骨髓增生异常综合征的遗传学研究进展

骨髓增生异常综合征(MDS)是起源于造血干细胞的恶性克隆性疾病,包括一组以骨髓无效造血、病态造血改变、克隆性染色体异常和高风险向急性髓性白血病(AML)转化的临床表现高度异质性疾病。目前认为,MDS临床表现的异质性很可能是由于基因不稳定性引起的,这种基因不稳定性主要表现在细胞遗传学异常、基因突变以及表观遗传学异常等〔1-2〕。随着遗传学技术的更新,近几年     

DNA甲基化在结直肠癌诊疗中的应用前景

目前认为结直肠癌的发生是在环境因素的作用下通过遗传学和表观遗传学的累积性改变所致。表观遗传学修饰,特别是基因启动子区域的DNA甲基化,被认为是肿瘤中普遍发生的分子改变。因此可通过检测基因的异常甲基化等表观遗传学改变对结直肠癌进行预防、早期诊断、临床治疗及预后评价。本文论述了结直肠癌相关基因甲基化状态的研究进展以及表观遗传学的临床应用,目的在于探讨表观遗传学在结直肠癌早期诊断及治疗中的意义。     

肿瘤表观基因型在临床中的应用

肿瘤不仅是遗传性疾病,同时也是由基因转录沉默所引起的表观遗传学性疾病.表观遗传学(epigenetics)是研究不涉及DNA序列变化的、可遗传的基因表达调控方式的一门科学.肿瘤中表观遗传学的改变包括影响基因差异表达的DNA甲基化、组蛋白乙酰化/组蛋白去乙酰化和染色质重塑等几个方面,表观基因型(epigenotype)是描述有共同基因型的不同类型细胞的基因表达模式和基因失活模式,表观遗传学机制决定了表观基因型的形成.肿瘤表观遗传学机制贯穿肿瘤发生、发展的整个过程,并具有一定的广泛性和组织特异性,因此认识肿瘤中表观基因型将对肿瘤的临床诊断、治疗和预防有着重要的指导意义.     

Raf激酶抑制蛋白(RKIP)基因与肿瘤的研究进展

肿瘤的发生、发展和转移是一个高度复杂的过程。基因的点突变、染色体易位、致癌基因的扩增、抑制基因的丧失都是导致癌变的主要原因。研究表明,促进肿瘤形成的遗传因素包括遗传学机制和表观遗传学机制两大类。细胞突变由DNA核苷酸序列改变而引起的称为遗传学改变;基因表达水平的变化由碱基修饰的改变而引起的称为表观遗传学改变。这两种改变相互交错存在,共同促进肿瘤的形成。除了上述因素外,信号     

DNA甲基化与结肠癌

DNA异常甲基化是肿瘤常见的表观遗传学改变.广泛的低甲基化和区域性高甲基化是基因异常表达的常见机制.某些基因异常甲基化与结肠癌发生密切相关,且常见于结肠癌发病早期.     

去甲基化药物治疗骨髓增生异常综合征的最新进展

骨髓增生异常综合征是一组异质性很强的造血干细胞的克隆性疾病。近年来随着表观遗传学概念和理论的建立,越来越多的证据表明表观遗传学的改变可能在MDS发生发展中起到重要作用。基因的表观遗传学异常可通过抑制DNA甲基转移酶（DNMT）恢复已沉默基因的表达,这可能是临床应用去甲基化药物治疗MDS理论依据之一。虽然目前去甲基化药物的具体作用机制尚未完全阐清,     

SFRP基因甲基化与消化系肿瘤相关性的研究进展

DNA启动子异常甲基化是人类基因组一种最常见的表观遗传学修饰改变,与肿瘤的发生发展及预后密切相关.分泌型卷曲相关蛋白(secreted frizzled-related proteins,SFRPs)作为Wnt信号通路的拮抗因子,在多种肿瘤中常由于其启动子的高甲基化而致该基因的表达沉默,从而减弱对Wnt信号通路的抑制作用,使得Wnt信号通路异常激活,促进了肿瘤的发生与发展.本文就SFRP基因甲基化在消化系肿瘤中的研究作一综述.     

胃癌的表观遗传学研究

胃癌高度恶性且预后较差,目前随着对胃癌基础研究的不断深入,表观遗传学改变在胃癌发生发展中的重要作用逐渐被人们认识,因此可通过检测基因的异常甲基化等表观遗传学改变对胃癌进行早期诊断、治疗及预后评价。本文总结分析胃癌相关基因甲基化状态及表观遗传学的临床应用前景,以期探讨表观遗传学对胃癌的早期诊断及治疗的指导作用。     

食管癌表观遗传调控机制研究进展

近年来随着对肿瘤研究的深入,人们发现DNA序列以外的表观遗传调控异常在肿瘤的发生、发展过程中更为普遍、也更为重要。这种基于非基因序列改变所致基因表达水平变化的表观遗传学研究,包含了DNA甲基化、染色质组蛋白修饰、隔离蛋白及非编码RNA等调控方式。异常的表观遗传机制影响基因的转录,贯穿肿瘤发生、发展的整个过程,并具有一定的广泛性和组织特异性。食管癌是最常见的恶性肿瘤之一,开展食管癌表观遗传研究为其诊断、治疗和预防等方面提供了新思路。     

遗传学及表观遗传学改变在骨髓增生异常综合征中的临床意义

骨髓增生异常综合征(MDS)是起源于造血干细胞异常改变的克隆性疾病。细胞遗传学异常如5q-、-7和7q-、20q-等分子遗传学异常如各种融合基因、抑癌基因缺失等及表观遗传学改变如抑癌基因异常甲基化等对MDS的明确诊断、预后分析及靶向治疗有着极其重要的价值。明确MDS发生发展及转归的分子机制对于寻求新的诊断及治疗靶点有重要意义。     

Diverse karyotypic abnormalities of the c-myc locus associated with c-myc dysregulation and tumor progression in multiple myeloma

Translocations involving c-myc and an Ig locus have been reported rarely in human multiple myeloma (MM). Using specific fluorescence in situ hybridization probes, we show complex karyotypic abnormalities of the c-myc or L-myc locus in 19 of 20 MM cell lines and approximately 50% of advanced primary MM tumors. These abnormalities include unusual and complex translocations and insertions that often juxtapose myc with an IgH or IgL locus. For two advanced primary MM tumors, some tumor cells contain a karyotypic abnormality of the c-myc locus, whereas other tumor cells do not, indicating that this karyotypic abnormality of c-myc occurs as a late event. All informative MM cell lines show monoallelic expression of c-myc. For Burkitt's lymphoma and mouse plasmacytoma tumors, balanced translocation that juxtaposes c-myc with one of the Ig loci is an early, invariant event that is mediated by B cell-specific DNA modification mechanisms. By contrast, for MM, dysregulation of c-myc apparently is caused principally by complex genomic rearrangements that occur during late stages of MM progression and do not involve B cell-specific DNA modification mechanisms.     

Cellular DNA content as a marker of neoplasia in man

Cellular DNA content was determined by means of flow cytometry with the use of DNA specific fluorochromes (ethidium bromide and mithramycin) in 516 human tissue samples from 440 subjects. Compared to human granulocytes as diploid reference standard, there was a 91 percent incidence of DNA content abnormality difference in DNA content of tumor G${}_{\mathrm{<mtext>1</mtext><mtext>0</mtext>}}$ cells indicating aneuploidy in 118 patients with neoplastic disease (including nine patients who lacked histopathologic evidence of malignancy at the time of study). Ninety-four percent of aneuploid tumors were hyperdiploid. Except for six solid tumors with biclonal abnormalities in DNA content, the remainder of neoplasms were characterized by uniform DNA content with little dispersion (small coefficient of variation of tumor G${}_{\mathrm{<mtext>1</mtext><mtext>0</mtext>}}$ populations). For the entire group of patients with malignant disease, three modal values of DNA content were recognized at low-degree hyperdiploidy, near triploidy and tetraploidy. Except for the prevalence of high-degree hyperdiploidy in melanomas and low-degree hyper- and hypodiploid abnormalities in malignant lymphomas, significant disease-specific patterns of abnormal DNA content were not apparent. The magnitude of ploidy abnormality was further influenced by patient age and proliferative activity of the tumor. Female patients displayed a preponderance of small-degree hyperdiploid and tetraploid tumors, whereas near-triploid abnormalities prevailed among male patients, who also harbored five of six biclonal tumors. Tumor cell ploidy did not vary among different sites of disease and upon sequential long-term follow-up examination. All 121 benign tumors had a diploid DNA content. Among the group of 209 patients with normal histology or reactive changes were seven patients with a previously established diagnosis of cancer with ploidy abnormality. This discrepancy indicates that monodispersal of the entire tissue aliquot for DNA flow cytometry is superior to histologic examination of focal neoplasia. There were two patients, one with recurrent benign pleural effusions and one with reactive lymphadenopathy, with ploidy abnormality by DNA content in whom malignant lymphoma developed. We conclude that flow cytometry of cellular DNA content is a rapid, objective, quantitative and sensitive method to determine a highly specific and stable tumor cell marker.     

Renal clear-cell carcinoma with X;1 translocation revealed by microscopic hematuria in a 23-year-old woman

Microscopic hematuria is an uncommon inaugural sign of kidney tumors in young asymptomatic patients. Renal clear-cell carcinoma was diagnosed in a 23-year-old female explored for microscopic hematuria. Radical nephrectomy removed a 7-cm tumor without local extension. The cytogenic study of the tumor disclosed X;1 translocation. The patient also had IgA deficiency. Von Hippel-Lindau disease or a cytogenetic abnormality in the tumor are to be searched for in young adults with renal clear-cell carcinoma.     

DNA低甲基化与肿瘤的关系

DNA甲基化异常包括全基因组的低甲基化和局部基因的高甲基化。在肿瘤的发生、发展过程中,DNA低甲基化比高甲基化更为常见。DNA甲基化且与肿瘤类型、肿瘤分期及肿瘤侵袭的顺序中表现出相当的特异性。DNA低甲基化对肿瘤的早期诊断和预防有重要意义。     

A case of multiple myeloma presenting as giant chest wall tumors with calcification]

A 60-year-old man was admitted for investigation of an abnormality detected in chest radiography: a giant tumor with calcification in the right middle lung field. A computed tomography (CT) scan revealed multiple tumors with calcification on the posterior chest wall. Histological analysis of the tumor specimen obtained by surgical biopsy demonstrated an increasing number of plasma cells accompanied with the deposition of amyloid. A bone marrow biopsy contained over 50% of plasma cells. We therefore diagnosed these tumors as multiple myeloma. It has been reported that multiple myeloma is usually characterized by osteolytic lesions; osteosclerotic changes are rare. Multiple myeloma should be taken into account as one of the causes of a chest wall tumor even if it is diffusely calcified.     

Management of large adrenal glands discovered incidentally

Incidental adrenal tumors are more and more often discovered with development of the new radiological techniques (CT scan, sonography). In such an occurrence, the largest panel of adrenal hormones measurements is needed. In the absence of hormonal abnormality, no exam can help for the clinical decision-making. According to epidemiological findings, we propose to operate upon tumors larger than 6 cm and to repeat CT scans at 2, 6 and 18 months for tumors smaller than 6 cm which should be operated upon if an enlargement of the adrenal tumor is demonstrated by a control exam. This attitude relies upon the quite higher frequency of adrenal adenomas (more than 99% of non-functioning adrenal tumors) and the more important risk of malignant adrenal carcinoma in front of a huge tumor. It appears to be the right choice in a cost-effectiveness perspective.     

Cortisol suppression test in patients with elevated adrenocorticotropic hormone levels

Increased adrenocorticotropic hormone (ACTH) levels after bilateral adrenalectomy could be secondary to a pituitary tumor, under replacement with cortisol, or an abnormality in the hypothalamic-pituitary-adrenal feedback loop. To distinguish between these possibilities, ACTH levels were measured before and after cortisol infusion (20 mg/h for 4 hours) in five groups: normal volunteers; patients with idiopathic adrenal insufficiency; and with bilateral adrenalectomy for Cushing's syndrome with no roentgenographic evidence of pituitary tumor, with pituitary tumors, and with equivocal roentgenographic studies (suspect pituitary tumors). Control ACTH levels in all groups of patients were higher than in normal volunteers but there was overlapping. Cortisol infusion suppressed ACTH in all subjects but the reductions in the last two groups were less than in the first three. The cortisol suppression test appears to be useful in determining whether increased ACTH level after adrenalectomy is due to a pituitary tumor.     

Biological and molecular aspects of gastroenteropancreatic neuroendocrine tumors

Neuroendocrine tumors of the digestive tract are rare entities characterized by significant phenotype differences and traditionally considered to originate from cells of the diffuse endocrine system of the pancreas and gut. Two major categories with significant phenotype and clinical behavior differences are identified as well-differentiated and poorly differentiated tumors. Investigation on the molecular basis of tumor development points to an important role for the multiple endocrine neoplasia syndrome type-1 (MEN1) gene because of its frequent abnormality observed both in well-differentiated and poorly differentiated tumors. Other genes are possibly involved, though the available data need support from studies on larger series of tumors.     

Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors.

Neuroblastoma (NB), a tumor arising from the sympathetic nervous system, is one of the most common malignancies in childhood. Several recent reports on the p53 genotype found virtually exclusive wild-type status in primary tumors, and it was postulated that p53 plays no role in the development of NB. Here, however, we report that the vast majority of undifferentiated NBs exhibit abnormal cytoplasmic sequestration of wild-type p53. This inability of p53 to translocate to the nucleus presumably prevents the protein from functioning as a suppressor. Thirty of 31 cases (96%) of undifferentiated NB showed elevated levels of wild-type p53 in the cytoplasm of all tumor cells concomittant with a lack of nuclear staining. p53 immunoprecipitation from tumor tissues showed a 4.5- to 8-fold increase over normal protein levels. All of 10 tumors analyzed harbored wild-type p53 by direct sequencing of full-length cDNA and Southern blot. In addition, no MDM-2 gene amplification was seen in all 11 tumors analyzed. In contrast, no p53 abnormality was detected in 14 differentiated ganglioneuroblastomas and 1 benign ganglioneuroma. We conclude that loss of p53 function seems to play a major role in the tumorigenesis of undifferentiated NB. This tumor might abrogate the transactivating function of p53 by inhibiting its access to the nucleus, rather than by gene mutation. Importantly, our results suggest that (i) this could be a general mechanism for p53 inactivation not limited to breast cancer (where we first described it) and that (ii) it is found in a tumor previously not thought to be affected by p53 alteration.     

Rearrangement of the p53 gene in human osteogenic sarcomas.

p53 is a 53-kDa nuclear protein that is associated with malignant transformation in several tumor model systems. In a survey of 134 human carcinomas, sarcomas, leukemias, and lymphomas obtained at surgery or from peripheral blood, we found rearrangements of the p53 gene only in osteogenic sarcomas (3 of 6 osteogenic sarcomas examined). Normal tissue from one of these patients had an unrearranged gene, indicating that the genetic abnormality in the tumor was acquired. Two of the sarcomas with rearranged genes expressed levels of p53 protein that were elevated relative to other tumors. Rearranged p53 genes were also found in human osteogenic sarcoma cell lines.