High-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity
High-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity
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DOI：
10.1002/gcc.20080
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发表时间：
2004-11-01
影响因子：
3.7
通讯作者：
Shen, CY
中科院分区：
文献类型：
--
作者：
Yang, TL;Su, YR;Shen, CY
在乳腺癌中，染色体19p13区域存在较高频率的基因组缺失。特别有趣的是，LKBI基因(也称为STKII)已经被定位到这个区域。LKBI导致Peutz-Jeghers综合征(PJS)，这是一种以皮肤粘膜色素沉着和胃肠道血肿为特征的遗传病，患癌症(包括乳腺癌)的风险增加。为了进一步阐明染色体19p13.2-13.3区域在乳腺癌发病机制中的作用，并更准确地确定用于定位克隆研究的候选肿瘤抑制基因(TSG)，我们使用24个微卫星标记对140例原发性乳腺肿瘤标本进行了详细的高分辨率等位基因分型分析，以检测该区域的等位基因丢失或杂合性丢失(LOH)。D19S883(30%)和D19S216(29%)的LOH频率最高，均位于19p13.3，D19S922(28%)，19p13.3~19p13.2，D19S865(39%)，19p13.2；此外，还发现至少4个常见的缺失区，包括LKBI基因座，集中在这4个标记上。在所有的病例中，我们在同一肿瘤的几个19p13.2-13.3位点上发现了不连续的等位基因丢失(LOH频率最高的标记与保持杂合性的标记相邻)，这表明存在多个TSG。有趣的是，在肿瘤中，随着肿瘤进展到更差的级别，这些标记的等位基因丢失的程度(以分数等位基因丢失衡量)显著增加(P<；0.05)。我们得出结论，19p13.2-13.3等位基因缺失是乳腺癌发病机制中的常见事件，常涉及多个局部TSG(包括LKBI)的不连续LOH，其同时失活可能有助于乳腺癌的进展。(C)2004年Wiley-Liss公司
In breast cancer, a high frequency of genomic deletion is found in chromosomal region 19p13. Of particular interest is that the LKBI gene (also known as STKII) has been mapped to this region. LKBI is responsible for Peutz-Jeghers syndrome (PJS), a genetic disease characterized by mucocutaneous pigmentation and gastrointestinal hematoma with an increased risk of developing cancer, including breast cancer. To further clarify the role of chromosomal region 19p13.2-13.3 in the pathogenesis of breast cancer and to identify more precisely candidate tumor-suppressor genes (TSGs) for positional cloning studies, we performed detailed high-resolution allelotyping analysis to detect allelic loss or loss of heterozygosity (LOH) in this region on microdissected samples from 140 primary breast tumors using 24 microsatellite markers. The highest frequencies of LOH were seen with D19S883 (30%) and D19S216 (29%), both at 19p13.3, D19S922 (28%), at 19p13.3-19p13.2, and D19S865 (39%), at 19p13.2; in addition, identification was made of at least four common deletion regions, including the LKBI locus, that are centered on these four markers. In all the cases, we found discontinuous allele loss at several 19p13.2-13.3 sites in the same tumor (with the markers with the highest frequency of LOH adjacent to markers retaining heterozygosity), suggesting the presence of multiple TSGs. Interestingly, in tumors, the extent of allelic loss at these markers (measured as the fractional allele loss) increased significantly as the tumors progressed to poorer grades (P < 0.05). We conclude that 19p13.2-13.3 allele loss is a common event in the pathogenesis of breast carcinoma that often involves discontinuous LOH of multiple, localized TSGs (including LKBI), the concurrent inactivation of which may contribute to breast cancer progression. (C) 2004 Wiley-Liss, Inc.