Niederacher D, Picard F, van Roeyen C, An H X, Bender H G, Beckmann M W
Department of Obstetrics and Gynecology, Düsseldorf, Germany.
Genes Chromosomes Cancer. 1997 Mar;18(3):181-92. doi: 10.1002/(sici)1098-2264(199703)18:3<181::aid-gcc5>3.0.co;2-y.
Loss of heterozygosity (LOH) on chromosome 17 is a frequent genetic alteration in breast cancer. To assess whether the location of potential tumor suppressor genes is compatible with the LOH pattern in individual tumors, we analyzed allele loss on chromosome 17 in 121 invasive ductal breast carcinomas and 16 benign breast tumors with 14 polymorphic microsatellite markers (4 on 17p and 10 on 17q). Fluorescent polymerase chain reaction (PCR) for typing microsatellites coupled with DNA fragment analysis in an automated DNA sequencer was applied. Frequencies of LOH varied from 29.4% (D17S1322) to 57.4% (TP53-Alu). No LOH could be detected in benign breast tumors. In 54 tumors the deletion patterns were consistent with the complete loss of 17p (n = 28), 17q (n = 9) or the whole chromosome 17 (n = 17). Five smallest regions of overlap (SROs) were identified in tumors with interstial deletion patterns. On 17p, two foci were detected affecting the TP53 locus and the hypermethylated in cancer I (HICI) region (17p13.3). On 17q, SRO1 was localized between markers THRAI and D17S855, centromeric to the breast/ovarian cancer gene BRCAI; SRO2 was flanked by markers AFM234 and NMEI, and SRO3 was centered between markers MPO and GH. Associations between LOH and histopathological characteristics were determined. Significant correlations were found between higher grade and loss of the TP53 gene (marker TP53, P = 0.019), loss of the BRCAI region (P < 0.009), LOH of marker AFM155 (P = 0.003) and marker NMEI (P = 0.026). For positive estrogen receptor status, only LOH of the THRAI marker correlated significantly, whereas highly significant correlations were determined between positive progesterone receptor and markers centromeric to the BRCAI region D17S250 (P = 0.00002), THRAI (P = 0.0006), and the intragenic BRCAI markers [D17S1322 (P = 0.021), D17S855 (P = 0.029)]. Results presented in this study identify five independent regions of chromosome 17 which are likely to contain potential tumor suppressor genes involved in the carcinogenesis of sporadic breast cancer.
17号染色体杂合性缺失（LOH）是乳腺癌中常见的基因改变。为评估潜在肿瘤抑制基因的位置是否与个别肿瘤中的LOH模式相符，我们用14个多态性微卫星标记（17p上4个，17q上10个）分析了121例浸润性导管乳腺癌和16例良性乳腺肿瘤中17号染色体上的等位基因缺失情况。采用荧光聚合酶链反应（PCR）对微卫星进行分型，并结合自动DNA测序仪中的DNA片段分析。LOH频率从29.4%（D17S1322）到57.4%（TP53 - Alu）不等。在良性乳腺肿瘤中未检测到LOH。在54例肿瘤中，缺失模式与17p（n = 28）、17q（n = 9）或整个17号染色体（n = 17）的完全缺失一致。在具有间质缺失模式的肿瘤中确定了五个最小重叠区域（SRO）。在17p上，检测到两个位点影响TP53基因座和癌症中高甲基化区域I（HICI，17p13.3）。在17q上，SRO1定位于标记THRAI和D17S855之间，位于乳腺癌/卵巢癌基因BRCA1的着丝粒侧；SRO2两侧为标记AFM234和NMEI，SRO3以标记MPO和GH之间为中心。确定了LOH与组织病理学特征之间的关联。在高级别与TP53基因缺失（标记TP53，P = 0.019）、BRCA1区域缺失（P < 0.009）、标记AFM155的LOH（P = 0.003）和标记NMEI的LOH（P = 0.026）之间发现了显著相关性对于雌激素受体阳性状态，仅THRAI标记的LOH有显著相关性，而在孕激素受体阳性与BRCA1区域着丝粒侧的标记D17S250（P = 0.00002）、THRAI（P = 0.0006）以及基因内BRCA1标记[D17S1322（P = 0.021）、D17S855（P = 0.029）]之间确定了高度显著的相关性。本研究结果确定了17号染色体上五个独立区域，这些区域可能包含参与散发性乳腺癌致癌过程的潜在肿瘤抑制基因。
