Molecular genetic defects in endometrial carcinomas: microsatellite instability, <Emphasis Type="Italic">PTEN</Emphasis> and beta-catenin (<Emphasis Type="Italic">CTNNB1</Emphasis>) genes mutations

Purpose The present study aims to assess the incidence of microsatellite instability (MSI) and mutations in the PTEN and beta-catenin (CTNNB1) genes in endometrial carcinomas and to analyze the detected defects in these factors in relation to each other and to the clinico-pathological features of tumors. Materials and methods In a series of 56 endometrioid endometrial carcinomas, the status of MSI was determined using nine polymorphic markers, and mutations in all exons of the PTEN gene and in exon 3 of the CTNNB1 gene were evaluated by SSCP and sequencing methods. Results Microsatellite instability was found in 18 carcinomas (32.1%, MSI+); the remaining 38 tumors were microsatellite stable (MSI−). In 15 cases (26.8%), a loss of heterozygosity (LOH) at the studied microsatellite markers also occurred. In 29 carcinomas (51.8%), mutations were found in the PTEN gene and in nine tumors (16.1%) in the CTNNB1 gene. PTEN mutations occurred significantly more frequently in MSI+ than in MSI− tumors (77.8 vs. 39.5%, p = 0.007), but, except for one, none of them was attributable to MSI. In contrast, incidence of CTNNB1 mutations in MSI+ and MSI− tumors no significantly differed between themselves (16.7 vs. 15.8%, p = 0.760). Interestingly, mutations in the CTNNB1 gene most frequently coexisted with mutations in the PTEN gene (7/9, 77.8%). However, this finding requires future verification on a larger group of cases. The incidence of MSI and PTEN, but not CTNNB1 mutations, was significantly more common in poorly, than in well-to-moderately, differentiated tumors (G3 vs. G1 + G2; p = 0.042, 0.039 and 0.958, respectively). Conclusion We conclude that most frequently occurring mutations in the PTEN gene may be a key event for the tumorigenesis of endometrioid endometrial carcinomas, while coexistence or absence of microsatellite instability or mutations in the CTNNB1 gene may reflect the heterogeneity of molecular mechanisms contributing to the development of these tumors.     

<Emphasis Type="Italic">Di</Emphasis>abetesintervention mit<Emphasis Type="Italic"> Ator</Emphasis>vastatin (DIATOR)

Zusammenfassung Statine haben bei der Prävention von vaskulären Ereignissen einen sehr hohen Stellenwert. Als Wirkmechanismus wird primär die Senkung des LDL-Cholesterins gesehen. In den letzten Jahren konnten zudem diverse immunmodulatorische Wirkungen nachgewiesen werden, die in dieser Übersichtsarbeit diskutiert werden. Diese neuen Erkenntnisse haben dazu geführt, dass vom Deutschen Diabeteszentrum eine multizentrische Interventionsstudie begonnen wurde, bei der die beim frisch manifesten Typ-1-Diabetes noch vorhandene residuelle Insulinproduktion durch eine Therapie mit Atorvastatin erhalten werden soll.     

Cardiovascular Concerns in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> Mutation Carriers

Purpose of review

BRCA1 and BRCA2 mutation carriers can be at increased cardiovascular risk. The goal of this review is to provide information about factors associated with increased cardiovascular risk, methods to prevent cardiovascular toxicities, and recommended screening guidelines.

Recent findings

BRCA1/2 mutation carriers who are diagnosed with cancer are often exposed to chemotherapy, chest radiotherapy, and/or HER2 directed therapies, all of which can be cardiotoxic. In addition, BRCA1/2 carriers often undergo prophylactic salpingoopherectomies, which may also increase cardiovascular risks.

Summary

Understanding the potential for increased cardiovascular risk in individuals with a BRCA1 or BRCA2 mutation, as well as gold standard practices for prevention, detection, and treatment of cardiac concerns in this population, is important.

     

DOG1在72例胃肠道间质瘤中的表达及临床意义

目的检测DOG1等抗体在胃肠道间质瘤（GIST）中的表达,并评价DOG1在GIST诊断中的价值。方法应用免疫组化S-P法检测72例GIST、20例平滑肌肿瘤、34例神经鞘瘤及28例孤立性纤维性肿瘤中DOG1、CD117、CD34、SMA、S100的表达情况。结果 GIST中DOG1阳性表达率为93.0%,CD117为88.9%,而CD34为72.2%;DOG1在平滑肌肿瘤、神经鞘瘤及孤立性纤维性肿瘤中均为阴性表达,CD117在平滑肌肿瘤及孤立性纤维性肿瘤中阳性率为3.3%及3.6%。CD117阴性者中DOG1阳性表达率为37.5%。且9例胃肠外GIST中DOG1、CD117及CD34的阳性率为100%、77.8%和44.4%。8例CD117阴性病例中,DOG1阳性表达率为37.5%（3/8）。结论 DOG1在诊断GIST中具有较高敏感性和特异性,在GIST的诊断、鉴别诊断及筛查格列卫等靶向药物治中是一种非常有价值的抗体。DOG1和CD117表达与肿瘤分化程度无关。评价GIST复发可能性,还应结合肿瘤大小、核分裂数/50HPF及肿瘤原发部位等综合因素。     

Mutation Analysis of <Emphasis Type="Italic">SPINK1</Emphasis> and <Emphasis Type="Italic">CFTR</Emphasis> Gene in Korean Patients with Alcoholic Chronic Pancreatitis

Several genetic mutations have been reported to increase susceptibility to chronic pancreatitis. However, their roles in alcoholic chronic pancreatitis are controversial. We investigated the prevalence of SPINK1 N34S and new CFTR Q1352H mutations in alcoholic chronic pancreatitis in Korea. Forty-three patients with alcoholic chronic pancreatitis were enrolled and 35 healthy individuals served as controls. The SPINK1 N34S mutation was detected by the PCR-RFLP technique. The CFTR Q1352H mutation was examined with PCR direct sequencing. Mean age of chronic pancreatitis and control groups was 53.2 and 51.3 years, respectively. A SPINK1 N34S was detected as a heterozygote in one (2.4%) patient with alcoholic chronic pancreatitis and a heterozygote CFTR Q1352H was detected in one other patient. In the control population, neither SPINK1 nor CFTR mutation was detected. This study shows that SPINK1 N34S and CFTR Q1352H mutations are uncommon and do not play an important role in chronic alcoholic pancreatitis in Korea.     

Establishment of thymoma-prone congenic rat strain,ACI.BUF/Mna-<Emphasis Type="Italic">Tsr1</Emphasis>/<Emphasis Type="Italic">Tsr1</Emphasis>

Purpose To confirm the presence of the susceptible gene for the thymoma development in the region that was assumed by the previous linkage study by Oyabu et al. (J Natl Cancer Inst 91:279–282, 1999), we tried to establish a congenic strain of rats. Methods Backcrossings between the BUF/Mna strain as a donor strain and the ACI/NMna strain as an inbred partner were repeated for 12 generations, examining whether rats had the thymoma development region, and then homozygous rats were yielded by mating among the heterozygotes. To detect the phenotypic expression, heterozygous ACI.BUF/Mna-Tsr1/+ (ACI-Tsr1/+) rats were generated by crossing female ACI.BUF/Mna-Tsr1/Tsr1 (ACI-Tsr1/Tsr1) rats with male ACI/NMna rats and were maintained for 24 months. Results These ACI-Tsr1/+ rats produced thymoma in 71%, showing a dominant trait. The thymomas were of the lymphocyte predominant type, as those developed in rats of the original BUF/Mna strain. Conclusions Thus, a new rat congenic strain, ACI-Tsr1/Tsr1, was established, revealing that thymoma develops in the dominant trait in ACI-Tsr1/+ rats.     

Novel <Emphasis Type="Italic">hMSH</Emphasis>2, <Emphasis Type="Italic">hMSH</Emphasis>6 and <Emphasis Type="Italic">hMLH</Emphasis>1 gene mutations and microsatellite instability in sporadic colorectal cancer

Purpose To detect the hMSH2, hMSH6 and hMLH1 DNA mismatch repair gene mutations and microsatellite instability in somatic colorectal cancer.Patients and methods The mutations of hMSH2, hMSH6, and hMLH1 genes, including microsatellite instability of BAT-26, BAT-40, D2S123, D5S346 and D17S250 were analyzed in 31 patients with colorectal.Results The results revealed that eight cases (25.8%) harbored mutations in DNA mismatch repair genes. Of these, five novel mutations including I237V in exon 4 of hMSH2, ins T at codon 1196 in exon 7 of hMSH6, and ins G at codon 154 in exon 6, N158H in exon 6, and del A at codon 257 in exon 9 of hMLH1 were identified. Moreover, several intronic polymorphisms, including c–g transversion at IVS-1 nt211 + 9 of hMSH2, del T in poly T track at IVS-6 nt3559-5, ATCT duplicate in IVS-7 nt 3642 + 35 and t–g transversion at IVS-10 nt4080 + 185 of hMSH6 were demonstrated in these patients. In addition, seven cases (22.5%) exhibited microsatellite instability (MSI).Conclusion These results suggested that the inactivation of DNA mismatch repair genes and microsatellite instability may play a minor role in somatic colorectal cancer development.     

Association of <Emphasis Type="Italic">Lewis</Emphasis> and <Emphasis Type="Italic">Secretor</Emphasis> gene polymorphisms and <Emphasis Type="Italic">Helicobacter pylori</Emphasis> seropositivity among Japanese-Brazilians

Background Secretor (Se) and Lewis (Le) genes are involved in the synthesis of Lewis b (Le^b) and type I antigens throughout the body, especially in the epithelial cells of gastric mucosa. Helicobacter pylori can attach to the gastric epithelial cells with the blood group antigen-binding adhesin, which binds to Le^b or H type I carbohydrate structures. In a previous study, a marked association between H. pylori seropositivity and polymorphism of the Se and Le genes was observed among Japanese outpatients of a gastroenterology clinic. The present work aims to investigate the associations between Se and Le gene polymorphisms and H. pylori infection among Japanese-Brazilians.Methods The subjects consisted of 942 healthy volunteer Japanese-Brazilians, who were tested for the presence of anti-H. pylori IgG antibodies and genotyped for Se and Le polymorphisms.Results The sex-age-adjusted odds ratios (aORs) for H. pylori seropositivity were 0.99 for the Sese genotype relative to the SeSe genotype (95% confidence interval [CI], 0.73–1.33), and 1.03 for sese relative to SeSe (95% CI, 0.71–1.48). On the other hand, the aOR for the subjects with the le allele (Lele or lele) relative to the LeLe genotype was 1.48 (95% CI, 1.07–1.79). When the Se and Le genotypes were analyzed in combination according to risk group, no statistically significant association was observed.Conclusions These results are inconsistent with previous work and may have been modulated by an external factor or some other unidentified factor. Japanese-Brazilians are genotypically the same as Japanese, but their lifestyle is adapted to that of Brazil. Further investigations are necessary to clarify this influence on susceptibility to H. pylori infection.     

Joint effects of HLA, <Emphasis Type="Italic">INS</Emphasis>, <Emphasis Type="Italic">PTPN22</Emphasis> and <Emphasis Type="Italic">CTLA4</Emphasis> genes on the risk of type 1 diabetes

Background/hypothesis HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. Methods We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, −DQA1 and −DQB1, the insulin gene (INS, −23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). Results The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene–gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). Conclusion Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

<Emphasis Type="Italic">hSNF5</Emphasis><Emphasis Type="Italic">/INI1</Emphasis> mutation analysis in acute myeloid leukemia

Previous studies indicated that region 11.2 of the long arm of chromosome 22 (22q11.2) might be a locus encoding a tumor suppressor gene, since its deletion is a recurrent genetic characteristic of aggressive pediatric cancer. This region is found in the human immunodeficiency virus integrase interactor 1 (hSNF5/INI1) gene. To investigate whether the hSNF5/INI1 gene is involved in leukemogenesis, mutation analysis of the hSNF5/INI1 gene was performed in the present study using 5 hematopoietic cell lines, acute myeloid leukemia (AML) specimen and normal control. We found two single nucleotide polymorphisms at the hSNF5/INI1 gene in exon 4 and exon 9. The results of this study suggest that the hSNF5/INI1 gene does not play an important role in the leukemogenesis of AML.     

Epigenetic factors Polycomb (<Emphasis Type="Italic">Pc</Emphasis>) and Suppressor of zeste (<Emphasis Type="Italic">Su</Emphasis>(<Emphasis Type="Italic">z</Emphasis>)2) negatively regulate longevity in <Emphasis Type="Italic">Drosophila melanogaster</Emphasis>

The process of aging is a hallmark of the natural life span of all organisms and individuals within a population show variability in the measures of age related performance. Longevity and the rate of aging are influenced by several factors such as genetics, nutrition, stress, and environment. Many studies have focused on the genes that impact aging and there is increasing evidence that epigenetic factors regulate these genes to control life span. Polycomb (PcG) and trithorax (trxG) protein complexes maintain the expression profiles of developmentally important genes and regulate many cellular processes. Here, we report that mutations of PcG and trxG members affect the process of aging in Drosophila melanogaster, with perturbations mostly associated with retardation in aging. We find that mutations in polycomb repressive complex (PRC1) components Pc and Su(z)2 increase fly survival. Using an inducible UAS-GAL4 system, we show that this effect is tissue-specific; knockdown in fat body, but not in muscle or brain tissues, enhances life span. We hypothesize that these two proteins influence life span via pathways independent of their PRC1 functions, with distinct effects on response to oxidative stress. Our observations highlight the role of global epigenetic regulators in determining life span.     

<Emphasis Type="Italic">GSTP1</Emphasis> and <Emphasis Type="Italic">MDR1</Emphasis> Genotypes and Central Nervous System Relapse in Childhood Acute Lymphoblastic Leukemia

The probability of event-free survival of childhood acute lymphoblastic leukemia (ALL) approaches 80% or more with the use of modern multiagent chemotherapeutic regimens. One major contribution to this success has been reduction of the rate of central nervous system (CNS) relapses to less than 5%. However, heterogeneity is observed with regard to the incidence of CNS relapse in homogenously treated patient populations. One potential explanation for this heterogeneity is variation in the genetic background of these populations. Glutathione S-transferase P1 and P-glycoprotein are implicated in resistance to a variety of chemotherapeutic agents and have been localized to the blood-brain barrier. In a matched case-control study, we investigated the associations between CNS relapse in childhood ALL and the presence of phenotypically relevant single nucleotide polymorphisms within the GSTP1 (codon 105 and 114) and MDR1 genes (ABCB1; coding for Pgp; exon 26, C3435T). Significant reductions in risk of CNS relapse were observed for patients homozygous for the GSTP1 Val105 allele as well as for patients with the MDR1 3435T/T or C/T genotype. For both genotypes, the effect was restricted to patients at intermediate or high risk of treatment failure. These results suggested a modulating role for host genetic variation in the development of CNS relapse in childhood ALL treated according to Berlin-Frankfurt-Münster protocols.     

<Emphasis Type="Italic">T-</Emphasis>Scores and <Emphasis Type="Italic">Z</Emphasis>-Scores

Bone mineral density (BMD) can be measured by a variety of techniques at several skeletal sites. Once measured, the manufacturers’ software uses the BMD to calculate a T-score and/or Z-score. Both T-scores and Z-scores are derived by comparison to a reference population on a standard deviation scale. The recommended reference group for the T-score is a young gender-matched population at peak bone mass, while the Z-score should be derived from an age-matched reference population. T-scores and Z-scores are widely quoted in scientific publications on osteoporosis and BMD studies, and are the values used for DXA diagnostic criteria and current clinical guidelines for the management of osteoporosis. Errors in BMD measurement, differences in reference populations, and variations in calculation methods used, can all affect the actual T-score and Z-score value. Attempts to standardize these values have made considerable progress, but inconsistencies remain within and across BMD technologies. This can be a source of confusion for clinicians interpreting BMD results. A clear understanding of T-scores and Z-scores is essential for correct interpretation of BMD studies in clinical practice.