard repairs have declined in popularity, giving way to procedures that directly address the pathology of detached or excessively lax capsular ligaments without distorting surrounding anatomy. Capsular repairs also allow correction of multiple components of instability.

Journal Article↗
PubMedDate not supplied

[Posttraumatic spinal instability and the methods for its surgical correction].

The paper deals with the outcomes of 982 patients with thoracic and lumbar spinal lesions and the data of biomechanical testing (298 studies on 103 specimens from the cervical, thoracic, and lumbar spine). Major types of acute posttraumatic spinal instability (such as axial instability, threatening fractured fragment instability, and threatening segmental instability) are defined and the stabilizing capacities of routine surgical techniques are assessed. The current systems for stabilizing the spine (transpedicular designs and plates for anterior spinal fixation is shown to be effective.

Humans↗
PubMed1999

Regional reproducibility of microsatellite instability in sporadic colorectal cancer.

The reproducibility of microsatellite instability from different regions of the same sporadic colon cancer has not been addressed. We therefore microdissected and extracted DNA from three to nine separate regions of 13 highly unstable sporadic colon cancers. Each region was then evaluated by polymerase chain reaction amplification of 17 microsatellites: 10 tetranucleotide repeats, 2 noncoding mononucleotide repeats (BAT-26 and BAT-40), and 5 coding mononucleotide repeats (TGFBRII, BAX, MSH3, MSH6, IGFIIR). Microsatellite instability showed 100% regional reproducibility with respect to either the panel of 10 tetranucleotide repeats or BAT-26, and nearly 100% reproducibility with BAT-40, although regional variation in the percent instability and the size of unstable alleles was present. TGFBRII was more frequently mutated than any other coding mononucleotide repeat; frame shifts in this gene were identified in nearly every region of every tumor. Each of the five coding repeats showed regional variability in at least one tumor, and 10 of the 13 tumors showed variability with at least one coding repeat. This variability took the form of different mutant alleles (TGFBRII, BAX, MSH3) or mutations present in some but not all regions of a tumor (MSH6, IGFIIR, BAX, MSH3). We conclude that the regional reproducibility of generalized microsatellite instability as measured by noncoding repeats indicates that sampling is not a problem in these highly unstable tumors, and that the mismatch repair deficiency phenotype is acquired in the very late adenoma stage or early cancer stage of sporadic colonic tumorigenesis. The high frequency of TGFBRII mutations is consistent with acquisition of these mutations at a similar stage of tumorigenesis. The regional variability with respect to the presence or absence of a mutation in the other four coding mononucleotide repeats could lead to sampling error and is consistent with a somewhat later time of acquisition of these mutations. Genes Chromosomes Cancer 26:106-114, 1999.

Adult↗
PubMed2000

Surgical treatment for stress urinary incontinence associated with valsalva induced detrusor instability.

PURPOSE: Detrusor instability initiated by increased intra-abdominal pressure that results in incontinence has always been difficult to treat. This form of incontinence may be due to traction on the pelvic nerves when increased abdominal pressure is applied to already weakened pelvic supportive tissue. In most patients pharmacological attempts to correct this problem fail. We describe a pubovaginal sling designed to stabilize the urethrovesical junction during the Valsalva maneuver, which is our treatment of choice for such patients. MATERIALS AND METHODS: From 1994 to 1998 we treated 36 patients with a pubovaginal sling procedure for Valsalva induced detrusor instability diagnosed on preoperative urodynamics. The sling material was in situ vaginal wall in 20 cases, free swing vaginal wall in 6, rectus fascia in 4, cadaveric fascia in 3 and synthetic material in 3. Urodynamic evaluation was performed preoperatively in all patients. Followup of 6 months to 4 years involved subjective questions and objective examination. RESULTS: Cure was achieved in 33 of the 36 patients (92%), of whom leak point pressure was less than 50, 50 to 100 and greater than 100 cm. water in 9, 17 and 7, respectively. In the 3 failed cases leak point pressure was 50 to 100 cm water, including 2 in which cotton swab test results were less than 30 degrees. Urge incontinence resolved in 75% of the patients. CONCLUSIONS: The pubovaginal sling procedure may cure Valsalva induced detrusor instability. Leak point pressure does not determine which patients do well. Evaluation for hypermobility may help to predict the success or failure of a procedure by identifying those in whom Valsalva induced detrusor instability results from traction on the pelvic nerves.

Adult↗
PubMedDate not supplied

The role of genomic instability in human carcinogenesis.

Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). Based upon this general observation, it has been suggested that cancer cells are genetically unstable, and that acquisition of genomic instability may represent an early step in the process of carcinogenesis and a general feature of many human tumors. Numerous studies have appeared that characterize the nature and frequency of occurrence of various molecular lesions in human tumors, and significant progress has been made towards the elucidation of the molecular mechanisms that govern genetic stability in normal cells and genetic instability in neoplastic cells. In this review, we examine the evidence that genomic instability plays a significant role in the genesis of various human tumors. Furthermore, we consider the possible molecular pathways to tumorigenesis in humans and how different forms of genetic instability may impact upon these pathways.

Cell Transformation, Neoplastic↗
PubMed1999

Microsatellite instability and frameshift mutations in genes involved in cell cycle progression or apoptosis in ovarian cancer.

The loss of mismatch repair enzymes increases the mutation rate in microsatellites and coding regions of the genome and appears to be involved in drug resistance. The replication error (RER+) phenotype, associated with microsatellite instability, has been widely described for both familial and sporadic colon cancers and for gastric and endometrial tumors. For ovarian cancer, the incidence of RER+ cases among sporadic tumors is still uncertain. We analyzed epithelial ovarian tumors and ovarian carcinoma cell lines for microsatellite instability and for mutations in the coding regions of different genes, including the recently discovered human CHK-1 gene, which has an important role in controlling cell cycle progression and whose coding region contains a poly(A)9 tract. Microsatellite instability and frameshift mutations in coding regions of BAX, TGFbetaRII, IGFIIR, E2F-4, ICE, and CHK-1 genes were analyzed in ovarian cancer samples and cell lines by polymerase chain reaction (PCR). Approximately 26% of patients showed microsatellite instability in two or more loci. BAT-26 locus showed no alteration in primary tumors. We detected a BAX mutation in one tumor sample and a TGFbetaRII mutation in one cell line. Our findings confirm the presence of the RER+ phenotype in sporadic ovarian cancer. The low rate of mutation in genes previously reported to be altered in colon and gastric cancer suggests that other not yet identified genes might be altered and could play a role in tumor progression and response to treatment in RER+ ovarian tumors.

Adult↗
PubMed2000

Correlation of genetic instability with mismatch repair protein expression and p53 mutations in non-small cell lung cancer.

To examine the etiological association of genetic instability in lung tumorigenesis, we investigated the frequency of microsatellite instability (MI) of eight dinucleotide repeat markers in 68 patients with non-small cell lung cancer. Twenty-eight patients (41.2%) evidenced instability in multiple tested microsatellite markers ranging from 3-7 and were defined as MI-positive patients. MI occurred more frequently in patients suffering from squamous cell lung carcinoma (P = 0.004). We examined the association between MI and expression of hMLH1 mismatch repair protein by immunohistochemical analysis of hMLH1 protein in paraffin-embedded tumors from 64 patients. Twenty MI-positive patients (76.9%) had no expression of hMLH1 protein. The data showed that MI was associated with altered hMLH1 expression (P = 0.03). To examine the role of genetic instability in the previous identified small intragenic deletion of the p53 gene, we explored the association between MI and p53 gene mutations. All patients, except one, containing small intragenic deletion in p53 gene showed MI (P = 0.018). In addition, we found that MI was not associated with the prognosis. Our data suggest that MI plays a significant role in non-small cell lung cancer tumorigenesis in Taiwan and that MI is associated with the altered expression of hMLH1 mismatch repair protein. In addition, MI may be involved in frequent small intragenic deletions of p53 gene.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Developmental instability predicts individual variation in verbal memory skill after caffeine ingestion.

OBJECTIVE: To determine the mediating effects of developmental instability on individual differences in response to caffeine. BACKGROUND: Individual variation of drug effects might reflect broad genomic factors as well as the direct effects of specific alleles. The current study tested the hypothesis that individual differences in developmental instability, in part determined by genomic characteristics, would predict individual variation in the magnitude of caffeine-induced verbal memory deficits. Minor physical anomalies and fluctuating asymmetry were used as measures of developmental instability. METHOD: One hundred participants were (1) administered one version of the Rey Auditory Verbal Learning Test; (2) given a dose of caffeine determined by body weight (3 mg/kg); (3) assessed for minor physical anomalies and fluctuating asymmetry; and (4) given an alternate randomized version of the Rey Auditory Verbal Learning Test. RESULTS: Consistent with predictions, a composite measure of developmental instability predicted the magnitude of caffeine-induced memory decrements. CONCLUSIONS: These results may have important implications for the genetic underpinnings of individual differences in drug effects.

Abnormalities, Multiple↗
PubMed2000

Nuclear and mitochondrial genome instability in human breast cancer.

We analyzed 40 pairs of breast normal/cancer tissues for the presence of mitochondrial (mt) genome instability and nuclear MSI in tumor cells. As mt, markers we used a (CA)n mt microsatellite (MS) starting at the 514-bp position of the D loop region and 4 informative MnlI sites located between the 16,108- and 16,420-bp positions of the D loop region. Nuclear microsatallite instability (MSI) was tested with 8 (CA)n MS, syntenic for the 13q chromosome arm. Moreover, we tested the spontaneous frequency of mtMSI and mt-MnlI mutations in 459 mother/descendant events. Mutations of mt-MnlI sites were found in 19 of 40 (47.5%) breast tumors, representing a 216-fold increase over the spontaneous rate in the female germline. Instability of the mtMS occurred in 17 of 40 (42.5%) breast cancers, which implies a 16-fold increase over the rate of spontaneous mutations. Nuclear MSI was found in 20 of 40 (50%) cases. In 15 of these cases the MSI was restricted to one locus, whereas in 5 instances the change of alleles was detected in 2 or 3 loci. Analysis of the correlation between mt and nuclear mutations showed no significant associations, suggesting that different systems are responsible for mt and nuclear genome instability in tumor cells. We propose that the two main mechanisms producing mtRFLP and mtMSI are damage by free radicals and error repair by the polymerase gamma, the first mechanism being a major cause of MnlI mutations and a secondary cause of mtMSI.

Alleles↗
PubMed2000

Racial disparity in the frequency of PTEN mutations, but not microsatellite instability, in advanced endometrial cancers.

Survival of African Americans with endometrial cancer is significantly worse than that of whites. Mutation of the PTEN tumor suppressor gene and microsatellite instability occur in some endometrial cancers, and they are associated with favorable prognostic features. The aim of this study was to determine whether there is a racial disparity in the frequency of these molecular alterations that contributes to differences in outcome in advanced endometrial cancer. We screened 140 stage III/IV endometrial adenocarcinomas (78 Caucasian, 62 African American) for mutations in the PTEN gene. Paired DNA samples were available in 100 cases and were analyzed for microsatellite instability using three polymorphic markers. African-American women had cancers with significantly higher stage and grade that were more often nonendometrioid. In addition, median survival of African Americans (1.0 years) was worse than that of whites (2.5 years; P = 0.02). PTEN mutation was seen in 20 of 140 (14%) cancers and was associated with endometrioid histology and more favorable survival. The frequency of PTEN mutations was significantly higher in whites (17 of 78; 22%) than in African Americans (3 of 62; 5%; P = 0.006). Microsatellite instability was found in 15% of cancers, exclusively in endometrioid cases, and was associated with favorable survival (P = 0.01). There was no racial difference in the frequency of microsatellite instability. We conclude that mutation of the PTEN tumor suppressor gene is associated with favorable survival in advanced endometrial cancer and is 4-fold more frequent in Caucasians relative to African Americans. This suggests that differences in the frequency of PTEN mutations contribute to the racial disparity in endometrial cancer survival.

Adenocarcinoma↗
PubMed2000

Update of genetics in colorectal carcinomas: genomic instability and somatic evolution.

INTRODUCTION: Currently, there are two contrasting viewpoints on what drives the process of carcinogenesis. The genomic (DNA or chromosomal) instability model contends that an increased mutation rate early in carcinogenesis is necessary for the multistage process, while the somatic evolution model postulates that normal mutation rate with selective advantage and clonal expansion is sufficient to cause cancer. METHODS: Evidence from colorectal carcinoma (CRC) for and against the two models are compared and contrasted. RESULTS: With the exception of hereditary non-polyposis colorectal carcinoma (HNPCC) where DNA instability attributable to mismatch repair deficiency is clearly demonstrated, the majority of CRC appear to progress through the selection of a series of mutations without the need of first acquiring a mutator phenotype. Aneuploidy or chromosomal instability is more likely to be a consequence of non-random selection of mutations in genes residing on the chromosome rather than the direct cause of cancer. Nevertheless, aneuploidy and/or DNA alterations can lead to secondary instability, hence, contributing to the phenotypes associated with carcinoma. CONCLUSIONS: Present knowledge, thus, points to multiple, mutually non-exclusive pathways for different cancer populations, further emphasising tumour heterogeneity.

Adenomatous Polyposis Coli↗
PubMed2000

Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.

Many lines of evidence suggest that the retinoblastoma protein interacting zinc finger gene RIZ is a strong candidate for the tumor suppressor locus on 1p36, a region commonly deleted in many human cancers with chromosomal instability. In addition, a role for RIZ in tumors of the microsatellite instability pathway is suggested by frequent frameshift mutations in hereditary non-polyposis colorectal carcinomas. Here we studied RIZ mutations in sporadic cancers with microsatellite instability. Frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas, 6 (33%) of 18 endometrial carcinomas, 14 (26%) of 51 of colorectal carcinomas, and 7 (54%) of 13 cell lines. Eleven tumor tissues showed biallelic inactivation of RIZ. In contrast, no frameshift mutations were found in 70 microsatellite stable tumors. These results suggest an important role for RIZ in sporadic cancers with microsatellite instability.

Alleles↗
PubMed2000

Intravesically administered ketoprofen in treatment of detrusor instability: cross-over study.

AIM: To evaluate the therapeutic efficacy of intravesically administered ketoprofen in patients with urodynamically verified detrusor instability. METHODS: This double-blind randomized placebo-controlled cross-over study included 30 patients with urodynamically verified detrusor instability. Their mean age was 44+/-3.6 years (range 37-49) and the median of the parity was 2 years (1-3). The mean duration of symptoms was 18.3+/-3.1 months (range 14-23). After a 6-week screening, patients were randomized to receive ketoprofen or placebo once a day for 4 weeks. Out of 30 patients, 16 started with ketoprofen, and 14 received placebo. After a week of washing period, 16 patients received placebo, and 14 received ketoprofen. The solution for intravesical application was 50 mL of saline with 2 mL (100 mg) of ketoprofen warmed to 37 degrees C. The placebo solution contained 2 mL of distilled water instead of ketoprofen. The assessment including micturition diaries, cystometric measurements, and bacteriological analysis of urine specimens was performed at the beginning of the study and after the treatment. RESULTS: The subjective cure rate was 18/30 after ketoprofen. The instability index was lower after ketoprofen than before treatment or after placebo (p<0.001). Maximal cystometric capacity and the urinary bladder volume at which the patients felt urgency to void were larger after ketoprofen than before it (p<0.001) or after placebo (p<0.001). The number of patients with uninhibited bladder contractions decreased significantly after ketoprofen, but not after placebo (p<0.001). No side effects were observed. CONCLUSION: Intravesically administrated ketoprofen is a feasible and effective treatment for detrusor instability.

Administration, Intravesical↗
PubMed2001

Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures.

A hallmark of cancer cells is their pronounced genetic instability, which has been implicated in both tumor development and negative treatment outcomes. Recently, it has been reported that ionizing radiation may induce a persistent state of hypermutability in mammalian cells that lasts for many (>30) cell divisions. In this study, we examined whether other stress signals (both DNA-damaging non-DNA-damaging) can initiate a similar process. We show that persistent genetic instability was induced by nongenotoxic stress exposures such as heat treatment, serum starvation, or the tumor microenvironment, as well as genotoxic stresses such as ionizing radiation and exposure to hydrogen peroxide. Progeny of 10-20% of surviving cells exhibited persistent and pronounced genetic instability at both an artificially transfected gene and a genomic minisatellite locus 23 cell divisions after the initial exposure. Stress-induced persistent genetic instability may be a general response of tumor cells to a wide range of genotoxic or nongenotoxic stress conditions.

Animals↗
PubMed2001

Evidence that genetic instability occurs at an early stage of colorectal tumorigenesis.

Chromosomal instability is believed to be a common feature of most human tumors, but the stage at which such instability originates has not been defined. At the molecular level, chromosomal instability is characterized by allelic imbalance (AI), representing losses or gains of defined chromosomal regions. We have assessed AI in early colorectal tumors using newly developed methods for assessing AI in complex cell populations. A total of 32 adenomas of average size (2 mm; range, 1-3 mm) were studied. AI of chromosome 5q markers occurred in 55% of tumors analyzed, consistent with a gatekeeping role of the adenomatous polyposis coli tumor suppressor gene located at chromosomal position 5q21. AI was also detected in each of the other four chromosomes tested. The fractions of adenomas with AI of chromosomes 1p, 8p, 15q, and 18q were 10,19, 28, and 28%, respectively. Over 90% of the tumors exhibited AI of at least one chromosome, and 67% had allelic imbalance of a chromosome other than 5q. These findings demonstrate that AI is a common event, even in very small tumors, and suggest that chromosomal instability occurs very early during colorectal neoplasia.

Adenoma↗