<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.     

No association between <Emphasis Type="Italic">MDR1</Emphasis> (<Emphasis Type="Italic">ABCB1</Emphasis>) 2677G>T and 3435C>T polymorphism and sporadic colorectal cancer among Bulgarian patients

Purpose Variation in genetic factors together with xenobiotic exposure may result in increased risk of colorectal cancer. The P-glycoprotein (P-gp) is highly expressed in the apical membrane of enterocytes, where it pumps xenobiotics from the enterocytes back into the intestinal lumen. Thus, polymorphisms that reduce the activity of the MDR1 (ABCB1) efflux pump are potential risk factors for colorectal carcinogenesis. The aim of the present study is to genotype the MDR1 2677G>T (rs2032582) and 3435C>T (rs1045642) polymorphism in patients with colorectal cancer and controls and to identify a possible association between individual genetic variation and susceptibility to colorectal cancer. Methods In the present study, 146 Bulgarian patients with sporadic colorectal cancer and 160 healthy Bulgarian volunteers were evaluated for the two polymorphisms in MDR1. Polymorphisms were identified using rapid-cycle real-time amplification with allele-specific probes and subsequent melting curve analyses on a LightCycler™ (Roche Diagnostics, Mannheim, Germany). Results No differences were found between the frequencies of the two mutant alleles in the tumor tissue from the cases and lymphocytes from the controls [frequencies of 2677T: 43.5% in patients and 44.1% in controls; frequencies of 3435T: 48.3% in patients and 50.9% in controls (both P > 0.05)]. The MDR1 polymorphic sequence of the tumor tissue always matched that of normal intestinal tissue from the same patient. Consequently, genotyping of DNA from archived tumor tissues is a valid alternative to the use of leukocyte DNA. Conclusions The present study suggests that MDR1 2677G>T and 3435C>T polymorphism is not a risk factor for sporadic colon cancer among Bulgarians and that somatic mutation at these sites is not involved in the genesis of colon tumors. Further examination using larger number of samples must be necessary to reach to more reliable conclusions.     

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.     

Aberrant methylation of <Emphasis Type="Italic">SOCS-1</Emphasis> was observed in younger colorectal cancer patients

Background Recently, it was demonstrated that suppressor of cytokine signaling-1 (SOCS-1) was frequently silenced by methylation of its CpG island in human hepatocellular carcinoma (HCC). To define the role of SOCS-1 in the tumorigenic pathway of the colorectum, we examined the methylation of SOCS-1 in tumors of colorectal cancer patients.Methods We examined 74 colorectal cancer patients, using a methylation-specific polymerase chain reaction (PCR; MSP) for SOCS-1 CpG island in primary tumors.Results Aberrant methylation of the SOCS-1 CpG island was detected in 6 of the 74 (8%) colorectal cancer specimens. No corresponding normal colorectal tissues showed SOCS-1 methylation. We then analyzed the correlation between the clinicopathological features and SOCS-1 aberrant methylation and found that younger age was significantly related to SOCS-1 methylation (P = 0.048).Conclusions These findings suggested that SOCS-1 may act as a tumor suppressor in at least some colorectal cancers and that SOCS-1 methylation may be a particular phenomenon related to an early onset of colorectal cancer.     

<Emphasis Type="Italic">p16</Emphasis><Superscript><Emphasis Type="Italic">INK4A</Emphasis></Superscript> Alterations are accompanied by aberrant protein immunostaining in endometrial carcinomas

Purpose To date, the significance of p16^INK4A tumor suppressor gene inactivation in sporadic endometrial cancer (EC) has only rarely been described. In this study, we examined the alteration type and frequency of gene alterations [point mutations, aberrant promoter methylation and loss of heterozygosity (LOH)] in 50 sporadic ECs, and correlated the genetic findings with the immunohistochemical expression of the p16^INK4A protein and the classical clinicopathological features.Methods Gene mutations were detected by PCR-SSCP-sequencing analysis, promoter hypermethylation by methylation-specific PCR (MSP), and LOH by PCR of the STS-marker c5.1.Results In total, p16^INK4A alterations were found in 14 of 50 (28%) sporadic ECs. In six (12%) cases, two alterations occurred simultaneously. Partial p16^INK4A deletions were found in four of 50 (8%) samples. There was one missense mutation (codon 70; CCCGCC) and one frameshift mutation (1-bp deletion in exon 2). Only 2 of 47 (4.2%) tumors exhibited aberrant promoter methylation. An allelic loss was detected in 12 of 50 (24%) carcinomas with a higher incidence in advanced endometrial carcinomas than in early-stage uterine tumors. p16^INK4A alterations were generally accompanied by gene silencing, confirmed by aberrant protein immunostaining (r=-0.442; P=0.001). There was a significant difference in the frequency of p16^INK4A alterations between early (stage I; 18%) and advanced (stages II–IV; 58%) ECs (P=0.022). One case showed complete protein loss, but absence of genetic alterations.Conclusions Our data indicate that p16^INK4A inactivation plays a role in the tumorigenesis of the subset of sporadic ECs, particularly in cases exhibiting an aggressive clinical behavior. We demonstrate that p16^INK4A methylation can act efficiently and similarly to other genetic alterations as one of the two necessary hits according to the Knudson two-hit hypothesis of tumor suppressor gene inactivation.     

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.     

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.     

<Emphasis Type="Italic">cagA</Emphasis> Gene and Protein Status Among Iranian <Emphasis Type="Italic">Helicobacter pylori</Emphasis> Strains

The wide geographic genetic diversity of Helicobacter pylori (Hp) and, in particular, the varying prevalence of cagA in different countries has been documented repeatedly. This study was designed to determine the frequency of cagA in Iranian Hp strains by means of genotyping and assessment of host antibodies. Helicobacter pylori strains from 235 patients, including 174 non-ulcer dyspepsia, 25 peptic ulcer and 36 gastric cancer patients, were studied. The frequencies of the 5′, middle and 3′ terminal regions of the cagA gene were 90.6, 57.6, 89%, respectively, with no correlation to the clinical outcomes. Antibodies against the CagA protein were present in 90.7% of patients. Multiple biopsy sampling in 97 cases revealed multiple infection in 16.5% of the patients. Sequencing of the seven variants of the 3′ end of the cagA gene revealed no clustering and the distribution of the Iranian strains among those of other countries. Our results from the genotyping and serology analyses confirm that the majority of Iranian Hp strains are cagA-positive.     

Meta-analysis of different test indicators: <Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection and the risk of colorectal cancer

BACKGROUND AND AIMS: Recent studies have demonstrated the relationship between Helicobacter pylori infection and the risk of colorectal carcinoma. However, the results of these studies remain controversial as the studies were relatively small in size and partially differed in designs, and so we reviewed the published studies and carried out a meta-analysis to further explore this relationship. MATERIALS AND METHODS: We performed an extensive systematic review to find all the published case-control studies up to Jan. 2007 using electronic searching, hand searching, and reference lists of retrieved articles. Odds ratio (OR) was employed to evaluate the relationship of H. pylori infection and risk of colorectal cancer. Summary estimates were obtained using random effect models according to the result of a statistical test for heterogeneity across the studies. The presence of possible publication bias was assessed using different statistical approaches. RESULTS: Thirteen studies were included, and summary OR 1.49 (95% confidence interval [CI] 1.17-1.91) was estimated for the association between H. pylori infection and colorectal cancer. Summary OR 1.56 (95% CI 1.14-2.14) was estimated for the association between immunoglobulin G antibody and colorectal cancer risk. By trimming and filling, the number of inputted studies was zero, and summary OR was still 1.49 (95% CI 1.17-1.91). The graphical funnel plot appeared asymmetrical, but there was no statistical evidence of publication bias. The method of fail-safe suggested that the effect of publication bias was small. CONCLUSION: Current evidence, though limited, suggests that there is a possible increase in risk of colorectal cancer because of H. pylori infection.     

The association between the <Emphasis Type="Italic">IFIH1</Emphasis> locus and type 1 diabetes

Aims/hypothesis We set out to validate a recently reported type 1 diabetes association from the IFIH1 gene variation in an independent cohort from a population of mixed European descent. Methods We genotyped five single-nucleotide polymorphisms in the IFIH1 locus, i.e. rs2111485, rs1990760, rs3747517, rs17783344 and rs984971589, in 589 type 1 diabetes nuclear family trios (1,767 individuals). Results This study independently replicated the reported genetic association using a family-based approach. Conclusions/interpretation The reported type 1 diabetes association is from a linkage disequilibrium region including three candidate genes, i.e. FAP, IFIH1 and GCA. Further variant discovery and fine mapping could help clarify a novel type 1 diabetes mechanism. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Case of B-Cell Lymphoma with Rearrangement of the <Emphasis Type="Italic">BCL1, BCL2, BCL6</Emphasis>, and <Emphasis Type="Italic">c-MYC</Emphasis> Genes

We managed a peculiar case of lymphoma showing immunohistochemical overexpression of cyclin D1. At initial examination the patient had meningeal lymphomatosis and general lymphadenopathy. Histologic examination of biopsy specimens of inguinal lymph nodes showed tumor cells and vague nodular growth resembling lymphoblasts. The results of flow cytometric analysis were positive for CD10, CD20, CD103, and immunoglobulin G (IgG) and Ig kappa and were negative for CD5, CD23, and terminal deoxynucleotidyl transferase activity. Results of immunohistochemical analysis of paraffin-embedded specimens were positive for cyclin D1 and Bcl2 in the tumor cells. Sixty percent of tumor cells had positive results for MIB1/Ki67. Cytogenetic and molecular studies revealed tumor cells simultaneously had t(14;18)(q32;q21), t(11;22)(q13;q11), t(8;14)(q24;q32), and t(3;14)(q27;q32) with the rearrangement of BCL1, BCL2, BCL6, and c-MYC genes. Lymphadenopathy showed a quick and complete response to doxorubicin-containing systemic chemotherapy with rituximab, but the central nervous system disease progressed and killed the patient.     

Role of <Emphasis Type="Italic">MTHFR</Emphasis> polymorphisms and folate levels in different phenotypes of sporadic colorectal cancers

BACKGROUND AND AIMS: By altering both DNA methylation and nucleotide synthesis, folate metabolism is thought to contribute to colorectal carcinogenesis. We examined the role of folate metabolism in three different phenotypes of sporadic colorectal cancers (CRCs), phenotypes that were classified by the status of microsatellite instability (MSI) and chromosomal instability (CIN): MSI-H, microsatellite stability (MSS)/aneuploidy, and MSS/diploid. PATIENTS AND METHODS: A total of 195 sporadic colorectal tumors and another 195 age- and gender-matched healthy volunteers in Taipei-Veteran General Hospital and Taipei City Hospital were collected. We analyzed for MTHFR (methylenetetrahydrofolate reductase) polymorphisms (C677T, A1297C), folate, and vitamin B(12) levels. We determined MSI status and DNA ploidy with fluorescent polymerase chain reaction and flow cytometry. Relations between clinicopathological variables and molecular variables were analyzed by chi (2) tests (with Yates' correction) for categorical variables and Student's t test for numerical variables. RESULTS: Folate levels (5.02+/-4.43 ng/ml) were significantly lower in cancer patients than in controls (7.22+/-4.46 ng/ml). Vitamin B(12) level was similar between cancer patients and controls. The frequency of the TT genotype of MTHFR C627T (12.3%) was slightly higher than controls (8.2%), but it did not reach statistical significance (p=0.174). Within the low-folate group (<5 ng/ml), the frequency of the TT genotype in cancer patients (14.4%) was significantly higher than in controls (4.6%). Sixteen patients who had MSI-H CRC (8.2%) had a significantly higher frequency of TT MTHFR (37.5%) and lower folate levels (3.56+/-2.41 ng/ml) than patients with MSS tumors (10.1%, 5.14+/-3.72 ng/ml). Patients with MSS/aneuploid tumors had significantly lower folate levels (4.50+/-3.06 ng/ml) than those with MSS/diploid tumors (6.69+/-4.73 ng/ml). CONCLUSION: Folate deficiency and the MTHFR genetic polymorphism play an important role in colorectal carcinogenesis, including MSI and CI. SYNOPSIS: Folate metabolism plays an important role in colorectal carcinogenesis. We demonstrate that patients with MSI-H tumors had higher frequency of TT MTHFR C627T (37.5%), and patients with MSS/aneuploid tumor had lower folate level (4.50+/-3.06 ng/ml).     

<Emphasis Type="Italic"> BAX</Emphasis> and <Emphasis Type="Italic">caspase-5</Emphasis> frameshift mutations and spontaneous apoptosis in colorectal cancer with microsatellite instability

Background and aims Hereditary nonpolyposis colorectal cancer (HNPCC) and a subset of sporadic colorectal cancers are characterized by microsatellite instability (MSI) and inactivating frameshift mutations of target genes. Inactivation of BAX, caspase-5 (cas-5), and other genes coding for pro-apoptotic proteins might contribute to tumor progression by enhancing escape from apoptosis. The aim of this study was to further characterize the role of BAX and cas-5 inactivation for spontaneous apoptosis.Methods Twenty-five colorectal cancers with MSI were analyzed for frameshift mutations in the BAX (G)8 and cas-5 (A)10 tract by fluorescence PCR, cloning, and sequencing. The rate of spontaneous apoptosis was examined by in situ DNA nick end-labeling. The results were compared with 25 stage-matched microsatellite stable (MSS) colorectal cancers.Results In colorectal cancer with MSI frameshift mutations in BAX and cas-5 were present in 16 of 25 (64%) and in 12 of 25 (48%) tumors, respectively, whereas neither mutant BAX nor cas-5 alleles were detected in all stage-matched sporadic MSS colorectal cancer. Tumors with MSI showed a higher apoptotic rate than MSS tumors (2.5±1.0 vs. 2.1±0.7; p <0.05), whereas the presence of BAX or cas-5 frameshift mutations had only minor influence on this finding (2.4±1.1% and 2.5±0.9%, respectively).Conclusion Mismatch-repair deficiency itself is associated with increased spontaneous apoptosis, not further accelerated by either inactivating BAX or cas-5 frameshift mutations.This work was supported by grants from the Johann Wolfgang Goethe University Frankfurt a.M. (F15/01) and the Paul and Ursula Klein Foundation     

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">MYH</Emphasis> mutations are rare in prostate cancer

Purpose Oxidative stress is considered a risk factor for prostate cancer development and is associated with the production of reactive oxygen species (ROS). The base excision repair gene MYH protects against ROS-mediated damage to DNA. Inherited MYH mutations predispose to colorectal adenomas and cancer. A compromised base-excision repair function due to defective MYH may contribute to prostate carcinogenesis. Here, we examine the genetic contribution of MYH to prostate cancer risk. Methods Patients diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) alone (n = 45), prostate cancer alone (n = 123) or both (n = 82) were screened for the two most common mutations in the MYH gene using PCR-based RFLP analysis. A single patient with an inherited MYH mutation as well as a subset of 26 patients presenting with a family history of colorectal cancer were screened for additional MYH mutations by direct sequencing of the entire coding region. Results Biallelic germline mutations in MYH were not detected among prostate cancer patients. Only a single patient was a heterozygous carrier for the Y165C missense mutation. Allelic deletion or somatic mutation of the remaining MYH allele was not identified in this patient’s tumor DNA. Two patients harbored V22M polymorphism and three patients were carriers of Q324H polymorphism. Conclusions MYH mutations are unlikely to contribute to prostate cancer risk.