Majewski Tadeusz, Lee Sangkyou, Jeong Joon, Yoon Dong-Sup, Kram Andrzej, Kim Mi-Sook, Tuziak Tomasz, Bondaruk Jolanta, Lee Sooyong, Park Weon-Seo, Tang Kuang S, Chung Woonbok, Shen Lanlan, Ahmed Saira S, Johnston Dennis A, Grossman H Barton, Dinney Colin P, Zhou Jain-Hua, Harris R Alan, Snyder Carrie, Filipek Slawomir, Narod Steven A, Watson Patrice, Lynch Henry T, Gazdar Adi, Bar-Eli Menashe, Wu Xifeng F, McConkey David J, Baggerly Keith, Issa Jean-Pierre, Benedict William F, Scherer Steven E, Czerniak Bogdan
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Lab Invest. 2008 Jul;88(7):694-721. doi: 10.1038/labinvest.2008.27. Epub 2008 May 5.
The search for the genomic sequences involved in human cancers can be greatly facilitated by maps of genomic imbalances identifying the involved chromosomal regions, particularly those that participate in the development of occult preneoplastic conditions that progress to clinically aggressive invasive cancer. The integration of such regions with human genome sequence variation may provide valuable clues about their overall structure and gene content. By extension, such knowledge may help us understand the underlying genetic components involved in the initiation and progression of these cancers. We describe the development of a genome-wide map of human bladder cancer that tracks its progression from in situ precursor conditions to invasive disease. Testing for allelic losses using a genome-wide panel of 787 microsatellite markers was performed on multiple DNA samples, extracted from the entire mucosal surface of the bladder and corresponding to normal urothelium, in situ preneoplastic lesions, and invasive carcinoma. Using this approach, we matched the clonal allelic losses in distinct chromosomal regions to specific phases of bladder neoplasia and produced a detailed genetic map of bladder cancer development. These analyses revealed three major waves of genetic changes associated with growth advantages of successive clones and reflecting a stepwise conversion of normal urothelial cells into cancer cells. The genetic changes map to six regions at 3q22-q24, 5q22-q31, 9q21-q22, 10q26, 13q14, and 17p13, which may represent critical hits driving the development of bladder cancer. Finally, we performed high-resolution mapping using single nucleotide polymorphism markers within one region on chromosome 13q14, containing the model tumor suppressor gene RB1, and defined a minimal deleted region associated with clonal expansion of in situ neoplasia. These analyses provided new insights on the involvement of several non-coding sequences mapping to the region and identified novel target genes, termed forerunner (FR) genes, involved in early phases of cancer development.
识别涉及的染色体区域，特别是那些参与隐匿性癌前病变发展并进展为临床侵袭性浸润癌的区域的基因组失衡图谱，能够极大地促进对人类癌症相关基因组序列的搜索。将这些区域与人类基因组序列变异相结合，可能会为其整体结构和基因组成提供有价值的线索。由此延伸，此类知识可能有助于我们理解这些癌症发生和发展过程中潜在的遗传成分。我们描述了一种人类膀胱癌全基因组图谱的构建，该图谱追踪了膀胱癌从原位前驱病变到浸润性疾病的进展过程。使用一组包含787个微卫星标记的全基因组面板，对从膀胱整个黏膜表面提取的多个DNA样本进行等位基因缺失检测，这些样本分别对应正常尿路上皮、原位癌前病变和浸润性癌。通过这种方法，我们将不同染色体区域的克隆性等位基因缺失与膀胱癌的特定阶段进行匹配，绘制出了膀胱癌发展的详细遗传图谱。这些分析揭示了与连续克隆的生长优势相关的三大波遗传变化，反映了正常尿路上皮细胞逐步转变为癌细胞的过程。这些遗传变化定位到3q22 - q24、5q22 - q31、9q21 - q22、10q26、13q14和17p13的六个区域，这些区域可能代表驱动膀胱癌发展的关键靶点。最后，我们在13号染色体q14区域内使用单核苷酸多态性标记进行高分辨率定位，该区域包含典型的肿瘤抑制基因RB1，并确定了一个与原位肿瘤克隆性扩增相关的最小缺失区域。这些分析为映射到该区域的几个非编码序列的作用提供了新的见解，并鉴定出了参与癌症发展早期阶段的新靶基因，即先驱（FR）基因。
