Biomedical subjects

Axel Benner

Publications and source records attributed to Axel Benner.

At least 19 recordsLinked to original sources

PubMed2007

Allelic variants of CAMTA1 and FLJ10737 within a commonly deleted region at 1p36 in neuroblastoma.

Deletion of a distal portion of 1p is seen in a wide range of human malignancies, including neuroblastoma. Here, a 1p36.3 commonly deleted region of 216 kb has been defined encompassing two genes, CAMTA1 and FLJ10737. Low expression of CAMTA1 has been recently shown to be an independent predictor of poor outcome in neuroblastoma patients. The present study surveys CAMTA1 and FLJ10737 for genetic alterations by fluorescence-based single strand conformation polymorphism (SSCP) using a panel of DNAs from 88 neuroblastomas, their matching blood samples and 97 unaffected individuals. Nucleotide variants encoding amino acid substitutions were found in both genes. One CAMTA1 variant (T1336I) was not detected in 97 unaffected individuals, another (N1177K) resides in a conserved domain of the CAMTA1 protein and was found hemizygous in six neuroblastomas. We found no evidence for somatic mutations in FLJ10737 or CAMTA1. Further investigations are needed to address the functional impact of the identified variants and their possible significance for neuroblastoma.

Alleles↗

PubMed2007

Long-term follow-up of patients with non-Hodgkin lymphoma following myeloablative therapy and autologous transplantation of CD34+-selected peripheral blood progenitor cells.

Graft engineering by CD34(+) selection of peripheral blood progenitor cells (PBPC) has been used in non-Hodgkin lymphoma (NHL) with the aim to reduce relapse related to tumor cells within the graft. From September 1995 to January 2000, 39 patients with newly diagnosed (n = 31) or relapsed (n = 8) NHL were treated in our institution with myeloablative therapy followed by CD34(+) selected autologous PBPC transplantation. Thirty-one patients were diagnosed with follicular lymphoma, and eight patients with mantle-cell lymphoma. All patients had advanced disease (26% of patients stage III and 74% stage IV, Ann Arbor classification). Induction therapy resulted in a complete remission in 17 patients and a partial remission in 22 patients. PBPC were mobilized after cytotoxic chemotherapy with granulocyte colony-stimulating factor support. CD34(+) selection was performed using immunomagnetic beads (Baxter Isolex 300SA or 300i Magnetic Cell Separation System). Most patients (85%) received total body irradiation and high-dose cyclophosphamide as myeloablative regimen. Twelve patients also received rituximab 375 mg/m(2) before radiation and before the start of the cyclophosphamide treatment. The mean CD34(+) cell number for transplantation was 6.5 x 10(6) CD34(+) cells/kg of body weight. Platelet recovery (>20,000/microl median on day 13) and leukocyte recovery (>1,000/microl median on day 12) were within expected range. The estimated median follow-up was 47 months. The probabilities of freedom from progression, overall survival, and event-free survival 4 years after transplantation were 96%, 90%, and 87%, respectively, for patients with follicular lymphoma and 42%, 63%, and 33%, respectively, for patients with mantle-cell lymphoma. Risk factors for relapse were age and extranodal manifestation of disease. The rate of lethal infections in the 12-month follow-up period was 8%. We conclude that CD34(+) selection of autologous transplants following myeloablative therapy is feasible and results in long-term remission in the majority of patients, but the procedure is probably related to a higher rate of lethal infections.

Adult↗

PubMed2006

Prevalence of BRCA1 and BRCA2 mutations in Pakistani breast and ovarian cancer patients.

Among Asian countries, Pakistan has the highest rates of breast and ovarian cancer. To assess the contribution of the BRCA1 and BRCA2 germ line mutations to these high rates, we conducted the first study of 176 Pakistani breast and ovarian cancer patients, selected on family history and on age of diagnosis. Comprehensive BRCA mutation screening was performed using a range of techniques, including denaturing high-pressure liquid chromatography, single strand conformational polymorphism analysis and protein truncation test, followed by DNA sequencing. Thirty deleterious germ-line mutations were identified in the 176 families (17.0%), including 23 in BRCA1 and 7 in BRCA2. Four mutations, 185delAG, 185insA, S1503X and R1835X, were recurrent; these accounted for 52% of all identified BRCA1 mutations. Haplotype analyses suggested founder effects for 3 of these. The prevalence of BRCA1 or BRCA2 mutations was 42.8% for families with multiple cases of breast cancer, and was 50.0% for the breast/ovarian cancer families. The prevalence of mutations was 11.9% for single cases of early-onset breast cancer (< or =30 years) and was 9.0% for single cases of early-onset ovarian cancer (< or =45 years). Our findings show that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer and early-onset breast and ovarian cancer cases in Pakistan.

Adult↗

PubMed2006

The 3' untranslated region C > T polymorphism of prohibitin is a breast cancer risk modifier in Polish women carrying a BRCA1 mutation.

The variable penetrance of breast cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB) gene alters mRNA function and has been shown to be associated with an increased breast cancer risk among young North-American women who have one first-degree relative with breast cancer. To investigate whether the PHB 3'UTR polymorphism acts as a modifier of hereditary breast cancer risk we performed a case-control study among female BRCA1 mutation carriers, which included 258 cases and 258 controls who were unaffected by ovarian cancer, in situ breast carcinoma or any other type of cancer. Controls were matched to cases by year of birth and BRCA1 mutation (5382insC, 300 T > G, 4153delA). Genotyping analysis was performed using RFLP-PCR. Odds ratios (OR) were calculated using conditional and penalised univariable and multivariable logistic regression. Multivariable penalised logistic regression revealed CT (OR(adj), 2.03; 95% CI, 1.17-3.59) and combined CT + TT (OR(adj), 2.12; 95% CI, 1.23-3.70) genotypes as significant modifiers of breast cancer risk. Breast cancer risk did not differ between carriers of the 300 T > G and 5382insC mutation. Our results suggest that the PHB 3'UTR T allele increases the risk of breast cancer in patients who are already at increased risk of disease.

3' Untranslated Regions↗

PubMed2006

Cytogenetics and age are major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from AMLSG trial AML HD98-B.

To assess the prognostic impact of cytogenetics in elderly patients with acute myeloid leukemia (AML) receiving intensive induction and consolidation treatment according to a single protocol specifically designed for patients above age 60, pretreatment samples from 361 patients registered for the AML HD98-B trial of the German-Austrian AML Study Group were analyzed by chromosome banding and fluorescence in situ hybridization, and cytogenetic findings were correlated with outcome. Using a proportional hazards model with backward selection, 3 prognostic subgroups were identified based on the influence of cytogenetic abnormalities on overall survival (OS): low-risk, t(15;17), and inv(16) in 25 of 361 patients (7%); standard-risk, normal karyotype, t(8;21), t(11q23), +8 within a noncomplex karyotype, and +11 within a noncomplex karyotype in 208 of 361 patients (58%); high-risk, all other aberrations in 128 of 361 patients (35%). On multivariate analysis, high-risk cytogenetics (hazard ratio [HR], 2.24) and age above 70 years (HR, 2.34) were independent prognostic factors affecting OS, and stratification according to these parameters demonstrated that a large subgroup of patients (55%), characterized by age 70 or older or high-risk cytogenetics, or both, had very unfavorable treatment results despite intensive chemotherapy. Thus, karyotype and age are major determinants of outcome in elderly patients with AML.

Acute Disease↗

PubMed2006

Gene expression signature predicting pathologic complete response with gemcitabine, epirubicin, and docetaxel in primary breast cancer.

PURPOSE: Primary systemic therapy (PST) with gemcitabine (G), epirubicin (E), and docetaxel (Doc) has resulted in a pathologic complete response (pCR) in 26% of primary breast cancer patients. This study was aimed at the identification of a gene expression signature in diagnostic core biopsy tissue samples that predicts pCR. PATIENTS AND METHODS: Core biopsy samples from patients with operable primary breast cancer, T2-4N0-2M0, enrolled onto two phase I and II trials evaluating GEDoc (n = 48) and GE sequentially followed by Doc (GEsDoc; n = 52) as PST were snap frozen and subjected to RNA expression profiling. A signature predicting pCR was discovered in the training set (GEsDoc) applying a support vector machine algorithm, and performance of this classifier was validated on the independent test set (GEDoc) by receiver operator characteristics analysis. RESULTS: We identified a signature consisting of 512 genes, which was enriched in genes involved in transforming growth factor beta and RAS-mediated signaling pathways, that predicts pCR with a sensitivity of 78%, a specificity of 90%, and an overall accuracy of 88% (95% CI, 75% to 95%). Apart from our signature, only HER2 overexpression was an independent predictor of pCR in multivariate analysis. CONCLUSION: In conclusion, our gene expression signature allows prediction of pCR to PST containing G, E, and Doc with unprecedented high overall accuracy and robustness.

Adult↗

PubMed2006

Identification of gains on 1q and epidermal growth factor receptor overexpression as independent prognostic markers in intracranial ependymoma.

PURPOSE: Pathogenesis of ependymomas is still poorly understood and molecular markers for risk-adapted patient stratification are not available. Our aim was to screen for novel genomic imbalances and prognostic markers in ependymal tumors. EXPERIMENTAL DESIGN: We analyzed 68 sporadic tumors by matrix-based comparative genomic hybridization using DNA microarrays containing >6,400 genomic DNA fragments. Novel recurrent genomic gains were validated by fluorescence in situ hybridization using a tissue microarray consisting of 170 intracranial ependymomas. Candidate genes were also tested for mRNA expression by quantitative real-time PCR, and protein expression was determined by immunohistochemistry on the tissue microarray. RESULTS: Chromosomal gain of 1q correlated with pediatric patients (P = 0.004), intracranial ependymomas (P = 0.05), and tumors of grade III (P = 0.002). Gain of 1q21.1-32.1 was associated with tumor recurrence in intracranial ependymomas (P < 0.001). Furthermore, gain of 1q25 as determined by fluorescence in situ hybridization represented an independent prognostic marker for either recurrence-free survival (P < 0.001) or overall survival (P = 0.003). Recurrent gains at 5p15.33 covering hTERT were validated by immunohistochemistry, and elevated protein levels correlated with adverse prognosis (P = 0.01). In addition to frequent gains and high-level amplification of epidermal growth factor receptor (EGFR) at 7p11.2, immunohistochemistry revealed protein overexpression to be correlated with poor prognosis (P = 0.002). EGFR protein status subdivides intracranial grade II ependymomas into two different risk groups (P = 0.03) as shown by multivariate analysis. CONCLUSIONS: Thus, the states of 1q25 and EGFR represent independent prognostic markers for intracranial ependymomas to identify patient subgroups with different risk profiles in further clinical investigations. Moreover, EGFR might serve as therapeutic target for more specific chemotherapy applications.

Adolescent↗

PubMed2006

One single dose of rituximab added to a standard regimen of CHOP in primary treatment of follicular lymphoma appears to result in a high clearance rate from circulating bcl-2/IgH positive cells: Is the end of molecular monitoring near?

Accurate monitoring of the t(14;18) translocation is regarded as highly desirable in patients with follicular lymphoma (FL) as absence of bcl-2/IgH positive cells has been correlated with a reduced risk of recurrence and, more recently, pre-treatment t(14;18) load with response to rituximab (R; Blood 2004;103:4416-23). With the arrival of R clinical and molecular remission rates for various lymphoma entities improved significantly, creating the need to carefully review and reassess the role of PCR negativity for clinical outcome, specifically when considering the prolonged presence of the drug as compared to chemotherapy. To determine the rate of molecular clearance achieved by the addition of different doses of R 16 newly diagnosed, t(14;18) positive patients with FL (Ann Arbor stages III/IV) were investigated before, during and after primary chemotherapy with six cycles of CHOP combined with varying (1, 3 or 6) cycle numbers of R (varR1-, varR3- or varR6-CHOP, respectively) regarding molecular remission status. For this purpose classic nested PCR as well as a newly established RQ-PCR employing juxtaposed hybridisation probes were employed to assess molecular remission prior, during and post therapy. Interestingly, administering just a single cycle of R (varR1-CHOP) in combination with a standard regimen of CHOP resulted in rapid and effective clearance of t(14;18) carrying cells from the peripheral blood of 4/5 patients in this treatment group. 6/8 (6/8) varR1-/varR3-CHOP patients were fully cleared and 8/8 (7/8) var6-CHOP patients as assessed by RQ- (nested) PCR. This indicates the high clearance capacity of this combination therapy approach even when adding a very low cycle number of R (1 and 3, respectively) to CHOP in primary therapy of FL. In summary, the relationship established between molecular clearance and minimal residual disease/risk of recurrence may have to be redefined in the times of R. Upcoming large prospective trials will have to elucidate to what degree the clearance of peripheral blood from t(14;18) positive cells can still be regarded as informative regarding absence of minimal residual disease, remission status and/or risk of recurrence.

Adult↗

PubMed2006

Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia.

PURPOSE: Immunoglobulin heavy chain variable-region (VH) gene mutation status and zeta-associated protein 70 (ZAP-70) expression are correlated in chronic lymphocytic leukemia (CLL), but their concordance is variable. The goal of this study was to elucidate additional factors potentially characterizing their discordance. PATIENTS AND METHODS: We evaluated ZAP-70 expression by flow cytometry, VH status by DNA sequencing, and genomic aberrations by fluorescence in situ hybridization in 148 CLL patients. The parameters were analyzed for their associations and their individual prognostic impact. RESULTS: ZAP-70 expression and VH mutation status were strongly associated in CLL without additional genetic high-risk-features as defined by the absence of 11q or 17p deletion and V3-21 usage (concordance 84%). In contrast, the proportion of discordant cases was significantly higher (39%), if such additional genetic high-risk features were present. Discordant cases with V3-21 usage were almost exclusively ZAP-70 positive and VH mutated (89%), whereas all but one of the discordant cases with high-risk aberrations were ZAP-70 negative and VH unmutated (92%). By multivariate regression analysis, two models were developed, which both include high-risk genomic aberrations and, alternatively, VH mutation status and V3-21 usage or ZAP-70 expression as independent outcome predictors. CONCLUSION: There were characteristic modes of discordance between ZAP-70 and VH mutation status depending on the presence or absence of additional genetic high-risk features such as 11q and 17p deletion or V3-21 usage. Although the biologic background for these findings is yet to be determined, these data have biologic and clinical implications regarding ZAP-70 as a pathogenic factor and outcome predictor, respectively.

Biomarkers, Tumor↗

PubMed2006

Molecular fingerprinting and autocrine growth regulation of endothelial cells in a murine model of hepatocellular carcinoma.

In a mouse model of hepatocellular carcinogenesis, highly vascularized tumors develop through two distinct morphologic phases of neovascularization. We show that increased vascular caliber occurs first, followed by extensive vessel sprouting in late-stage carcinomas. To define molecular pathways in tumor neovascularization, endothelial cells were directly purified from normal liver and advanced tumors. Gene expression profiling experiments were then designed to identify genes enriched in the vascular compartment. We report that Cathepsin S is the major protease specifically overexpressed during vessel sprouting. We also show that the CC chemokines CCL2 and CCL3 are secreted by neovessels and stimulate proliferation through their cognate receptors in an autocrine fashion. This suggests that chemokine signaling represents the most prominent signaling pathway in tumor-associated endothelial cells and directly regulates vessel remodeling. Furthermore, high angiogenic activity is associated with attenuated lymphocyte extravasation and correlates with expression of the immunomodulatory cytokine interleukin 10. This is the first comprehensive study addressing liver-specific vascular changes in a murine autochthonous tumor model. These novel insights into liver angiogenesis infer an environmental control of neovascularization and have important implications for the design of antiangiogenic therapies.

Animals↗

PubMed2006

Reduced expression of CAMTA1 correlates with adverse outcome in neuroblastoma patients.

PURPOSE: A distal portion of 1p is frequently deleted in human neuroblastomas, and it is generally assumed that this region harbors at least one gene relevant for neuroblastoma development. A 1p36.3 commonly deleted region, bordered by D1S2731 and D1S214 has been defined. The present study surveys whether expression of genes mapping to this region is associated with tumor behavior. EXPERIMENTAL DESIGN: Candidate genes localized within the deleted region were identified by sequence data analysis. Their expression was assessed in a cohort of 49 primary neuroblastomas using cDNA microarray analysis. Gene expression patterns associated with known prognostic markers and patient outcome were further evaluated by quantitative real-time reverse transcription-PCR in a cohort of 102 neuroblastomas. RESULTS: The commonly deleted region spans 261 kb and encompasses two genes, FLJ10737 and CAMTA1. We found no evidence for an association of FLJ10737 expression with established prognostic variables or outcome. In contrast, low CAMTA1 expression characterized tumors with 1p deletion, MYCN amplification, and advanced tumor stages 3 and 4. Moreover, low CAMTA1 expression was significantly associated with poor outcome (P < 0.001). In multivariate analysis of event-free survival, the prognostic information of low CAMTA1 expression was independent of 1p status, MYCN status, tumor stage, and age of the patient at diagnosis (hazard ratio, 3.52; 95% confidence interval, 1.21-10.28; P = 0.02). CONCLUSIONS: Our data suggest that assessment of CAMTA1 expression may improve the prognostic models for neuroblastoma and that it will be important to define the biological function of CAMTA1 in this disease.

Age Factors↗

PubMed2006

Frequent amplifications and abundant expression of TRIO, NKD2, and IRX2 in soft tissue sarcomas.

Copy number gains and high-level amplifications of the short arm of chromosome 5 are frequently observed in soft tissue sarcomas. To identify genes from this region possibly involved in tumor progression, we analyzed 34 soft tissue sarcomas (10 pleomorphic and 8 dedifferentiated liposarcomas, 6 malignant fibrous histiocytomas, and 10 malignant peripheral nerve sheath tumors (MPNST)) using a DNA microarray including 418 BAC clones representing 99% of chromosome arm 5p. In seven tumors, distinct high-level amplifications were identified affecting four different subregions. From these regions, genes TERT, TRIO, SKP2, FBXO32, NKD2, SLC6A3, IRX2, POLS, FYB, PTGER4, and FGF10 were selected for detailed quantitative expression analysis (RQ-PCR) based on their potential tumorigenic function. Of these, TRIO, coding for a guanidine nucleotide exchange factor, was consistently overexpressed in all cases, while IRX2 and NKD2, both involved in the regulation of developmental processes via the WNT pathway, showed a characteristic expression only in MPNSTs. Detailed nonparametric multidimensional scaling analysis further showed that the expression of TRIO, IRX2, and NKD2 strongly correlated with the gene copy number. In conclusion, we found TRIO, IRX2, and NKD2 frequently affected by high-level amplifications as well as up-regulated in a gene-dosage dependent manner. Thus, these genes represent candidate targets of 5p amplifications in soft tissue sarcomas and might play a crucial role during the progression of this disease.

Adaptor Proteins, Signal Transducing↗

PubMed2006

The outcome of autologous stem cell transplantation in patients with plasma cell disorders and dialysis-dependent renal failure.

Patients with multiple myeloma and end-stage renal failure on dialysis are frequently not considered eligible for high-dose therapy (HDT) due to higher transplant-related mortality (TRM). Our aim was to evaluate the toxicity and survival of dialysis-dependent patients after HDT with melphalan (100 mg/m(2)) compared to those of patients without renal insufficiency (melphalan 200 mg/m(2)) in a matched pairs analysis of 34 patients. No significant differences were observed between hematologic toxicity, TRM or disease response. Dialysis patients showed comparable event-free and overall survival. They required significantly extended intravenous antibiotic treatment and longer hospitalization. Thus, melphalan 100 mg/m2 is less toxic, yet equally efficient and improves the prognosis of this group of patients.

Adult↗

PubMed2005

Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes.

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.

Apoptosis↗

PubMed2005

Genomic and protein expression profiling identifies CDK6 as novel independent prognostic marker in medulloblastoma.

PURPOSE: Medulloblastoma is the most common malignant brain tumor in children. Despite multimodal aggressive treatment, nearly half of the patients die as a result of this tumor. Identification of molecular markers for prognosis and development of novel pathogenesis-based therapies depends crucially on a better understanding of medulloblastoma pathomechanisms. PATIENTS AND METHODS: We performed genome-wide analysis of DNA copy number imbalances in 47 medulloblastomas using comparative genomic hybridization to large insert DNA microarrays (matrix-CGH). The expression of selected candidate genes identified by matrix-CGH was analyzed immunohistochemically on tissue microarrays representing medulloblastomas from 189 clinically well-documented patients. To identify novel prognostic markers, genomic findings and protein expression data were correlated to patient survival. RESULTS: Matrix-CGH analysis revealed frequent DNA copy number alterations of several novel candidate regions. Among these, gains at 17q23.2-qter (P < .01) and losses at 17p13.1 to 17p13.3 (P = .04) were significantly correlated to poor prognosis. Within 17q23.2-qter and 7q21.2, two of the most frequently gained chromosomal regions, confined amplicons were identified that contained the PPM1D and CDK6 genes, respectively. Immunohistochemistry revealed strong expression of PPM1D in 148 (88%) of 168 and CDK6 in 50 (30%) of 169 medulloblastomas. Overexpression of CDK6 correlated significantly with poor prognosis (P < .01) and represented an independent prognostic marker of overall survival on multivariate analysis (P = .02). CONCLUSION: We identified CDK6 as a novel molecular marker that can be determined by immunohistochemistry on routinely processed tissue specimens and may facilitate the prognostic assessment of medulloblastoma patients. Furthermore, increased protein-levels of PPM1D and CDK6 may link the TP53 and RB1 tumor suppressor pathways to medulloblastoma pathomechanisms.

Biomarkers, Tumor↗

PubMed2005

The bcl-2/IgH rearrangement in a population of 204 healthy individuals: occurrence, age and gender distribution, breakpoints, and detection method validity.

This study assessed prevalence, frequency, age and gender distribution and breakpoint locations, and detection method validity for the bcl-2/IgH rearrangement in 204 healthy individuals. For this purpose, both classic two-step, nested, semi-quantitative PCR as well as a newly established sequence-specific, hybridization probe-based real-time quantitative PCR (RQ-PCR) were employed and tested for their sensitivity and specificity for detecting t(14;18) positive cells in healthy blood donors. Interestingly, almost a quarter (24%; 39/204) of all healthy individuals carried the translocation, confirming data of one large prior report [Summers KE, Goff LK, Wilson AG, Gupta RK, Lister TA, Fitzgibbon J. Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma. J Clin Oncol 2001;19(2):420-4]. Regarding presence as well as frequency of the translocation, no correlation to age (mean frequency 2.0:10(4), with a median of or=40 years) nor gender was detected. Comparing the two PCR approaches, a 95.1% concordance (194/204) regarding t(14;18) detection was determined for nested and RQ-PCR, with nested PCR being slightly more sensitive (reproducible detection limit l:10(5) cells versus 1:10(4); maximum detection limit l:10(6) versus 1:10(5)). Sequence analysis confirmed individual breakpoints for all samples analyzed (29/29), indicating detection validity for both PCR approaches and ruling out contamination. The breakpoint location distribution pattern appeared to be comparable to the pattern seen with follicular lymphoma (FL) patient collectives. In conclusion, clonal bcl-2/IgH rearrangements are indeed a very frequent observation in healthy individuals, and appear to be independent of age and gender in regard to presence and frequency. This represents a conflicting finding in context of potential biological significance, and presents a potential disruptive factor for minimal residual disease (MRD) monitoring in FL patients. Prospective future trials will have to clarify the biological significance of this important observation.

Adolescent↗

PubMed2005

Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios.

Anorexia nervosa (AN) is a severe and complex psychiatric disorder with a significant genetic contribution. Previously, we found an association between AN and the 158Val/Met polymorphism of the catechol-O-methyltransferase (COMT) gene in a family-based study of 51 Israeli AN trios. In the present study, we extended the original sample to include 85 family trios [66 AN restricting (AN-R) and 19 bingeing/purging (AN-BP) subtype] and performed a family-based transmission disequilibrium test (TDT) analysis for five SNPs in the COMT and two in the adjacent ARVCF gene. Association was found between AN-R and several SNPs in the COMT-ARVCF region including the 158Val/Met polymorphism. TDT analysis of 5-SNP haplotypes in AN-R trios revealed an overall statistically significant transmission disequilibrium (P < 0.001). Specifically, haplotype B [COMT-186C-408G-472G(158Val)-ARVCF-659C(220Pro)-524T(175Val)] was preferentially transmitted (P < 0.001) from parents of AN-R patients to their affected daughters, while haplotype A [COMT-186T-408C-472A(158Met)-ARVCF-659T(220Leu)-524C(175Ala)] was preferentially (P = 0.01) not transmitted. Haplotype B was associated with increased risk (RR 3.38; 0.95CI 1.98-6.43) while haplotype A exhibited a protective effect (RR 0.40; 0.95CI 0.21-0.70) for AN-R. Preferential transmission of the risk alleles and haplotypes from the parents was mostly contributed by the fathers. No significant transmission disequilibrium of alleles or haplotypes was found for AN-BP trios. The risk and protective haplotypes may carry molecular variations in the COMT gene or its vicinity that are relevant to the pathophysiology of restrictive anorexia nervosa in the Israeli-Jewish population.

Adolescent↗

PubMed2005

German populations with infrequent CHEK2*1100delC and minor associations with early-onset and familial breast cancer.

CHEK2*1100delC is associated with a twofold increased breast cancer risk. This was shown in a collaborative analysis of European populations, but not in other populations from Europe and the US. Accordingly, there is a need to clarify the role of CHEK2*1100delC in breast cancer. We established its prevalence in two German populations GENICA (Northrhine-Westphalia, n = 724) and KORA (Bavaria, n = 600) and in women with breast cancer. The latter included cases (n = 688) from the GENICA breast cancer case-control study, patients with early-onset breast cancer (n = 86) and patients with familial breast cancer (n = 71). The latter patient groups were previously investigated for BRCA1/2-mutations and tested negative. Mutation analysis was performed by combined PCR/DHPLC methodology. CHEK2*1100delC was found in 0.9% of GENICA controls and was absent in the KORA controls indicating a significant difference between the two populations (P= 0.03). The frequency of CHEK2*1100delC in age-matched cases of the GENICA collection was 0.8% and thus not different from controls (OR 0.88, 95% CI 0.21-3.50). In patients with early-onset disease CHEK2*1100delC was found at a frequency of 2.3% referring to an increased breast cancer risk of 2.56 (95% CI 0.25-14.58). In patients with familial disease the frequency was 1.4% referring to an increased risk of 1.53 (95% CI 0.03-12.93). Our data showed variations in CHEK2*1100delC prevalence within German populations suggesting possible inaccuracies in breast cancer risk assessments from non population-based studies. In patients with a high-risk profile however, CHEK2*1100delC was indicative for this risk and highest for early-onset breast cancer.

Adult↗