Androgen receptor gene mutation,rearrangement, polymorphism

Genetic aberrations of the androgen receptor (AR) caused by mutations, rearrangements, and polymorphisms result in a mutant receptor that has varied functions compared to wild type AR. To date, over 1,000 mutations have been reported in the AR with most of these being associated with androgen insensitivity syndrome (AIS). While mutations of AR associated with prostate cancer occur less often in early stage localized disease, mutations in castration-resistant prostate cancer (CRPC) patients treated with anti-androgens occur more frequently with 10-30% of these patients having some form of mutation in the AR. Resistance to anti-androgen therapy usually results from gain-of-function mutations in the LBD such as is seen with bicalutamide and more recently with enzalutamide (MDV3100). Thus, it is crucial to investigate these new AR mutations arising from drug resistance to anti-androgens and other small molecule pharmacological agents.     

Primary pulmonary lymphoma diagnosed by gene rearrangement: Report of a case

We report herein the case of a 59-year-old asymptomatic man who was referred to our department for investigation of an abnormal shadow detected on a routine chest roentogenogram. Computed tomography (CT) showed an infiltrative shadow and air bronchogram in the right middle lobe without mediastinal lymphadenopathy, and a right middle lobectomy was performed with hilar and interlobar lymph node excision. Microscopically, the tumor consisted of small lymphoid cells without atypia, admixed with neutrophils and other mononuclear cells, but there was no invasion of the bronchial cartilage or visceral pleura, or any lymph node involvement. Most of the tumor cells were positive for L26 and some for UCHL-1. Although a germinal center was not seen, pseudolymphoma could not be ruled out. Southern blot analysis of the frozen tissues revealed clonal rearrangements of the immunoglobulin heavy-chain J_H and light-chain J_k, whereby the tumor was diagnosed as malignant lymphoma of the small lymphocytic B-cell type. Thus, when such lymphoproliferative diseases which are difficult to diagnose are encountered, frozen tissue should be preserved for genetic analysis.     

Confirmation of the heterogeneity of posttransplant Epstein-Barr virus-associated B cell proliferations by immunoglobulin gene rearrangement analyses

Immunoglobulin gene rearrangement analysis is a sensitive method for determining clonality of B cell proliferations. We have examined tissue obtained from five renal and one cardiac allograft recipient with Epstein-Barr virus-associated B cell proliferations for immunoglobulin gene rearrangements. Biopsies from two patients with lesions that were hyperplastic morphologically, polyclonal by cellular immunoglobulin staining, and had diploid karyotypes, had no detectable gene rearrangements and were, therefore, consistent with benign reactive processes. These patients are alive without evidence of disease 37 and 57 months after diagnosis. In a biopsy from one patient with a lesion that was malignant lymphoma morphologically, monoclonal by cellular immunoglobulin staining, and had clonal cytogenetic abnormalities, clonal gene rearrangements were detected in a majority of cells, confirming their neoplastic nature. In biopsies from an intermediate group of three patients with morphologically malignant proliferations that were composed predominantly of a polyclonal population of B cells, clonal gene rearrangements were also found, consistent with early malignant transformation in a subpopulation of cells. These findings confirm the heterogeneity of the posttransplant EBV-associated lymphoproliferative diseases and have significant implications for our understanding of the pathogenesis of EBV-induced infections and related lymphomas.     

Analysis of immunoglobulin H gene rearrangement by polymerase chain reaction in primary central nervous system lymphoma

OBJECT: Diagnosing primary central nervous system lymphoma (PCNSL) may be difficult either because of a paucity of tumor cells in the brain biopsy specimens or a failure to demonstrate monoclonality on immunomorphological studies. Monoclonality can also be demonstrated by amplification of the rearranged immunoglobulin H genes by polymerase chain reaction (PCR) to the framework region (FR)3 and FR2 complementarity determining region (CDR)-III and CDR-II of these genes. The PCR method is feasible with formalin-fixed, paraffin-embedded biopsy material and has proven to be helpful in the diagnosis of non-Hodgkin lymphoma on biopsy samples obtained from various locations in the body. Nevertheless, few studies have addressed the value of this method in the context of PCNSL. In the present study, the contribution of both FR3 single and FR2 seminested PCR procedures for confirming the diagnosis of PCNSL was estimated retrospectively in 30 cases of PCNSL and in three cases of epidural lymphoma. METHODS: Twenty-eight cases of immunophenotypically confirmed PCNSL and two of suspected lymphoma were studied. Tissue specimens obtained in 22 cases of other cerebral diseases, among which were various inflammatory conditions. were used as negative controls. In 18 (60%) of 30 cases the results of FR3 PCR demonstrated monoclonality, whereas FR2 PCR showed monoclonality in 12 cases (40%). In 11 cases FR3 PCR yielded monoclonal patterns and FR2 PCR did not, whereas reversibly in five cases FR2 PCR proved monoclonality and FR3 PCR failed to do so. Adding the results of FR3 to those of FR2 PCR, monoclonal patterns were obtained in 23 (77%) of 30 cases. In both cases in which lymphoma was suspected but not proven immunomorphologically, FR3 PCR revealed monoclonality, as did FR2 PCR in one case. In all 22 control lesions either polyclonal patterns were seen or no consistent patterns were obtained. In the PCNSL group, older age of patients and multifocal presentation of lesions on neuroimaging were significantly associated with worse survival. No correlation between histological subtype and clinical outcome was elucidated. CONCLUSIONS: The application of FR3 and FR2 PCR is a useful additional tool in making the diagnosis of PCNSL. Moreover, in some cases the PCR method may be essential in distinguishing neoplasia from reactive conditions.     

直肠癌旁移行粘膜中γδ T细胞含量及受体基因重排的研究

目的 探讨直肠癌旁移行粘膜中γδＴ细胞含量和受体基因重排表达情况与直肠癌局部复发之间的关系,方法 运用双色免疫荧光标记流式细胞仪分析法和多聚酶链反应技术,检测１３例中低位直肠癌患者的癌旁移行粘膜上皮淋巴细胞（ＴＭＬ）,肿瘤浸润淋巴细胞（ＴＩＬ）,正常直肠粘膜上皮淋巴细胞（ＩＥＬ）中γδＴ细胞含量,γδＴ细胞受体δ链可变区（γδ－ＴＣＲＶδ）基因重排表达。结果 ＴＭＬ中γδＴ细胞的含量显著地高于ＴＩ     

胆管癌TMS1/ASC基因甲基化及其临床意义

肿瘤发生是多基因协同作用、多因素共同参与、综合发展的结果。研究发现肿瘤抑制基因失活与其启动子区域表遗传性改变即CpG岛甲基化状态直接关联;因此CpG岛甲基化在肿瘤发生、发展过程中发挥着关键作用。TMS1/ASC基因是近年发现     

Significance of p53 gene abnormalities in carcinogenesis of human gastrointestinal tract]

Allelic loss and mutation of the p53 gene are common events of esophageal, gastric and colorectal cancers occurring from an early stage. Moreover, p53 mutation takes place in intestinal metaplasia and adenoma of the stomach. p53 mutation spectra differ among esophageal, gastric and colorectal cancers suggesting exposure to different endogenous and exogenous mutagens. The in vivo and in vitro results indicate that the clonal expansion of p53 mutant cell may be associated with tumor progression. Although wild type p53 transfection technique may provide for cancer therapy, there is a rather serious problem about it.     

p53,p21在乳癌中的表达及意义

目的 探讨p53,p21蛋白在乳癌中表达的临床意义。方法 用免疫组化SP法对20例癌旁乳腺组织和69例乳癌组织中p53和p21蛋白进行半定量检测。结果 癌旁乳腺组织中p53和p21表达阴性;乳腺癌组织中p53和p21阳性率分别为47．8％和43．5％;随细胞分化程度降低;p53表达阳性率明显升高,p21表达的阳性率明显降低。p21表达的阳性率在有、无淋巴结转移组差异显著（P＜0．05）;p53阳性、p21阴性组术后5年无瘤生存率明显低于p53阴性、p21阳性组（P＜0．05）;在乳癌组织中p21表达与p53明显相关（P＜0．05）。结论 p53和p21在乳癌中的表达可判断乳癌细胞分化程度及患者预后。     

抑癌基因PLAGL1在人肝细胞癌中的表达及其意义

目的 探讨抑癌基因PLAGL1在人肝细胞癌和癌旁组织中的表达及其意义.方法 随机选取肝细胞癌(HCC)30例和远离癌组织的癌旁组织30例,免疫组织化学分析PLAGL1蛋白表达,分析其意义.培养正常肝细胞株L02和肝癌细胞株HepG2细胞,采用逆转录-聚合酶链反应(RT-PCR)方法检测其PLAGL1 mRNA表达水平.探讨与肝癌细胞组织中PLAGL1蛋白表达相关性.结果 PLAGL1蛋白在癌旁组织中表达明显强于肝细胞癌组织,2例(7%)肝细胞癌组织中PLAGL1表达成阳性,27例(90%)癌旁组织中表达成阳性,两组之间PLAGL1的表达水平差异有统计学意义(χ2=38.44,P<0.05).RT-PCR结果显示PLAGL1 mRNA在L02细胞中明显高于HepG2细胞.结论 PLAGL1蛋白的表达下调可能与肝细胞癌的发生和发展相关,PLAGL1蛋白表达下降与PLAGL1 mRNA下调相平行.     

p16基因和p21基因表达异常与膀胱癌预后的Meta分析

目的探讨p16基因和p21基因表达异常对膀胱癌预后的影响.方法以“bladder carcinoma”或“bladder neoplasm”、“prognosis”、“p16”/“p21”和“膀胱癌”、“预后”等为检索词,检索Medline、PubMed、中国生物医学文献及中国学术期刊数据库有关p16基因和p21基因表达异常与膀胱癌预后的文献,应用Meta分析Dersimonian-Laird模型对这些文献进行综合定量评价.结果纳入Meta分析的19篇文献累计病例1584例,阳性率40.4%;其中p16基因表达异常12篇,累计病例975例,阳性率37.4%;p21基因异常表达7篇,累计病例609例,阳性率45.4%.p16基因表达异常、p21基因表达异常、p16基因和p21基因表达异常与膀胱癌预后的合并RH值分别为3.70（95%CI 3.42～3.99）、3.01（95%CI 2.81～3.21）和3.18（95%CI 3.01～3.35）.结论p16基因和p21基因表达异常是膀胱癌患者预后不良的生物标记物,有助于膀胱癌的治疗决策.     

Significance of retinoblastoma and mdm2 gene expression as prognostic markers for soft-tissue sarcoma

The growth regulatory function of the retinoblastoma protein (RB) can be suppressed by mdm2 via RB/mdm2 interaction by perturbation of the RB suppression of the E2F function. The goal of this study was to examine the clinical value of immunohistochemical (IHC) RB detection and its relationship to mdm2 overexpression in a cohort of 198 adult primary soft-tissue sarcomas (STS). RB overexpression reveals, multivariately, a correlation with survival (RR = 1.59, P = 0.037) as well as mdm2 positivity (RR = 2.32, P = 0.0035). Stratification of RB results to mdm2 staining shows a prognostic graduation in four levels. Patients with positivity for both antibodies have the highest risk (RR = 3.30, P = 0.002) and the poorest prognosis (projected 5-year survival rate, 18.6%); those with negativity for both antibodies show the most favourable prognosis (projected 5-year survival rate, 63.4%). Intermediately, an isolated RB overexpression (projected 5-year survival rate, 46.1%) is more favourable than an isolated mdm2 positivity (projected 5-year survival rate, 33.5%). To sum up, this study proves that RB and mdm2 overexpression have an individual and also an additive effect on prognosis in STS. Received: 3 June 1997     

乳癌p53与雌、孕激素受体的表达及临床意义

目的 探讨乳癌p53与雌、孕激素受体的表达及其临床意义。方法 应用免疫组化技术PAP法，测定200例乳癌的p53与雌、孕激素受体。结果 p53( )，雌激素受体（ER）（＋），孕激素受体（PR）（＋）分别为34.0%,63.0%和64.0%。ER（＋）及PR（＋）共96例，ER（－）及PR（－）共35例，ER和PR表达一致率为79.0%。显示上述三指标的阳性表达与病人腋淋巴结转移、病理组织类型无关，但与病人年龄、月经状况有关。结论 乳癌p53阳性预后差，ER及PR阳性比阴性的患者预后好，p53，ER和PR测定有助于指导乳癌的临床治疗和判断预后。     

Significance of the CAG repeat polymorphism of the androgen receptor gene in prostate cancer progression

PURPOSE: The CAG repeat polymorphism of the androgen receptor gene has been associated with an increased prostate cancer risk, and the repeat length correlated with cancer stage and grade at presentation. Men with an allele length of 18 CAG repeats, controlling for grade, stage and serum PSA level at diagnosis using Cox proportional hazard modeling. RESULTS: Overall, the CAG repeat allele was not predictive of recurrence; tumor grade, stage and PSA level at diagnosis were the only predictors of recurrence in a multivariate analysis. However, for patients at low risk for recurrence (Gleason score 2 to 6, stage pT2, and PSA 18 CAG repeats. In contrast, for patients at high risk of recurrence (Gleason score >/= 7, stage pT3/4, or PSA >10 ng./ml.), the relative risk associated with the 18 CAG repeat allele. CONCLUSIONS: The length of the CAG repeat polymorphism of the androgen receptor gene may be important for prostate cancer recurrence among patients who are otherwise at low risk for recurrence after radical prostatectomy. These findings have potential implications for patient selection for adjuvant treatment, and for the development of novel treatments.     

乳癌组织中GST-Pi,ToPoII和PgP 耐药基因的表达

目的 探讨乳癌组织中GST－Pi，ToPoII和PgP耐药基因的表达及其生物学意义。方法 采用即用型免疫组化微波加热法，检测52例乳癌GST－Pi，ToPoII和PgP耐药基因。结果 （1）52例乳癌中的GST－Pi，ToPoII和PgP的阳性表达率分别为50.0%(26/52),17.3%(9/52)和11.5%(6/52);(2）浸润性导管癌对三种耐药基因均呈不同程度的阳性表达，较其它组织学类型的乳癌的耐药基因更为广泛。（3）乳癌中的GST－Pi，ToPoII和PgP阳性表达大多与年龄无明显关系，但40－49岁和60－69岁年龄组的三种耐药基因阳性表达较其他年龄组为高。结论 （1）部分乳癌患者的体内存在多向耐药基因，或癌细胞内（原发）存在GST－Pi，ToPoII和PgP，对抗癌药物已产生耐药性。（2）对乳癌患者在中前进行耐药基因检测，有助于联合用药的合理选择、提高疗效及延长患者生存期。     

尿脱落细胞CD44基因变异表达产物对膀胱癌诊断价值的研究

应用逆转录－聚合酶链反应和Ｓｏｕｔｈｅｒｎ印迹杂交技术对３０例尿液标本脱落细胞ＣＤ４４基因含Ｖ６外显子的表达产物进行检测，并与尿细胞检查结果进行比较。结果显示：９０％的膀胱癌尿脱落细胞均检测到ＣＤ４４基因含Ｖ６外显子的拼接变异转录物的过量表达；