High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss
High-resolution chromosome 3p allelotyping of breast carcinomas and precursor lesions demonstrates frequent loss of heterozygosity and a discontinuous pattern of allele loss
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DOI：
10.1016/s0002-9440(10)61679-3
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发表时间：
2001-07-01
影响因子：
6
通讯作者：
Minna, JD
中科院分区：
文献类型：
--
作者：
Maitra, A;Wistuba, II;Minna, JD
我们对45例原发性乳腺癌、47例乳腺癌前上皮病灶和18例乳腺癌细胞系的显微解剖样本进行了高分辨率等位基因分型，分析了杂合性丢失（洛），使用了一组27个多态性染色体3 p标记。在45例原发性乳腺肿瘤中，39例（87%）检测到染色体3 p某些区域的等位基因丢失。3p21.3区域的洛性丢失频率最高（69%），其次是3 p22 -24（61%）、3p21.2-21.3（58%）、3 p25（48%）、3p14.2（45%）、3p14.3（41%）和3 p12（35%）。对所有数据的分析揭示了至少9个离散区间，显示了频繁的等位基因丢失：D3S1511-D3S1284 D3 S1300-D3 S1234 [以D3 S1300为中心的脆性组氨酸三联体（FHIT）/FRA 3B区，具有纯合缺失]，D3 S1076-D3 S1573，D3 S4624/ Luca2.1-D3 S4597/P1.5、D3 S1478-D3 S1029、D3 S1029（具有纯合缺失）、D3 S1612-D3 S1537、D3 S1233-D3 S1597和D3 S1597-端粒;本研究中未检查的其他局部洛区域很可能也存在于染色体3 p上。在多个病例中，在同一肿瘤中的几个3 p位点存在不连续的等位基因丢失。47例癌前病变中有21例（45%）表现为3 p洛缺失，包括13例导管原位癌中的12例（92%），7例顶浆腺化生中的2例（29%），25例普通上皮增生中的7例（28%）。在癌前乳腺上皮中，3p21.3区域的洛丢失频率最高（36%），其次是3p21.2-21.3（20%），3p14.2/FHIT区域（11%），3 p25（10%）和3 p22 -24（5%）。在肿瘤和伴随的癌前病变中均显示洛缺失的39个3 p位点中，34个（87%）显示相同的亲本等位基因缺失（P = 1.2 × 10（-6），累积二项式检验）。此外，当21个肿瘤前样本显示洛与其伴随的癌症进行比较，67%是克隆相关的，20%是潜在的克隆相关，但分歧，13%是克隆无关。总体而言，这证明了肿瘤前病灶与肿瘤的克隆相关性的可能性很高。我们的结论是：染色体3 p等位基因丢失是乳腺癌发病机制中的常见事件;涉及多个局部位点，其经常显示不连续的洛缺失，中间标记保留杂合性;并且见于早期肿瘤前阶段，其显示与浸润性癌症的克隆相关性。
We performed high-resolution allelotyping for loss of heterozygosity (LOH) analysis on microdissected samples from 45 primary breast cancers, 47 mammary preneoplastic epithelial foci, and 18 breast cancer cell Lines, using a panel of 27 polymorphic chromosome 3p markers. Allele loss in some regions of chromosome 3p was detected in 39 of 45 (87%) primary breast tumors. The 3p21.3 region had the highest frequency of LOH (69%), followed by 3p22-24 (61%), 3p21.2-21.3 (58%), 3p25 (48%), 3p14.2 (45%), 3p14.3 (41%), and 3p12 (35%). Analysis of all of the data revealed at least nine discrete intervals showing frequent allele loss: D3S1511-D3S1284 (U2020/DUTT1 region centered on D3S1274 with a homozygous deletion), D3S1300-D3S1234 [fragile histidine triad (FHIT)/FRA3B region centered on D3S1300 with a homozygous deletion], D3S1076-D3S1573, D3S4624/ Luca2.1-D3S4597/P1.5, D3S1478-D3S1029, D3S1029 (with a homozygous deletion), D3S1612-D3S1537, D3S1233-D3S1597, and D3S1597-telomere; it is more than likely that additional localized regions of LOH not examined in this study also exist on chromosome 3p. In multiple cases, there was discontinuous allele loss at several 3p sites in the same tumor. Twenty-one of 47 (45%) preneoplastic lesions demonstrated 3p LOH, including 12 of 13 (92%) ductal carcinoma in situ, 2 of 7 (29%) apocrine metaplasia, and 7 of 25 (28%) usual epithelial hyperplasia. The 3p21.3 region had the highest frequency of LOH in preneoplastic breast epithelium (36%), followed by 3p21.2-21.3 (20%), 3p14.2/FHIT region (11%), 3p25 (10%), and 3p22-24 (5%). In 39 3p loci showing LOH in both the tumor and accompanying preneoplasia, 34 (87%) showed loss of the same parental allele (P = 1.2 x 10(-6), cumulative binomial test). In addition, when 21 preneoplastic samples showing LOH were compared to their accompanying cancers, 67% were clonally related, 20% were potentially clonally related but were divergent, and 13% were clonally unrelated. Overall this demonstrated the high likelihood of clonal relatedness of the preneoplastic foci to the tumors. We conclude that: chromosome 3p allele loss is a common event in breast carcinoma pathogenesis; involves multiple, localized sites that often show discontinuous LOH with intervening markers retaining heterozygosity; and is seen in early preneoplastic stages, which demonstrate clonal relatedness to the invasive cancer.