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PubMed2001

Increased chromosomal imbalances in recurrent pituitary adenomas.

Eight pituitary adenomas (four gonadotroph cell adenomas, three prolactin cell adenomas, one null cell adenoma) and their respective recurrences in the same patients were studied by comparative genomic hybridization. Chromosomal imbalances were found in seven of eight patients affecting two of eight primary and seven of eight recurrent tumors. Overall, pituitary adenomas showed an average of 1.6 chromosomal imbalances per primary and 3.4 per recurrent tumor (P < 0.01). Prolactin cell adenomas showed an average of 4.3 chromosomal changes per primary and 6.3 per recurrent tumor, which were significantly more common than in gonadotroph cell adenomas (0 vs 1.7 changes; P < 0.05) and the null cell adenoma (0 vs 1.0 changes; P < 0.05). The most common changes were gains of 4q (in three of eight recurrences), 5q, and 13q (in two of eight recurrences each) as well as losses of chromosome 2 (in both primary and recurring tumors of two patients), 1p, 8q, 10, and 12q (in two of eight recurrences). Minimal common regions associated with recurrent adenomas were gains of 4q31.2-34 (three recurrences), 5q14-23 and 13q21-31 and losses of 12q24.3-qter (two recurrences each). The average MIB-1 proliferation indices were 1.2% for primary and 1.9% for recurrent adenomas (P < 0.005). Our findings suggest that acquisition of certain chromosomal imbalances is related to and may underlie adenoma recurrence.

Adult↗
PubMed2005

[Recurrent model of the dependence of a recessive lethal mutation on fitness components and its solution].

Experimental modeling and subsequent analysis of microevolutionary processes often involves estimation of fitness components, such as male mating competitiveness, female fecundity, progeny viability, meiotic drive upon the formation of sexual products, and so on. In this connection, we have developed a new method for estimating the relationship among fitness components and their effect on selection on frequencies of the mutant individuals in several generations, which can be applied to the case of rapid elimination of a lethal mutation from the population. The method of estimating unknown fitness components is based on the known estimates of other components and a relationship among the known and unknown components calculated from the frequency dynamics. Using the new method, a biological explanation of non-uniqueness of the admissible solutions. The method employs analysis of the form of the admissible solution region (at preset confidence intervals for the observed frequencies) in the space of the possible values.

Animals↗
PubMedDate not supplied

Telomerase activity as prognostic factor in gastrointestinal stromal tumors of the stomach.

BACKGROUND/AIMS: Although size and mitotic counts have been reliable predictors of clinical outcome, identification of gastrointestinal stromal tumor (GIST) of the stomach with a metastatic potential through hematoxylin and eosin staining is not always accurate. Telomerase activity, often detected in malignant tumors, may have a role as a marker for high-grade malignancy. METHODOLOGY: Immunostaining with antibodies against KIT protein, CD34, and other molecules that are relevant for evaluation of cell differentiation and proliferation was performed for 36 primary gastric submucosal tumors to confirm the diagnosis of GIST. DNA was extracted from the surgically resected specimens of 24 of 36 patients, and c-kit mutation was analyzed by direct sequencing after PCR amplification of the exon 11. Telomerase activity was quantitatively evaluated for all 36 patients using fluorescence-based telomeric amplification assay protocol (TRAP) analysis. RESULTS: c-kit mutation was observed in 58% of the patients evaluated. Telomerase activity was detected in 14 specimens (39%), but not in the specimens without c-kit mutation. All 5 patients who suffered from metastatic or recurrent disease exhibited c-kit mutation and a high level of telomerase activity. CONCLUSIONS: Measurement of telomerase activity, along with c-kit mutation analysis, is useful for identifying GIST with a potential for malignant behavior.

Adult↗
PubMed2026

Metagenomic Deep Sequencing Identifies Gene Mutations Associated with Chemotherapeutic Resistance in Vitreoretinal Lymphoma.

PURPOSE: To identify gene mutations associated with chemotherapeutic resistance in patients with vitreoretinal lymphoma (VRL) using metagenomic deep sequencing (MDS) of intraocular specimens. METHODS: Patients with VRL confirmed by cytopathology and immunohistochemistry, flow cytometry, and/or polymerase chain reaction for MYD88, were included. Intraocular specimens underwent MDS of the host genome. Gene mutations were identified and cross-referenced with the Catalogue of Somatic Mutations in Cancer database to determine associations with chemotherapeutic resistance. RESULTS: Forty-nine patients with VRL underwent MDS, with six specimens from four patients revealing eight gene mutations associated with chemotherapeutic resistance. Four specimens from three patients harbored mutations associated with methotrexate resistance, the mainstay of VRL treatment. In one patient, serial sampling from the initial vitrectomy and two subsequent recurrences revealed distinct resistance-associated mutations at each time point. Despite multi-agent therapy including rituximab, consolidation regimens, and lenalidomide, this patient ultimately succumbed to the disease, whereas the other three patients remained in long-term remission. CONCLUSIONS: Our findings demonstrated that specific gene mutations associated with chemotherapeutic resistance may be harbored by VRL. The detection of different resistance mutations at sequential time points in one patient may reflect clonal selection, treatment pressure, or variable detection sensitivity. The ability to easily sample ocular fluid and detect different mutations associated with tumor recurrence or persistence may provide insights into tumor pathogenesis and could inform prognosis and influence treatment decisions. These findings establish a foundation for developing targeted PCR assays for identified resistance genes, which could transform clinical practice in VRL.

Chemotherapeutic resistance-associated mutations↗
PubMed2000

The ret/PTC mutations are common in sporadic papillary thyroid carcinoma of children and young adults.

The ret/PTC rearrangements (PTC-1, PTC-2, and PTC-3) are characteristic of papillary thyroid cancer (PTC). In adults, PTC-1 is common and may be associated with an aggressive clinical course. The incidence and significance of ret/PTC mutations are less well understood in children. We examined spontaneous PTC from 33 patients (23 females and 10 males) with a median age of 18 yr (range, 6-21 yr) and a median follow-up of 3.5 yr (range, 0-13.4 yr). The ret/PTC mutations were identified in 15 tumors (45%), including 8 PTC-1 (8 of 15, 53%), 2 PTC-2 (2 of 15, 13%), 2 PTC-3 (2 of 15, 13%), and 3 (3 of 15, 20%) combined PTC mutations (PTC-1 and PTC-2). This distribution is significantly different (P = 0.001, by chi2 analysis) from that reported for children with radiation-induced PTC. There was no correlation between the presence or type of ret/PTC mutation and patient age, tumor size, focality, extent of disease at diagnosis, or recurrence. We conclude that ret/PTC mutations are 1) common in sporadic childhood PTC, 2) predominantly PTC-1, 3) frequently multiple, and 4) of different distribution than that reported for children with radiation-induced PTC.

Adolescent↗
PubMed2005

Mutations of epidermal growth factor receptor of non-small cell lung cancer were associated with sensitivity to gefitinib in recurrence after surgery.

The epidermal growth factor receptor (EGFR) gene has recently been reported to be mutated in a subset of non-small cell lung cancers (NSCLC), with the mutations being correlated with the patients' drug sensitivity to gefitinib, an EGFR kinase inhibitor. In this study, we searched for EGFR mutations in patients with lung cancer using primary tumor specimens obtained at initial surgery and examined whether their recurrent tumors showed a response to gefitinib depending on the presence of the activating mutation. Among 12 lung cancers that were treated with gefitinib after recurrence, we found that all four tumors which showed a response to gefitinib had an activating mutation in EGFR, whereas none of the remaining eight tumors had a mutation. Southern blot analysis showed that two of the four responsive tumors had the EGFR gene amplification. We also examined another 73 NSCLC specimens (47 males and 26 females; 53 adenocarcinomas and 20 non-adenocarcinomas) which were not treated with gefitinib to determine whether NSCLCs with an EGFR mutation have different clinicopathological properties and/or unique genetic alterations of the other cancer-associated genes. We found that 13 (18%) of 73 tumors had a mutation of the EGFR gene, with the most being detected in female adenocarcinomas. Comparing the alterations in KRAS and P53 with the EGFR mutation, we found that 10 tumors with the KRAS mutation did not have an EGFR mutation, suggesting that each mutation occurs exclusively during the development of lung cancer. These results suggest that the mutation analysis of the EGFR gene using the specimens obtained at surgery might be useful in selecting the appropriate treatment(s) for recurrent lung cancer patients.

Adenocarcinoma↗
PubMed2006

Androgen receptor action in hormone-dependent and recurrent prostate cancer.

The importance of androgens and androgen receptors (AR) in primary prostate cancer is well established. Metastatic disease is usually treated with some form of androgen ablation, which is effective for a limited amount of time. The role of AR in prostate cancers that recur despite androgen ablation therapy is less certain. Most of these tumors express prostate specific antigen (PSA), an androgen-regulated gene; moreover, AR is generally highly expressed in recurrent prostate cancer. We propose that AR continues to play a role in many of these tumors and that it is not only the levels of AR, ligands, and co-regulators, but also the changes in cell signaling that induce AR action in recurrent prostate cancer. These pathways are, therefore, potential therapeutic targets.

Androgens↗
PubMed1999

[A case of congenital plasminogen abnormality with recurrent cerebrovascular ischemic attacks].

We reported a 10-year-old boy with congenital plasminogen abnormality resulting in recurrent cerebrovascular ischemic attacks. He suddenly developed dystonia of the left upper limb at 9 years of age. MRI demonstrated small infarcts in the right thalamus and caudate nucleus. He then had a transient ischemic attack at 10 years. He complained of headache, vertigo, diplopia, and unsteady gait. DNA analysis revealed that he was heterozygotic for abnormal plasminogen. Thus, congenital plasminogen abnormality was suspected to be a cause of recurrent cerebrovascular ischemic attacks in this case.

Cerebral Infarction↗
PubMed2004

Detection of mitochondrial DNA mutations using temporal temperature gradient gel electrophoresis.

Mitochondrial disorders are a group of clinically and genetically heterogeneous diseases. Common recurrent mitochondrial DNA (mtDNA) point mutations account for the molecular defects of a small proportion of patients. In order to identify mtDNA mutations, comprehensive mutational analysis of the entire mitochondrial genome is necessary. We developed the temporal temperature gradient gel electrophoresis (TTGE) method to screen for mutations in mtDNA. The entire mitochondrial genome was amplified using 32 pairs of overlapping primers followed by TTGE analysis of the DNA fragments. TTGE method was first validated on 200 DNA fragments containing known mutations or polymorphisms. On TTGE, homoplasmic nucleotide substitutions show a single band shift and heteroplasmic mutations show multiple banding patterns. The known mutations or polymorphisms were correctly identified. TTGE was then used to screen for unknown mutations in the mitochondrial genome. DNA banding patterns, deviated from wild-type, suggestive of either homoplasmic or heteroplasmic mutations, were followed by direct DNA sequencing to identify the mutations. Numerous mutations and polymorphisms were detected. The results demonstrated that TTGE detects and distinguishes heteroplasmic mutations from homoplasmic polymorphisms. It also detects heteroplasmic changes in the background of a homoplasmic polymorphism. Overall, TTGE was proven to be a simple, rapid, sensitive, and effective mutation detection method.

DNA Primers↗
PubMed1998

Ki-67 and p53 in T2 laryngeal cancer.

OBJECTIVE: To study the relationship between the proliferative capacity, represented by the immunohistochemical labeling index (LI) of proliferation marker Ki-67, and the p53 status, as in theory an intact p53 cell cycle checkpoint system should result in a lower proliferative capacity. STUDY DESIGN: From a group of 128 patients with a T2 laryngeal carcinoma, presented from 1989 to 1993 at the University Hospital Utrecht, 20 patients with recurrent disease and 16 patients without recurrent disease were randomly selected. All patients received primary irradiation. METHODS: Denaturing gradient gel electrophoresis and immunohistochemistry determined the p53 status. MIB-1 staining was used to determine the Ki-67 LI. RESULTS: In 36% of specimens we found a p53 mutation with overexpression (LI, 31%). In 8% a p53 mutation without p53 overexpression was found (LI, 18%). Forty-two percent showed no mutation but, nevertheless, overexpression (LI, 35%). Neither mutation nor overexpression was found in 14% (LI, 38%). No correlation exists between p53 status and proliferative capacity of tumors (analysis of variance [ANOVA]; P = .104). The proliferation rate as established with Ki-67 LI positively correlates with response to radiotherapy (P = .006). CONCLUSIONS: 1. Overexpression of wild-type p53 protein does not result in cell cycle arrest measurable by a lower Ki-67 LI in comparison with cases overexpressing mutant type p53 protein. 2. A high Ki-67 LI correlates with a favorable response to radiotherapy.

Aged↗
PubMed2001

Basic science of hormonal therapy for prostate cancer.

New developments in molecular and cellular biology are rapidly increasing knowledge of the mechanisms of androgen action in the prostate. Molecular profiling of recurrent cancer after androgen deprivation therapy has revealed genetic changes related to cell survival and proliferation. It is now clear that loss of the androgen receptor (AR) does not explain androgen-independent growth of a majority of recurrent cancers. Rather, overexpression, mutation, and ligand-independent activation of the AR may confer enhanced sensitivity to androgen or other growth factors. Therefore, the term "androgen-independent" is often a misnomer. This emerging concept is the basis of novel strategies to prevent or slow recurrence.

Journal Article↗
PubMed1998

Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis.

Long-term hepatitis B immune globulin (HBIG) has been shown to reduce hepatitis B virus (HBV) reinfection in patients transplanted for hepatitis B. The aim of this study was to determine the prevalence of HBV S gene mutations in liver transplant recipients who developed recurrent hepatitis B despite HBIG prophylaxis, and to determine if these mutations can revert after withdrawal of HBIG. The entire S gene sequences in pre- and posttransplant sera from 20 patients who developed recurrent hepatitis B despite HBIG prophylaxis were compared. Ten (50%) patients had 18 amino acid substitutions involving the 'a' determinant in the posttransplant samples. These mutations were absent in 93% of the pretransplantation clones analyzed. There was a significant correlation between the development of mutations in the 'a' determinant region and the duration of HBIG therapy. Most of the mutations result in changes in predicted antigenicity of the S protein. During follow-up, mutations in 14 (78%) of 18 affected codons in the 'a' determinant region reverted back to the pretransplantation sequences; only 1 codon had a de novo change after the withdrawal of HBIG. Two control patients who did not receive HBIG had no change in the 'a' determinant in their posttransplantation samples. These data support the hypothesis that mutations in the S gene were induced or selected by immune pressure exerted by HBIG. HBV S mutants may play a role in HBV reinfection in liver transplant recipients who received HBIG prophylaxis.

Adult↗
PubMed1996

Dyslipidaemia in a boy with recurrent abdominal pain, hypersalivation and decreased lipoprotein lipase activity.

UNLABELLED: An 8-year-old boy with frequently recurring pancreatitis-like abdominal pain, Fredrickson type V dyslipidaemia, and significantly decreased post-heparin plasma lipoprotein lipase (LPL) activity is described. In order to exclude familial LPL deficiency, the complete LPL coding gene sequence was analysed revealing compound heterozygosity for two mutations (Asp9Asn, Ser447Ter) which are not supposed to considerably impair lipolytic enzyme activity. However, until now the combination of both these mutations in one patient has not been observed. In addition to the common symptoms of LPL deficiency, a striking feature of unknown origin was hypersalivation. Treatment including a fat-restricted diet, omega-3 fatty acids, and nicotinic acid led to long symptoms-free intervals. Symptoms recurred however when the diet was not strictly adhered to. CONCLUSION: LPL deficiency is a rare cause of abdominal pain in childhood and deserves careful treatment in order to avoid pancreatitis. The presented patients is a unique compound heterozygote for two mutations which do not abolish lipolytic activity in the homozygote state. Identification of other individuals with this genotype is necessary to understand the phenotype in our patient.

Abdominal Pain↗
PubMed1994

p53 gene mutations as markers of tumor spread in synchronous oral cancers.

OBJECTIVE: To demonstrate how genetic mutations may be used as specific markers for the study and management of head and neck squamous cell carcinomas. DESIGN: Mutations in the p53 gene were identified by DNA sequencing in synchronous primary head and neck squamous cell carcinomas from one patient. The polymerase chain reaction and mutant-specific oligomer probes were used to detect rare tumor cells in surgical margins, lymph nodes, and swabs of the oral cavity. PATIENTS: Selected from a consecutive series of individuals with head and neck squamous cell carcinomas at a tertiary referral center. RESULTS: Two synchronous primary invasive cancers displayed different missense mutations in the p53 gene. The mutated sequence from one primary tumor was detected in metastases from both sides of the neck. Infiltrating cells from this biologically aggressive tumor were also detected by a polymerase chain reaction-based assay in a histologically normal surgical margin, accurately predicting tumor recurrence. CONCLUSIONS: p53 gene mutations were useful as molecular markers to distinguish between tumors in this case. The potential utility of detection of tumor cells in surgical margins and saliva by molecular techniques merits further investigation.

Biomarkers, Tumor↗
PubMed2003

Activated protein C resistance acquired through liver transplantation and associated with recurrent venous thrombosis.

We report a new case of recurrent, extra-hepatic, deep vein thrombosis occurring after orthotopic liver transplantation for hepatocellular carcinoma complicating 'mixed' alcoholic and post-hepatitic C cirrhosis. Coagulation tests showed activated protein C resistance. The patient's genomic DNA was negative for the factor V Leiden mutation. Analysis of the grafted liver DNA showed that the donor was a heterozygous carrier of the factor V Leiden mutation and that the recipient's activated protein C resistance was acquired through the transplantation. Screening of candidate liver donors for a prothrombotic tendency is controversial. However, this case suggests that patients who develop venous thrombosis after liver transplantation should be screened for thrombophilic abnormalities, bearing in mind that genetic abnormalities which do not affect clotting test results, such as the G20210A mutation in the factor II gene, can only be diagnosed by testing the donor or graft.

Activated Protein C Resistance↗
PubMed2001

Ciliary dyskinesia associated with hydrocephalus and mental retardation in a Jordanian family.

OBJECTIVE: To describe the presentation and genetic transmission of ciliary dyskinesia syndrome associated with hydrocephalus and mental retardation in 3 generations of a family. PATIENTS AND METHODS: A large Jordanian family included 9 individuals in 3 generations with recurrent pulmonary infections; 4 male siblings have been diagnosed as having mental retardation, and a maternal uncle was believed to have been similarly affected. Chromosome analysis of the family showed a normal karyotype. RESULTS: Electron microscopy of the nasal cilia from 3 affected siblings showed features of primary ciliary dyskinesia. Computed tomographic scans of the brains of all 4 affected siblings showed hydrocephalus. CONCLUSIONS: The recurrent pulmonary infections and hydrocephalus in this large Jordanian family are likely related to ciliary dyskinesia, which appears to follow an autosomal recessive mode of inheritance. The unusual presentation of ciliary dyskinesia, hydrocephalus, and mental retardation may be due to a new genetic mutation.

Abnormalities, Multiple↗
PubMed2000

Loss of heterozygosity on chromosome 6p21.2 as a potential marker for recurrence after radiotherapy of human cervical cancer.

Cervical carcinomas develop as a result of multiple genetic alterations, and specific alterations lead to specific clinical behavior. However, the effect of such alterations on the recurrence of cervical cancer after radiotherapy remains unknown. Chromosome arm 6p is one of those most frequently involved in a loss of heterozygosity (LOH) in patients with cervical carcinoma. The aim of this study was to identify the correlation between the LOH on chromosome 6p21.2 and the recurrence of cervical cancer after radiotherapy. A total of 62 patients with cervical cancer (stage I, 4 patients; stage II, 9 patients; stage III, 37 patients; and stage IV, 12 patients) were included in this study. All patients were treated with definitive radiotherapy. We analyzed specimens from the tumors and venous blood of all patients. Tumors and normal DNA were analyzed by PCR for genetic losses at three polymorphic microsatellite loci (D6S276, D6S1624, and D6S1583). Chromosome 6p21.2 is involved in the LOH in 46.8% (29 of 62) of the informative carcinomas. Ten patients had a local recurrence, 4 had distant metastases, and 13 had both local recurrence and distant metastases after radiotherapy. To evaluate the relationship between the recurrence after radiotherapy and LOH on chromosome 6p21.2, we divided the patients into those with cancer recurrence (n = 27) and those without recurrence (n = 35). LOH on chromosome 6p21.2 was correlated with recurrence after radiotherapy (P = 0.006). The tumors in patients with recurrence were significantly larger than those in patients without recurrence (P = 0.003). However, there was no correlation between the sizes and stages of tumors and the LOH on chromosome 6p21.2. In addition, both overall survival and relapse-free survival were significantly worse for the patients with LOH as compared with those without LOH (P = 0.02 and P = 0.002, respectively). The results of this study suggest that LOH on 6p21.2 is correlated with recurrence of cervical carcinoma after radiotherapy.

Adult↗