MOLECULAR CYTOGENETICS OF HUMAN BREAST-CANCER
MOLECULAR CYTOGENETICS OF HUMAN BREAST-CANCER
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DOI：
10.1101/sqb.1994.059.01.074
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发表时间：
1994-01-01
期刊：
影响因子：
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通讯作者：
WALDMAN, F
中科院分区：
文献类型：
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作者：
GRAY, JW;COLLINS, C;WALDMAN, F
人类实体瘤通过多种有利的遗传异常的积累而进展是公认的。可能涉及的基因包括那些影响增殖率的基因（Murray 1992; Weinert和Lydall 1993），细胞凋亡（绿色等人，1994年;克尔等人，1994年），遗传稳定性和/或DNA修复保真度（Hartwell 1992; Bronner等1994; Fishel等1993），分化（Sell和Pierce 1994）、粘连（Juliano和Varner 1993;伯恩斯坦和Liotta 1994）和血管生成（Harris和Horak 1993; Horak等1993; Weinstat-Saslow和Steeg 1994）。这些基因可以是显性的或隐性的，并且它们可以通过扩增、结构重排或易位而被差异调节，或者通过丢失和/或突变而失活。此外，有证据表明，平均而言，某些异常比其他异常发生得更早（Fearon and Vogelstein 1990; Bullerdiek et al. 1994）。这一点很重要，因为筛查早期异常可能有助于癌症检测，而检测后期异常可能提供有关疾病进展程度的信息。这些基因的表征可能揭示进展过程的生物学信息，这将提示新的治疗可能性。遗传进展过程在结肠癌中得到最好的理解，其中涉及APC或KRS的异常似乎平均发生在早期，其次是涉及p53和DCC的异常（Fearon和Vogelstein 1990）。对于其他肿瘤，如乳腺癌，这一点还不太清楚，因为癌症进展的形态学和组织学指标并不明显。尽管如此，细胞遗传学研究，杂合性缺失（洛）分析，和基因剂量分析Southern分析揭示了许多异常，可能参与人类乳腺癌的进展。迄今为止涉及的基因包括Her-2/neu（Slamon et al. 1987; Lupu and Lippman 1993）、c-MYC（Galley et al. 1993）、细胞周期蛋白-D（吉莱特et al. 1994）和EMS（Karlseder et al. 1994）的扩增以及细胞周期调控基因如p53和RB 1（步行者and Varley 1993）的失活。然而，许多（如果不是大多数）与乳腺癌进展有关的遗传异常仍有待发现。基因扩增是导致基因表达上调的一种常见机制（Stark等，1989）。事实上，最近的一项细胞遗传学研究表明，超过50%的人类乳腺癌发生了显著扩增，并且大多数相关区域与已知癌基因无关（Saint-Ruf et al. 1990）。洛分析显示lp和q处的损失（博格等人，1992年; Bieche等人，1993年; Leger等人，1993年），3页13 -14（Chen等人，1994年），11页13（Winqvist等人，1993年），13 q（Thorlacius等，1991），16 q22 -23（Cleton-Jansen et al. 1994; Tsuda et al. 1994）、17 p13（Matsumura et al. 1992;凯西et al. 1993）、17 q21（Cropp et al. 1993）和18 q。其中一些区域，如17 p13、13 q14和18 q（Thompson et al. 1993），分别含有已知的癌基因，如p53、RB 1和DCC。此外，已证实遗传性乳腺癌与17 q21遗传标记之间存在关联（BRCA 1; Cropp et al. 1994）。然而，大多数异常区域的相关基因是未知的。荧光原位杂交（FISH）（Lichter等，1988; Pinkel等，1988）和比较基因组杂交（CGH）（A. Kallioniemi et al. 1992 a; Ried et al. 1994）提供了关于人类乳腺癌遗传变化的额外信息。CGH是有用的，因为它提供了基因拷贝数异常的单位变化的全基因组视图，涉及超过约10个单位。
Progression of human solid tumors through accumulation of multiple advantageous genetic abnormalities is well established. Genes that may be involved include those that influence proliferation rate (Murray 1992; Weinert and Lydall 1993), apoptosis (Green et al. 1994; Kerr et al. 1994), genetic stability and/or DNA repair fidelity (Hartwell 1992; Bronner et al. 1994; Fishel et al. 1993), differentiation (Sell and Pierce 1994), adhesion (Juliano and Varner 1993; Bernstein and Liotta 1994), and angiogenesis (Harris and Horak 1993; Horak et al. 1993; Weinstat-Saslow and Steeg 1994). These genes may be either dominant or recessive, and they may be differentially regulated through amplification, structural rearrangement, or translocation, or inactivated through loss and/or mutation. In addition, there is evidence that some abnormalities, on average, occur earlier than others (Fearon and Vogelstein 1990; Bullerdiek et al. 1994). This is important since screening for early abnormalities may facilitate cancer detection, and detection of later abnormalities may provide information about the extent of disease progression. Characterization of these genes may reveal information about the biology of the progression process that will suggest new therapeutic possibilities. The genetic progression process is best understood in colon cancer where abnormalities involving APC or KRS seem, on average, to occur early, followed by abnormalities involving p53 and DCC (Fearon and Vogelstein 1990). It is less well understood for other tumors, such as breast cancer, because morphological and histological indicators of cancer progression are not as distinct. Nonetheless, cytogenetic studies, analyses of loss of heterozygosity (LOH), and gene dosage analyses by Southern analysis have revealed numerous abnormalities that may be involved in the progression of human breast cancer. Genes so far implicated include amplifications of Her-2/neu (Slamon et al. 1987; Lupu and Lippman 1993), c-MYC (Galley et al. 1993), cyclin-D (Gillett et al. 1994), and EMS (Karlseder et al. 1994) and inactivation of cell cycle regulatory genes such as p53 and RB1 (Walker and Varley 1993). However, many, if not most, of the genetic abnormalities involved in breast cancer progression remain to be discovered. Gene amplification is one common mechanism leading to up-regulation of gene expression (Stark et al. 1989). In fact, a recent cytogenetic study indicates that significant amplification occurs in more than 50% of human breast cancers and that most of the involved regions are not associated with known oncogenes (Saint-Ruf et al. 1990). Analyses of LOH show loss at lp and q (Borg et al. 1992; Bieche et al. 1993; Leger et al. 1993), 3p13-14 (Chen et al. 1994), 11p13 (Winqvist et al. 1993), 13q (Thorlacius et al. 1991), 16q22-23 (Cleton-Jansen et al. 1994; Tsuda et al. 1994), 17p13 (Matsumura et al. 1992; Casey et al. 1993), 17q21 (Cropp et al. 1993), and 18q. Some of these regions, eg, 17p13, 13q14, and 18q (Thompson et al. 1993), contain known cancer genes, eg, p53, RB1, and DCC, respectively. In addition, linkage has been demonstrated between heritable breast cancer and genetic markers at 17q21 (BRCA1; Cropp et al. 1994). However, the involved genes are unknown for most regions of abnormality. Fluorescence in situ hybridization (FISH)(Lichter et al. 1988; Pinkel et al. 1988) and comparative genomic hybridization (CGH)(A. Kallioniemi et al. 1992a; Ried et al. 1994) yield additional information about genetic changes in human breast cancer. CGH is useful because it provides a genome-wide view of unit changes in gene copy number abnormalities that involve more than about 10 …