Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis
Two distinct tumor suppressor loci within chromosome 11p15 implicated in breast cancer progression and metastasis
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DOI：
10.1093/hmg/7.5.895
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发表时间：
1998-05-01
影响因子：
3.5
通讯作者：
Chen, P
中科院分区：
文献类型：
--
作者：
Karnik, P;Paris, M;Chen, P
染色体11 p15已经引起了相当大的关注，因为该区域对人类疾病的生物学重要性。除了是在几种成人和儿童癌症中显示杂合性丢失（洛杂合性丢失）的重要肿瘤抑制基因座外，连锁分析还表明11 p15含有贝克威斯-维德曼综合征的基因。此外，已知的印迹基因在11p15.5区域的聚类表明，目标基因也可能是印迹的。然而，定位克隆的努力，以确定目标基因已经复杂的大尺寸（类似于10 Mb）和复杂的洛合性缺失在11 p15。在这里，我们分析了94个匹配的正常和乳腺肿瘤样本使用17个多态性标记，映射到11p15.5-15.4。我们已经精确地定义了11p15.5内标记D11 S1318和D11 S4088（类似于500 kb）之间的乳腺肿瘤抑制基因的位置。该区域的洛缺失发生率与所分析的乳腺肿瘤的35-45%相似。此外，我们还精确定位了洛缺失的第二个关键区域，该区域位于11 p15.5-p15.4的标记物D11 S133-D11 S1323（类似于336 kb），该区域在55-60%的乳腺肿瘤中丢失。这两个11 p位点的缺失与乳腺肿瘤的临床和组织病理学特征有显著的相关性。区域1的洛缺失与早期恶性肿瘤和侵袭性显著相关（P = 0.016），相反，更近端区域2的缺失高度预测侵袭性转移性疾病（P = 0.012）。因此，染色体11 p15上的两个不同的肿瘤抑制基因座可能有助于乳腺癌的肿瘤进展和转移。这个有趣的染色体区域的精细定位应该有助于靶基因的克隆，并为理解导致成人和儿童癌症演变的机制提供关键线索。
Chromosome 11p15 has attracted considerable attention because of the biological importance of this region to human disease. Apart from being an important tumor suppressor locus showing loss of heterozygosity (LOH) in several adult and childhood cancers, 11p15 has been shown by linkage analysis to harbor the gene(s) for the Beckwith-Wiedemann syndrome. Furthermore, the clustering of known imprinted genes in the 11p15.5 region suggests that the target gene may also be imprinted. However, positional cloning efforts to identify the target genes have been complicated by the large size (similar to 10 Mb) and complexity of LOH at 11p15. Here, we have analyzed 94 matched normal and breast tumor samples using 17 polymorphic markers that map to 11p15.5-15.4. We have defined precisely the location of a breast tumor suppressor gene between the markers D11S1318 and D11S4088 (similar to 500 kb) within 11p15.5. LOH at this region occurred in similar to 35-45% of breast tumors analyzed. In addition, we have fine-mapped a second, critical region of LOH, that spans the markers D11S133-D11S1323 (similar to 336 kb) at 11p15.5-p15.4, that is lost in similar to 55-60% of breast tumors. There is a striking correlation between the loss of the two 11p loci and the clinical and histopathological features of breast tumors. LOH at region 1 correlated significantly (P = 0.016) with early events in malignancy and invasiveness, in contrast, the loss of the more proximal region 2, is highly predictive (P = 0.012) of aggressive metastatic disease. Thus, two distinct tumor suppressor loci on chromosome 11p15 may contribute to tumor progression and metastasis in breast cancer. The fine mapping of this intriguing chromosomal region should facilitate the cloning of the target genes and provide critical clues to understanding the mechanisms that contribute to the evolution of adult and childhood cancers.