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PubMed2007

The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family.

In the inherited syndromes, MUTYH-associated polyposis (MAP) and hereditary nonpolyposis colorectal cancer (HNPCC), somatic mutations occur due to loss of the caretaker function that base-repair (BER) and mismatch repair (MMR) genes have, respectively. Recently, we identified a large branch from a MSH6 HNPCC family in which 19 family members are heterozygous or compound heterozygous for MUTYH germ line mutations. MSH6/MUTYH heterozygote mutation carriers display a predominant HNPCC molecular tumour phenotype, with microsatellite instability and underrepresentation of G>T transversions. A single unique patient is carrier of the MSH6 germline mutation and is compound heterozygote for MUTYH. Unexpectedly, this patient has an extremely mild clinical phenotype with sofar only few adenomas at age 56. Four out of five adenomas show characteristic G>T transversions in APC and/or KRAS2, as seen in MUTYH associated polyposis. No second hit of MSH6 is apparent in any of the adenomas, due to retained MSH6 nuclear expression and a lack of microsatellite instability. Although this concerns only one case, we argue that the chance to find an additional one is extremely small and currently a mouse model with this genotype combination is not available. Moreover, the patients brother who is also compound heterozygous for MUTYH but lacks the MSH6 germline mutation presented with a full blown polyposis coli. In conclusion, these data would support the notion that abrogation of both MSH6 DNA mismatch repair and base repair might be mutually exclusive in humans.

Adult↗
PubMed2000

Vertigo is an underestimated symptom of ocular disorders: dizzy children do not always need MRI.

Vertigo, instability, dizziness, or equilibrium disorders are not usually considered as consequences of ophthalmologic problems. We present data indicating that ocular disorders can be responsible for these symptoms in children. In a population of 523 pediatric patients with vertigo or disequilibrium and referred for vestibular testing in our otolaryngology department during a 5-year period, 27 children presented with normal vestibular and somatic neurologic examinations but with ophthalmologic disorders (vergence insufficiency or latent strabismus with binocular vision in 70% and anisometropia in 41%). These patients represented 24% of all vergence insufficiencies detected and 4% of all orthoptic examinations performed in the pediatric ophthalmology department. These ocular abnormalities were considered to be the initial cause of the problems. In two thirds of these patients the symptoms were completely resolved by simple ophthalmologic treatment. No other additional tests, such as magnetic resonance imaging, were required. Therefore we propose that every child complaining of vertigo or dizziness but with normal clinical somatic neurologic and vestibular examinations should have a complete ophthalmologic examination before additional, more costly, investigations. This should lead to better screening and more appropriate care of ocular disorders in children and avoid unnecessary magnetic resonance imaging.

Child↗
PubMed2006

No evidence of significant silencing of Fanconi genes FANCF and FANCB or Nijmegen breakage syndrome gene NBS1 by DNA hyper-methylation in sporadic childhood leukaemia.

Fanconi anaemia (FA) and Nijmegen breakage syndrome (NBS) carry a high risk of haematological cancer. Affected cellular pathways may be modulated in sporadic malignancies and silencing of FANCF through methylation has been shown to cause somatic disruption of the FA pathway. Combined bisulphite restriction analysis for methylation of FANCF, FANCB and NBS1 was used to investigate 81 sporadic acute childhood leukaemias. No methylation was detected at any associated CpG sites analysed. This does not exclude very low levels of FANCF, FANCB or NBS1 methylation, but suggests other factors are responsible for chemo-sensitivity and chromosomal instability in sporadic childhood leukaemia.

Acute Disease↗
PubMed1996

Differences in the spectrum of spontaneous mutations in the hprt gene between tumor cells of the microsatellite mutator phenotype.

We have determined the frequency and spectrum of spontaneous mutations at the hprt locus in LoVo, HCT116, LS180 and DLD-1 colon carcinoma cell lines exhibiting microsatellite genetic instability. Each cell line has a different mutator gene. LoVo and HCT116 cells have mutated hMSH2 and hMLH1 genes, respectively, which account for the majority of hereditary non-polyposis colorectal cancer (HNPCC). LS180 cells are wild type for these genes and also for hPMS1 and hPMS2 mismatch repair genes. DLD-1 cells harbor a mutated GTBP mismatch binding factor and a mutated DNA Polymerase delta. The mutation rate at the hprt locus was several hundred fold higher in these cell lines relative to control cell lines without microsatellite instability. The mutations were frameshifts (deletions and insertions of a single nucleotide in short repeats) and single base substitutions (transversions and transitions). Some mutations were shared by these four cell lines. However, every cell line also exhibited a distinctive spectrum of mutations suggesting that each mutator gene induces a particular mutator phenotype. These results also suggest that the frequency and spectrum of somatic mutations in tumor cells of the microsatellite mutator phenotype may have diagnostic applications to discriminate among the diverse underlying mutator genes.

Base Sequence↗
PubMed1986

[Fragile sites on human chromosomes and cancer-specific chromosomal rearrangements].

Heritable fragile sites are specific points on human chromosomes which appear as nonstaining gaps or breaks under certain physiological conditions and are inherited in a Mendelian codominant fashion. Recent findings of a correlation between fragile sites and breakpoints involved in specific chromosomal rearrangements seen in some neoplasias suggest that fragile sites may be unique sites particularly susceptible to chromosome breakage and rearrangement under in vivo physiological conditions. The majority of known fragile sites, including fragile X, are classified in the folate-sensitive group and are expressed under conditions of thymidylate stress. In thymidine-auxotrophic somatic cell hybrids constructed by cell fusion between fragile X cells and thymidylate synthase-negative mouse mutant cells, we have shown that thymidine deprivation alone can induce the expression of fragile X, suggesting that the primary DNA structure itself is responsible for its expression. Elucidation of the DNA structure of fragile sites may provide a clue to the understanding of genetic instability in the human genome and its possible involvement in cancer-specific chromosomal rearrangements.

Animals↗
PubMedDate not supplied

[Psychosomatic aspects of adolescence].

During adolescence physical, psychic and social changes occure more rapidly and to a greater extent than during any other period of live. The marked changes concern not only the outern appearence, but also its intrapsychic representations, the body image. The complex integrative processes towards the identity as man or woman cannot be mastered without a certain emotional and physical instability. This is particularly the case if, in addition, nearly infantile disturbances in the socialisation or conflicts specific for this life period are, or have been, present. They can in the sense of a disposition lead to the manifestation of more or less severe crisis in adolescence. These crises interfere not only with the body image, but in many cases with the somatic functions as well. In the study three general aspects of this developmental problem are discussed as far they are relevant in the therapy of psycho-somatic disturbances in adolescents. 1. The implication of the adolescent phase in the course of psycho-somatic diseases. 2. Diseases which mainly occure in adolescence and are predominantly confined to this life period or are mainly influenced by it. 3. The influence which conflicts and phase-specific anxieties and fantasies exercise on the development and establishment of a mature body image and an adult identity.

Adolescent↗
PubMed1997

Integration of Epstein-Barr virus in Burkitt's lymphoma cells leads to a region of enhanced chromosome instability.

BACKGROUND: Several lymphomas are associated with Epstein-Barr virus (EBV) infection. However EBV is not detectable in 100% of cases using standard staining techniques. It still remains an open question whether in these EBV-negative cases EBV has never infected the cell, whether it has infected the cell and escapes conventional screening methods, or whether it has been lost again after initial infection. MATERIALS AND METHODS: The physical status of EBV in the Burkitt's lymphoma cell line BL60-P7 as well as in three somatic cell hybrids between BL60-P7 and its autologous EBV-immortalized lymphoblastoid cell line IARC 277 was analyzed using conventional cytogenetics, Southern blotting, and fluorescence in situ hybridization (FISH). RESULTS: Integration of EBV into the host genome of the lymphoma cell line BL60-P7 leads to an achromatic gap which causes a 'vulnerable site'. In hybrid cells, loss of integrated EBV, together with an adjacent chromosomal fragment, occurs during long-term cultivation. The integrated EBV genome, including genes encoding for LMP and EBER, is partly deleted. CONCLUSION: We assume that integration of EBV into the host cell genome could be a more common event in lymphoma cells. Partially deleted EBV might escape standard detection assays. The integration might constitute a chromosomal region prone to break events akin to the phenomenon of fragile sites, leading to the loss of viral DNA as well as chromosomal DNA. This observation makes it tempting to speculate that under certain conditions EBV can act in lymphomagenesis by a so-called hit-and-run mechanism.

Blotting, Southern↗
PubMed1998

Increased somatic recombination in methylation tolerant human cells with defective DNA mismatch repair.

We have studied whether spontaneous intrachromosomal recombination is altered in methylation tolerant human cells with a defect in mismatch repair. Somatic recombination was analysed in HeLaMR cells containing the vector pTPSN, which carries two copies of the gene for hygromycin resistance. The hygromycin genes are both inactivated by an inserted HindIII linker but hygromycin-resistant clones can arise by recombination. The spontaneous rate of recombination in a clone of HeLaMR cells containing a single integrated copy of pTPSN (HeLaG1) was 3.1x10(-6)/cell per generation. Two methylation tolerant variants from HeLaG1 cells (clone 12 and clone 15) were isolated by exposure to MNNG. Clone 12 cells exhibited a 16-fold increase in spontaneous mutation rate at the HPRT gene and extensive microsatellite instability at both mono- and dinucleotide repeats. Microsatellite instability limited to mononucleotide repeats was found in clone 15, whereas the mutation rate at HPRT was not significantly affected. A mismatch binding defect in extracts of clone 15 could be complemented by exogenous GTBP but not by purified hMSH2 protein. These data suggest that clone 15 is defective in GTBP. Extracts of clone 12 were unable to correct a single C:T mispair and complementation by extracts of human colorectal carcinoma cells with known deficiencies in mismatch repair indicated a defect in hMutLalpha. Western blotting with antibodies against different human mismatch repair proteins showed that clone 12 cells did not express hPMS2 protein, but expression of hMLH1, hMSH2 and GTBP appeared normal. The spontaneous recombination rate of clone 12 was 19-fold higher than the parental HeLaG1 cells, whereas no increase was observed in clone 15. Analysis of individual recombinants showed that hygromycin resistance arose exclusively by gene conversion. Our data indicate that mismatch correction regulates somatic recombination in human cells.

Base Sequence↗
PubMed1993

Insertional mutagenesis by transposable elements in the mammalian genome.

Several mammalian repetitive transposable genetic elements were characterized in recent years, and their role in mutagenesis is delineated in this review. Two main groups have been described: elements with symmetrical termini such as the murine IAP sequences and the human THE 1 elements and elements characterized by a poly-A rich tail at the 3' end such as the SINE and LINE sequences. The characteristic property of such mobile elements to spread and integrate in the host genome leads to insertional mutagenesis. Both germline and somatic mutations have been documented resulting from the insertion of the various types of mammalian repetitive transposable genetic elements. As foreseen by Barbara McClintock, such genetic events can cause either the activation or the inactivation of specific genes, resulting in their identification via an altered phenotype. Several disease states, such as hemophilia and cancer, are the result of this apparent aspect of genome instability.

Animals↗
PubMed2002

Densely methylated MLH1 promoter correlates with decreased mRNA expression in sporadic colorectal cancers.

It has been reported that MLH1 is silenced by promoter methylation, and that this phenomenon is associated with microsatellite instability (MSI) in sporadic colorectal cancer (CRC). To clarify the significance of MLH1 promoter methylation in sporadic CRC, we examined the correlation between methylation status over the entire promoter region and mRNA expression in cases showing high-frequency MSI (MSI-H). MLH1 promoter methylation was analyzed using the bisulfite modification sequencing in 48 MSI-H cases. We also screened for somatic mutation, loss of heterozygosity, and immunohistochemical staining of MLH1. The results showed that methylation patterns could be subdivided into three types: methylation of more than 80% of the CpG sites analyzed (type 1 methylation), methylation of less than 20% (type 2 methylation), and methylation mainly in the region 500 to 921 bases upstream from the translation start site (type 3 methylation). Of the three types, only type 1 methylation correlated with decreased mRNA expression. The frequency of type 1 methylation was significantly higher in cases involving the proximal colon (66.7%, 18/27) compared to that of the distal colon and rectum (23.8%, 5/21, P = 0.004). Immunohistochemical staining of MSI-H cases showed that decreased MLH1 was found in 77.1% (37/48). Of the cases with decreased MLH1, type 1 methylation was present in 59.5% (22/37). Overall, our data suggested that the type 1 methylation pattern may affect MLH1 mRNA expression, such that the majority of MSI-H cases in sporadic CRC, especially proximal colon cancer, exhibited type 1 methylation.

Adaptor Proteins, Signal Transducing↗
PubMed1997

Inactivation of Smad4 in gastric carcinomas.

Allelic loss of chromosome 18q has been noted in intestinal type gastric adenocarcinomas. Smad4 is a gene located at 18q that was recently cloned in humans and found to be significantly altered in pancreatic cancers. We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric adenocarcinomas of all histopathological types and pathological stages. Microdissected specimens were used for mutational analysis of Smad4 at the nucleotide level, including the entire coding region and intron/exon boundaries. Allelic imbalance was also analyzed at the Smad4 locus using two nearby microsatellite markers. One case of apparent biallelic inactivation of Smad4 was found in our study of 35 gastric carcinomas. A nonsense point mutation at codon 334 was demonstrated, which, similar to other Smad4 mutations, is predicted to truncate the conserved COOH-terminal domain of this protein. This Smad4 C to T transition mutation was proven to be somatically acquired. Allelic loss was also noted on chromosome 18q at a marker near Smad4 in this mutated gastric cancer, apparently producing complete inactivation of Smad4 in this tumor. Significant 18q allelic loss (56% of 34 informative cases) was noted in our gastric carcinomas using microsatellite markers near the Smad4 locus, regardless of histological subtype or pathological stage. Additionally, three cases of microsatellite instability were observed. Thus, Smad4 inactivation was noted in our gastric carcinomas; however, this event was rare. The frequent loss of chromosomal arm 18q observed in gastric cancers suggests the presence of other tumor suppressor genes in this region that are involved in gastric tumorigenesis. Further studies are needed to identify these other targets of inactivation during gastric cancer development.

Adenocarcinoma↗
PubMed2026

Uptake of germline testing for Lynch Syndrome in patients with deficient mismatch repair/ microsatellite-high colorectal cancer in the public hospital system in South Australia.

Lynch syndrome (LS) accounts for approximately 4% of colorectal cancer (CRC) cases and arises from pathogenic variants in mismatch repair (MMR) genes. Australian guidelines recommend universal MMR or microsatellite instability (MSI) screening in all CRC patients; however, real-world uptake remains variable. This study evaluated rates of MMR/MSI screening, germline testing, and genetics referrals across two major public hospitals in South Australia. A retrospective review of 1775 patients discussed at colorectal multidisciplinary team meetings in the Royal Adelaide and Queen Elizabeth hospitals between January 2021 and December 2023 was conducted to identify rates of MMR/MSI screening and subsequent referral of eligible patients to genetics. Of the 1129 colorectal cancer cases identified, MMR/MSI testing was performed in 93.2% (1052/1129), with deficiency detected in 12.5% (131/1052). Of these, 37% (49/131) were eligible for genetics referral after exclusion of somatic causes. Among eligible patients, 73.5% (36/49) were referred, and 43% (21/49) underwent germline testing. LS was confirmed in 12 patients (9% of deficient MMR CRC), while 9 patients (6.9%) were classified as having Lynch-like syndrome. Despite high screening rates, gaps remain in genetics referral and testing. Barriers included lack of reflex testing, loss to follow-up, and patient refusal. Targeted system-level interventions and improved genomic education are needed to enhance adherence to guidelines and optimise patient outcomes.

Humans↗
PubMed2005

MUC gene abnormalities in sporadic and hereditary mucinous colon cancers with microsatellite instability.

Aim of this study was verifying whether mucin producing colon cancers (CRCs) could develop through a molecular pathway involving microsatellite instability (MSI) and MUC gene alterations. Out of 49 CRCs expressing variable amounts of mucin, 22 (44.9%) were MSI-H and 5 (10.2%) were MSI-L. MUC genes were analyzed by Southern blotting and extra bands were evident in the Variable Number Tandem Repetition (VNTR) regions of MUC2 (5 cases) and MUC5AC (2 cases), but not MUC1 and MUC4 genes. Since the somatic VNTR abnormalities were detected in 6 MSI-H and in 1 MSI-L tumors, they seem to be peculiar of mismatch repair defective CRCs. Our finding suggests that alteration and/or loss of structurally normal MUC genes may be an important step in the neoplastic molecular pathway of a subset of CRCs and that mutations involving VNTR repetitive sequences may exist in MSI tumors as a direct and/or indirect consequence of an inefficient MMR system.

Base Pair Mismatch↗
PubMed2026

The Landscape of Genomic and Socioeconomic Variables in Patients with Colorectal Cancer Based on Genetic Ancestry.

BACKGROUND: Despite differences in tumor alterations across genetic ancestries, investigations of the colorectal cancer molecular landscape have used self-reported ethnicity instead of genetic ancestry. METHODS: We used tumor and matched normal whole-exome sequencing data from 16,388 patients with stage I to IV colorectal cancer to investigate colorectal cancer's germline and somatic molecular landscape and the potential influence of socioeconomic factors (Distressed Communities Index, DCI) across diverse genetic ancestries. Genetic ancestry determined via supervised local ancestry inference included African (AFR, N = 1,697), Native American (AMR, N = 1,291), East Asian (EAS, N = 2,247), European (EUR, N = 9,726), Levantine Middle Eastern (LME, N = 1,192), and South Asian (SAS, N = 184). RESULTS: Microsatellite instability (MSI) was the most common form of hypermutation (80.8%), higher in the EUR genetic ancestry than in the AFR, AMR, and EAS genetic ancestry. Among germline findings, positive results were most common in high-penetrance genes associated with Lynch syndrome. Enrichment patterns included MLH1 (SAS) and PMS2 (AFR). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between the EUR and other ancestry groups in both MSI and microsatellite stable tumors. Mutational signatures suggested enrichment of reactive oxygen species and POLE in AFR, colibactin in EAS, and aflatoxin and NTHL1 in SAS. DCI scores differed by ancestry (higher distress in AFR/AMR than in EUR), but driver mutation frequencies did not vary across DCI quintiles. CONCLUSIONS: Genetic ancestry shapes hereditary risk, tumor biology, and environmental exposures. IMPACT: These findings suggest that incorporating ancestry into screening, trials, and precision oncology may improve equity, though outcome-linked prospective studies and implementation research are warranted.

Aged↗
PubMed1998

Chronic "brain death": meta-analysis and conceptual consequences.

OBJECTIVE: One rationale for equating "brain death" (BD) with death is that it reduces the body to a mere collection of organs, as evidenced by purported imminence of asystole despite maximal therapy. To test this hypothesis, cases of prolonged survival were collected and examined for factors influencing survival capacity. METHODS: Formal diagnosis of BD with survival of 1 week or longer. More than 12,200 sources yielded approximately 175 cases meeting selection criteria; 56 had sufficient information for meta-analysis. Diagnosis was judged reliable if standard criteria were described or physicians made formal declarations. Data were analyzed by means of Kaplan-Meier curves, with treatment withdrawals as "censored" data, compared by log-rank test. RESULTS: Survival probability over time decreased exponentially in two phases, with initial half-life of 2 to 3 months, followed at 1 year by slow decline to more than 14 years. Survival capacity correlated inversely with age. Independently, primary brain pathology was associated with longer survival than were multisystem etiologies. Initial hemodynamic instability tended to resolve gradually; some patients were successfully discharged on ventilators to nursing facilities or even to their homes. CONCLUSIONS: The tendency to asystole in BD can be transient and is attributable more to systemic factors than to absence of brain function per se. If BD is to be equated with death, it must be on some basis more plausible than loss of somatic integrative unity.

Adolescent↗
PubMed2002

[The effect of transposon P(GUS . p53.259H)on the frequency of tumor clones in Drosophila melanogaster wtsp2/+ heterozygotes].

We showed that transposon P(GUS.p53.259H), mapped to chromosome 3 and carrying a dominant mutation p53(259)H.GUS, has a positive effect on the frequency of spontaneous and carcinogen-induced tumor mosaic clones warts- in Drosopila melanogaster heterozygotes for the tumor suppressor gene warts located in the same chromosome. The transposon effect could be explained either by the arrest of apoptosis in the cells expressing mutant p53(259)H.GUS gene and containing carcinogen-induced pre-mutations, and/or by genetic instability introduced into chromosome 3 by the P(GUS.p53.259H) transposon itself. The effect of the P(GUS.p53.259H) appeared to be carcinogen-specific. It substantially increased the frequency of tumors induced by supermutagenic platinum complex, oxoplatin, and did not increase the frequencies of tumors induced by polycyclic aromatic hydrocarbons, benzo(alpha)pyrene and pyrene. In the spectrum of mutations induced by all carcinogens tested, somatic recombination events prevailed over somatic mutations. Hence, carcinogen-specificity of the P(GUS.p53.259H) effect cannot be explained by preferential induction of somatic mutations or somatic recombination by one of the carcinogens. Organ-specificity of the increased frequency of mosaic warts- clones induced by P(GUS.p53.259H) was established.

Animals↗
PubMed1994

Somatic and gonadal mosaicism of the Huntington disease gene CAG repeat in brain and sperm.

Huntington disease is associated with an unstable and expanded (CAG) trinucleotide repeat. We have analysed the CAG expansion in different tissues from 12 affected individuals. All tissues examined were found to display some repeat mosaicism, with the greatest levels detected in brain and sperm. Regions within the brain showing most obvious neuropathology, such as the basal ganglia and the cerebral cortex, displayed the greatest mosaicism, whereas the cerebellar cortex, which is seldom involved, displayed the lowest degree of CAG instability. In two cases of childhood onset disease we detected differences of 8 and 13 trinucleotides between the cerebellum and other regions of the brain. Our results provide evidence for tissue specific instability of the CAG repeat, with the largest CAG repeat lengths in affected regions of the brain.

Adult↗
PubMed2000

Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers.

Microsatellite instability (MSI) is a hallmark of hereditary nonpolyposis colorectal cancer, and in these patients, results from inherited defects in DNA mismatch repair genes, mostly MSH2 and MLH1. MSI also occurs in 15% of sporadic colorectal cancers, but in these tumors, its basis is less well characterized. We investigated 46 sporadic MSI+ colorectal cancers for changes in MSH2 and MLH1 protein expression, followed by the analysis of somatic mutation, loss of heterozygosity (LOH), and promoter hypermethylation as possible underlying defects. Most cases (36/46, 78%) showed lost or reduced MLH1 expression. Among these, a majority (83%) was associated with MLH1 promoter hypermethylation, whereas the rates of LOH and somatic mutation of MLH1 were 24% and 13%, respectively. Hypermethylation and LOH were inversely correlated, suggesting that they had alternative functions in the inactivation of MLH1. MSH2 expression was lost in 7/46 (15%), and of these, 2 (29%) showed LOH and/or somatic mutation of MSH2. We conclude that most sporadic MSI+ colorectal cancers have an MLH1-associated etiology and that epigenetic modification is a major mechanism of MLH1 inactivation. Moreover, we found a significantly lower prevalence for MLH1 promoter hypermethylation in hereditary nonpolyposis colorectal cancer tumors with MLH1 germline mutations (12/26, 46%), which might explain some differences that are known to occur in the clinicopathological characteristics and tumorigenic pathways between sporadic and hereditary MSI+ colorectal cancers.

Adaptor Proteins, Signal Transducing↗