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PubMed2001

Evaluation of the roles of common genetic mutations in leukoaraiosis.

OBJECTIVES: Leukoaraiosis, a relatively frequent neuroimaging entity, is presumed to be primarily a vascular problem. However, it can be explained only in part by vascular risk factors. With the assumption of genetic susceptibility, the roles of common genetic polymorphisms and mutations in leukoaraiosis were examined in this study. MATERIAL AND METHODS: A detailed clinical scrutiny of 843 Hungarian neurological patients with mild cognitive-like complaints revealed 229 subjects with leukoaraiosis that was probably vascular in origin: 143 with leukoaraiosis alone (group 1), and 86 with leukoaraiosis plus cerebral infarction (group 2). In all 229 patients, the methylenetetrahydrofolate reductase C677T (MTHFR C677T) mutation and angiotensin-converting enzyme (ACE I/D) polymorphism were examined by means of the PCR technique. The prevalences of the different genotypes for the examined mutations in the 2 groups were analysed in comparison with the data on 362 neuroimaging alteration-free subjects as controls. RESULTS: The ACE D/D genotype (38.37%, P<0.0005; OR 2.46, 95% CI, 1.49-4.08) and ACE D allele (61%; P<0.001) were more frequent in group 2 than in the control group (20.17%; 47%). Neither the homozygous nor the heterozygous MTHFR C677T mutation alone was found to be a risk factor for leukoaraiosis. The homozygous MTHFR C677T mutation combined with the ACE D/D genotype was significantly more frequent in group 1 (11.89%, P<0.0005; OR 4.75, 95% CI, 2.12-10.65), in group 2 (12.79%, P<0.0005; OR 5.16, 95% CI, 2.12-12.6) and in combined group 1+2 (12.23%, P<0.0005; OR 4.9, 95% CI, 2.33-10.3) than in the control group (2.76%). CONCLUSION: These data indicate that the contributions of the ACE D/D genotype and the homozygous MTHFR C677T mutation to leukoaraiosis should be taken into consideration not as major, but as additive factors. These findings draw attention to the fact that genetic polymorphisms that alone are insignificant can be risk factors for leukoaraiosis if they cluster in the same subjects.

Aged↗
PubMed2003

Tumor formation by genetic mutations in the components of the Wnt signaling pathway.

The genetics of development and cancer have converged in the identification of intra- and extra-cellular signaling pathways that are aberrantly regulated in cancer, and are also central to embryonic patterning. The Wnt signaling pathway has provided an outstanding example of this. The genes for beta-catenin, APC, and Axin in the Wnt signaling pathway are often mutated in human cancers. In all such cases, the common denominator is the activation of gene transcription by beta-catenin. The resulting gene expression profile should provide a significant clue to the developmental mechanisms of cancers carrying defects in the Wnt signaling pathway. In this review, the functions of beta-catenin, APC and Axin, and the alterations of the three genes in human cancers are described.

Axin Protein↗
PubMed2026

Genetic mutations in metastatic adenocarcinoma of unknown primary.

INTRODUCTION: Although several genomic alterations have been reported in adenocarcinoma of unknown primary (ACUP), molecularly targeted therapies are not yet clinically established, and comprehensive genomic profiling (CGP) is rarely used in daily practice. AIM: We aimed to clarify the molecular landscape and prognostic impact of key mutations in recurrent or metastatic ACUP. MATERIALS AND METHODS: Data from 480 consecutive ACUP patients registered in Japan's National Cancer Center (C-CAT) between June 2019 and August 2025 were analyzed. Somatic mutations were identified using the FoundationOne CDx platform. Overall survival (OS) was assessed by Kaplan-Meier analysis, log-rank tests, and multivariate Cox proportional hazards modeling. RESULTS: The most frequent alterations were TP53 (59.4%), KRAS (31.5%), CDKN2A (26.3%), KMT2D (22.3%), LTK (17.9%), NOTCH3 (16.9%), STK11 (16.3%), CDKN2B (15.8%), ERBB2 (15.4%), and GNAS (15.2%). Patients harbored an average of 17.3 9.9 mutations. Mutations in GNAS (p = 0.046) and PIK3CA (p = 0.025) were associated with better OS, whereas ARID1A (p = 0.049) and NOTCH1 (p = 0.038) predicted worse OS. In Cox analysis, hazard ratios (HR [95% CI]) were 0.57 (0.36-0.92, p = 0.020) for GNAS, 0.57 (0.33-0.96, p = 0.033) for PIK3CA, 1.98 (1.27-3.09, p = 0.0024) for ARID1A, and 1.84 (1.17-2.91, p = 0.0090) for NOTCH1. CONCLUSIONS: GNAS and PIK3CA mutations were linked to favorable outcomes, while ARID1A and NOTCH1 alterations indicated poor prognosis in ACUP. These results highlight the prognostic significance of specific genomic alterations and support integrating CGP into the clinical management of ACUP.

Humans↗
PubMed1996

Multilocus DNA fingerprinting reveals high rate of heritable genetic mutation in herring gulls nesting in an industrialized urban site.

Genotoxins, such as polycyclic aromatic compounds, are ubiquitous in urban and industrial environments. Our understanding of the role that these chemicals play in generating DNA sequence mutations is predominantly derived from laboratory studies with specific genotoxins or extracts of contaminants from environmental media. Most assays are not indicative of the germinal effects of exposure in situ to complex mixtures of common environmental mutagens. Using multilocus DNA fingerprinting, we found the mutation rate in herring gulls inhabiting a heavily industrialized urban harbor (Hamilton Harbour, Ontario) to be more than twice as high as three rural sites: Kent Island, Bay of Fundy; Chantry Island, Lake Huron; and Presqu'ile Provincial Park in Lake Ontario. Overall we found a mutation rate of 0.017 +/- 0.004 per offspring band in Hamilton, 0.006 +/- 0.002 at Kent Island, 0.002 +/- 0.002 from Chantry Island, and 0.004 +/- 0.002 from Presqu'ile Provincial Park. The mutation rate from the rural sites (pooled) was significantly lower than the rate observed in Hamilton Harbour (Fisher's exact test, two-tailed; P = 0.0006). These minisatellite DNA mutations may be important biomarkers for heritable genetic changes resulting from in situ exposure to environmental genotoxins in a free-living vertebrate species.

Air Pollutants↗
PubMed2004

[BRCA1 and BRCA2 have reached the clinical medicine. The 10-year old finding of the genetic mutation makes it now possible to prevent breast cancer].

Increased knowledge of breast cancer genetics has improved the possibilities to predict the future risk of a woman to be diagnosed with breast cancer. In certain families, presymptomatic testing of breast cancer susceptibility genes may be offered, leading to an even more accurate individual risk prediction. As a result, advice regarding follow-up and risk reducing measures may be given to the individuals with the highest risks of cancer. Preventive surgery drastically reduces the risk of having breast or ovarian cancer respectively. The value of increased controls in hereditary high risk women is insufficiently investigated. Further studies are warranted to elucidate the efficacy of chemoprevention in women at a very high risk of breast cancer, e.g. mutation carriers of BRCA1 and BRCA2.

Breast Neoplasms↗
PubMed2006

Genetic mutation profile of isovaleric acidemia patients in Taiwan.

Isovaleric acidemia (IVA), a rare recessive autosomal disorder, is caused by isovaleryl-CoA dehydrogenase (IVD) deficiency. IVA may present with symptoms during the acute stage of severe metabolic acidosis, ketosis, vomiting, and altered mental status. With the help of newborn screening (NBS) by tandem mass spectrometry (MS/MS), IVA can now be diagnosed presymptomatically. According to statistic data, the incidence of IVA in Taiwan was about 1/365,000. In this study, six IVA patients from five families were investigated and followed-up clinically. As for the timing, two patients were found before MS technique introduced to Taiwan, the others were identified after MS/MS applied to NBS. The blood level of C5-carnitine in our patients was 7.43-18.96 microM (with upper limit in our laboratory <0.51 microM) and all of their urines contained raised amounts of 3-hydroxyisovaleric acid and isovalerylglycine. Molecular analysis of their IVD gene revealed six mutation profiles, among which the 149G-->A (Arg21His) and 1174 C-->T (Arg363Cys) mutations have been reported previously, while the other four mutations, 386A-->G (His100Arg), 347C-->T (Ser87Phe), 1007G-->A (Cys307Tyr) and 1199A-->G (Tyr371Cys), were first reported. Specially, we found 1199A-->G (Tyr371Cys) mutated was a common recurring missense mutation in our population (4 in 10 mutant alleles).

Adult↗
PubMed2002

Neuropsychological manifestations of the genetic mutation for Huntington's disease in presymptomatic individuals.

A triplet repeat (CAG) expansion mutation in the huntingtin gene on chromosome 4 is responsible for Huntington's disease (HD). Presymptomatic genetic testing for this mutation has identified clinically normal persons who are virtually certain to develop this dementing illness if they live a normal lifespan. The present study sought to determine whether these "mutation-positive" persons have impairments in cognitive functioning. Seventy-five mutation-positive persons did not differ from 128 mutation-negative persons on tests selected for their sensitivity to early-stage HD. Interestingly, however, those with the mutation viewed themselves as more likely to develop HD than did those without the mutation. Among mutation-positive subjects, having a longer CAG repeat mutation was likewise not associated with cognitive impairment. However, being closer to estimated disease onset (a product of repeat length and parent's age at onset) was associated with selected cognitive impairments. When viewed in light of previous studies showing atrophy of the caudate nucleus and putamen in mutation-carriers who are close to onset but not those far from onset, these results suggest that subtle changes in brain and behavior may be detected shortly before subjects with the HD mutation develop sufficient signs and symptoms for diagnosis. Conceptual and methodological problems associated with the search for presymptomatic cognitive and behavioral indicators of dementing illness are discussed.

Adult↗
PubMed2002

Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway.

Patients with genetic lesions in the Type-1 cytokine/cytokine receptor pathway exhibit a selective susceptibility to severe infections with poorly pathogenic mycobacteria and non-typhi salmonella spp. These experiments of nature demonstrate that IL-12-dependent IFNgamma production is critical for granuloma formation and therefore host immunity against such pathogens. The essential role of granuloma formation for protective immunity to these organisms is emphasized by the differing granuloma forming capabilities and resultant clinical sequelae observed in these patients which seems to reflect their ability to produce or respond to IFNgamma (Fig. 9). At one pole of this spectrum, represented by the complete IFNgammaR1/2 deficient patients, there is a complete absence of mature granuloma formation, whereas with the less severe mutations (i.e. partial IFNgammaR1/2, complete IL-12p40 and complete IL-12Rbeta1 deficiency), granuloma formation is very heterogenous with wide variations in composition being observed. This suggests that in the latter individuals, who produce partial but suboptimal IFNgamma responses, other influences, including pathogen virulence and host genotype may also affect the type and scale of the cellular response elicited.

Genetic Predisposition to Disease↗
PubMed2007

Familial effects of BRCA1 genetic mutation testing: changes in perceived family functioning.

This study expands recent research that examines how the receipt of BRCA1 genetic test results affects family adaptability and cohesion 1 year after genetic risk notification. Study participants were members of a large Utah-based kindred with an identified mutation at the BRCA1 locus. The final sample, 90 men and 132 women, contributed information before genetic testing (baseline) and 4 months and/or 1 year after receipt of genetic test results. After controlling for other factors such as family coping resources (Family Crises-Oriented Personal Evaluation Scale) and strains (Family Strains Index) and the tested individual's anxiety levels before genetic testing (state anxiety subscale), men and women reported significant declines in family cohesion 1 year after genetic risk notification (P < 0.01). There is suggestive evidence that carrier men reported increasing adaptability 1 year after risk notification (+0.21 points per month; P < 0.10). Having a carrier sister had a positive influence on women's perceived family cohesion and adaptability levels, whereas a personal history of cancer, having a great deal of caregiving involvement for a female relative with cancer, anxiety, and some types of coping resources had a negative effect on men's perceived family cohesion and adaptability levels. Although results showed that tested parents are perceiving a decline in family functioning after genetic risk notification, there is no evidence to suggest that the decline is due to carrier status. In fact, it is other life circumstances that exist at the time of the genetic testing process that seem to influence the degree to which families adjust to the experience and test results.

Adaptation, Psychological↗
PubMed2004

Family environments of women seeking BRCA1/BRCA2 genetic mutation testing: an exploratory analysis.

Although there is some understanding of the shared characteristics and predictors of psychological distress of women participating in hereditary breast and ovarian cancer registries, these same characteristics are only beginning to be identified in research on community women seeking genetic testing for BRCA1/BRCA2 gene mutations. This study provides an initial exploration of characteristics associated with family environments for 51 community women waiting to receive such genetic testing results. Thirty-four of the 36 women classified on family environment type of the Family Environment Scale (FES) were from Personal Growth-Oriented families. Comparisons of women with and without personal cancer histories resulted in a trend for women with personal cancer histories to be classified as from Independence-Oriented families. Reported distress appears to vary for different family emphases based on family and personal cancer history. A moral-religious family emphasis consistently appeared to be associated with decreased psychological distress. Preliminary analyses comparing these community women (who were not part of a hereditary registry but were self- or physician-referred) seeking genetic testing with normal and distressed family means found that increased cohesion and expressiveness may be related to decreased conflict, indicative of potentially supportive family environments for these women. When compared with normative data, a subset consisting of the Ashkenazi Jewish women showed a trend of less cohesion than normal families, but similar cohesion levels as distressed families.

Adaptation, Psychological↗
PubMed2026

Genetic Mutation and Epigenetic Silencing Drive Antigen-Negative Relapse in CD7 CAR T-Treated T-cell Lymphoid Malignancies.

UNLABELLED: CD7 is a promising target for chimeric antigen receptor (CAR) T-cell therapy in T-cell lymphoid malignancies; however, antigen loss-mediated relapse has emerged as a major challenge. In this study, we systematically analyzed the genetic and epigenetic alterations of paired specimens (pretreatment and relapsed) from 10 patients with T-cell lymphoma/leukemia receiving CD7 CAR T cells. Overall, we identified three distinct mechanisms underlying CD7 loss: first, frameshift insertion (patient 4; c.164dupG:p.R55fs) or deletion (patient 7; c.122delG:p.G41Efs*19) resulting in truncation of the CD7 transmembrane domain in two of 10 patients; second, hypermethylation of the CD7 promoter in seven of 10 patients without CD7 mutation; third, simultaneous occurrence of promoter region hypermethylation and multiple in-frame mutations with predicted functional interference in one of 10 patients (patient 2). Collectively, these findings demonstrate that both clonal heterogeneity and epigenetic plasticity drive antigen-negative relapse in T-cell lymphoid malignancies under the selective pressure of CD7 CAR T-cell therapy. SIGNIFICANCE: Understanding mechanisms of antigen-negative relapse is critical for developing effective CD7-targeting CAR-T therapies against T-cell lymphoid malignancies. Our study identifies both genetic truncation mutations and epigenetic silencing as contributors to CD7-negative relapse. Monitoring and preventing these events is warranted to improve treatment outcomes.

Humans↗
PubMed1998

Multiple sclerosis: the increased frequency of the ICAM-1 exon 6 gene point mutation genetic type K469.

Intracellular adhesion molecule-1 (ICAM-1) plays an important role in the cascade of adhesion events in the homing of inflammatory cells to the central nervous system (CNS) in experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS). Two single-base ICAM-1 polymorphisms have been described, in exons 4 and 6, changing codons 241 and 469 in the ICAM-1 gene, respectively. Both polymorphisms result in amino acid changes and can potentially lead to different interactions of ICAM-1 with its ligands. To detect ICAM-1 gene polymorphisms in MS, we have developed a highly sensitive and site-specific, two-stage, nested polymerase chain reaction. Genomic DNA was extracted from blood cells of 79 MS patients and 68 control subjects. The results were confirmed by direct dideoxy chain termination sequencing. The frequency of exon 6 allele T was found to be significantly higher in MS patients than in controls (68% vs 49%). Most interesting, the frequency of exon 6 homozygote K469 was significantly higher in MS patients than in controls (53% vs 34%). Higher frequency of the K469 genotype was found to be independent of possible linkage with the previously described MS susceptibility factor, the HLA class II DR2 allele. In the present study, we have shown for the first time the ICAM-1 gene polymorphisms in MS. The results indicate increased frequency of ICAM-1 exon 6 allele T in MS patients, which may contribute to the MS genetics background.

Base Sequence↗