Genetic and molecular markers of urothelial premalignancy and malignancy
Genetic and molecular markers of urothelial premalignancy and malignancy
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DOI：
10.1080/003655900750169338
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发表时间：
2000-01-01
影响因子：
--
通讯作者：
Sauter, G
中科院分区：
文献类型：
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作者：
Cordon-Cardo, C;Cote, RJ;Sauter, G
膀胱肿瘤的分子遗传学改变可分为原发性和继发性畸变。原发性分子改变可定义为与癌症发生直接相关的改变。这些通常被发现为唯一的异常，并且通常与特定的肿瘤有关。然后是涉及低级别/高分化肿瘤产生的特征性原发性异常，其使细胞增殖不稳定，但对细胞"社会"相互作用或分化以及细胞死亡或凋亡的速率几乎没有影响。其他分子事件导致高级别肿瘤，其破坏生长控制，包括细胞周期和凋亡，并且对生物学行为具有重大影响。一个主要的目标，导致低级别的乳头状浅表性膀胱肿瘤位于9号染色体，而p53基因的改变是常见的扁平原位癌。其他分子改变必须阐明，因为许多非侵袭性肿瘤既没有9号染色体也没有p53改变。利用组织显微切割技术和分子遗传学检测的新方法需要进一步阐明这一问题。继发性遗传或表观遗传异常可能是偶然的，也可能决定肿瘤的生物学行为。这些遗传改变的累积而不是顺序可能是赋予协同活性的关键因素。在这方面，值得注意的是，许多被改变的基因作用于两个公认的关键生长和衰老途径，TP53和RE。这些特定的分子畸变可能是特别重要的，以评估其在膀胱癌的管理中的使用，因为它们在疾病的进行性形式中的共性。因此，临床试验正在进行中，以探索它们在特定情况下的使用，特别是在局部晚期疾病的手术治疗中，并确定辅助化疗是否对此类患者有益。分子改变在非侵袭性膀胱肿瘤的治疗中的应用仍有待确定。我们对膀胱癌进展中重要的分子改变的认识还远未完成，需要进一步研究以进一步阐明进展和治疗反应中涉及的关键途径。根据癌前条件，识别和解释表型变化的意义的困难施加了一定的限制，因为在解释形态学标准时存在不断发展的命名和再现性问题。然而，涉及乳头状浅表性肿瘤中染色体9q和INK4A位点的分子改变与扁平原位癌病变中染色体14q和8q，p53和RE的变化可能表明导致尿路上皮肿瘤发生不同途径的早期事件的分子基础。研究旨在揭示遗传不稳定性的临床相关性，以及分子或表观遗传学改变，在尿路上皮和癌前病变，否则形态正常的外观需要进一步推进知识在该领域。膀胱癌的临床进展将促进新的动物模型平行的人类疾病。分子诊断学，特别是特异性抗原表达，荧光原位杂交和微卫星分析，已显示出很大的前景作为筛选和后续的方法，并可能补充尿细胞学在诊断和表征新的和复发性疾病。此外，使用高通量基因组/蛋白质组学分析，与全面的数据库相关联，并与强大的生物信息学相结合，将是阐明膀胱肿瘤发生和癌症进展所涉及的调控和信号传导途径的组成部分的关键因素。
The molecular genetic changes reported in bladder tumors can be classified as primary and secondary aberrations. Primary molecular alterations may be defined as those directly related to the genesis of cancer. These are frequently found as the sole abnormality and are often associated with particular tumors. Then are characteristic primary abnormalities involved in the production of low-grade/well- differentiated neoplasms, which destabilize cellular proliferation but have little effect on cellular "social" interactions or differentiation, as well as the rate of cell death or apoptosis. Other molecular events lead to high-grade neoplasms which disrupt growth control, including the cell cycle and apoptosis, and which have a major impact on biological behavior. A primary target leading to low-grade papillary superficial bladder tumors resides on chromosome 9, while p53 gene alterations are commonly seen in flat carcinoma in situ. Other molecular alterations must be elucidated, as many non-invasive neoplasms have neither chromosome 9 nor p53 alterations. Novel approaches utilizing tissue microdissection techniques and molecular genetic assays are needed to shed further Light on this subject. Secondary genetic or epigenetic abnormalities may be fortuitous, or may determine the biological behavior of the tumor.Multiple molecular abnormalities are identified in most human cancers studied, including bladder neoplasms. The accumulation, rather than the order, of these genetic alterations may be the critical factor that grants synergistic activity. In this regard, it is noteworthy that many of the genes that are altered act upon the two recognized critical growth and senescence pathways, TP53 and RE. These particular molecular aberrations may be especially important to evaluate for their use in the management of bladder cancer because of their commonality in progressive forms of the disease. Thus, clinical trials are underway to explore their use in specific situations, particularly in the surgical management of locally advanced disease, and to determine whether adjuvant chemotherapy in such patients may be of benefit. The use of molecular alterations in the management of non-invasive bladder neoplasms remains to be firmly established. Our knowledge of molecular alterations important in bladder cancer progression is far from complete, and further study is necessary to further elucidate crucial pathways involved in progression and therapeutic response.As per preneoplastic conditions, difficulties in identifying and interpreting the significance of phenotypic changes have imposed certain Limitations, as has an evolving nomenclature and issues of reproducibility in interpreting morphological criteria. Nevertheless, molecular alterations involving chromosome 9q and the INK4A locus in papillary superficial tumors vs changes in chromosomes 14q and 8q, p53 and RE in flat carcinoma in situ lesions may indicate a molecular basis for early events that lead to varying pathways in urothelial tumorigenesis. Studies aimed at revealing the clinical relevance of genetic instability, as well as molecular or epigenetic alterations, in urothelium and preneoplastic lesions of otherwise morphologically normal appearance are needed to further advance knowledge in the field.Clinical advances in bladder cancer will be facilitated by novel animal models paralleling the human disease. Molecular diagnostics, particularly specific antigen expression, fluorescence in situ hybridization and microsatellite analyses, have shown great promise as screening and follow-up methodologies, and may supplement urine cytology in the diagnosis and characterization of new and recurrent disease. In addition, the use of high-throughput genomic/proteomic assays, linked to comprehensive databases, and coupled with robust bioinformatics will be key elements in elucidating the components of regulatory and signaling pathways involved in bladder tumorigenesis and cancer progression.