Suzuki H, Freije D, Nusskern D R, Okami K, Cairns P, Sidransky D, Isaacs W B, Bova G S
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-2411, USA.
Cancer Res. 1998 Jan 15;58(2):204-9.
The long arm of chromosome 10 is frequently affected by allelic loss in prostate cancer. PTEN/MMAC1, a candidate tumor suppressor gene located at 10q23.3, a region commonly deleted in prostate cancer, was recently identified and found to be deleted or mutated in cancer cell lines derived from a variety of human tissues including prostate. To examine the role of PTEN/MMAC1 in the progression of prostate cancer, we screened a unique set of 50 metastatic prostate cancer tissues from 19 cancer-death patients for alterations in the PTEN/MMAC1 gene, using single-strand conformational polymorphism analysis and direct sequencing to identify sequence changes and microsatellite analysis to examine allelic loss in the vicinity of PTEN/MMAC1. Overall, gene alterations (deletions or point mutations) were observed in at least 1 metastatic site in 12 of the 19 patients studied. Two cases had homozygous deletions that were confirmed by fluorescence in situ hybridization analysis. Four patients harbored point mutations, with one mutation being found in all four tumors (a primary lesion and three different metastases) from the same patient. The remaining three mutations were detected in only one of multiple metastases. Loss of heterozygosity was found in 10 of 18 informative cases, with 1 case showing a unique pattern of microsatellite instability in each of six different metastases examined. Loss of the same allele was found in all metastases in a given patient in 9 of 10 cases. These results indicate that PTEN/MMAC1 gene alterations occur frequently in lethal prostate cancer, although a substantial amount of mutational heterogeneity is found among different metastatic sites within the same patient. These latter findings emphasize the potentially complex genetic relationship that can exist between various clonal lineages of prostate cancer cells as they evolve during the metastatic process and suggest a molecular basis for phenotypic heterogeneity of different prostate cancer foci in patients with disseminated disease.
10号染色体长臂在前列腺癌中常因等位基因缺失而受到影响。PTEN/MMAC1是一个候选肿瘤抑制基因，位于10q23.3，这是前列腺癌中常见的缺失区域，最近被鉴定出来，并且在来源于包括前列腺在内的多种人体组织的癌细胞系中发现该基因被缺失或发生突变。为了研究PTEN/MMAC1在前列腺癌进展中的作用，我们使用单链构象多态性分析和直接测序来鉴定序列变化，并通过微卫星分析来检测PTEN/MMAC1附近的等位基因缺失，对来自19例癌症死亡患者的一组独特的50个转移性前列腺癌组织进行了PTEN/MMAC1基因改变的筛查。总体而言，在所研究的19例患者中，有12例在至少1个转移部位观察到基因改变（缺失或点突变）。2例经荧光原位杂交分析证实为纯合缺失。4例患者存在点突变，其中1例突变在同一患者的所有4个肿瘤（1个原发灶和3个不同转移灶）中均被发现。其余3个突变仅在多个转移灶中的1个中检测到。在18例信息充足的病例中，有10例发现杂合性缺失，其中1例在检测的6个不同转移灶中的每一个中均表现出独特的微卫星不稳定性模式。在10例患者中的9例中，在给定患者的所有转移灶中均发现相同等位基因的缺失。这些结果表明，PTEN/MMAC1基因改变在致命性前列腺癌中频繁发生，尽管在同一患者的不同转移部位发现了大量的突变异质性。后一项发现强调了前列腺癌细胞的各种克隆谱系在转移过程中进化时可能存在的潜在复杂遗传关系，并为播散性疾病患者不同前列腺癌病灶的表型异质性提供了分子基础。
