ATBF1 and NQO1 as candidate targets for allelic loss at chromosome arm 16q in breast cancer: absence of somatic ATBF1 mutations and no role for the C609T NQO1 polymorphism.
ATBF1 and NQO1 as candidate targets for allelic loss at chromosome arm 16q in breast cancer: absence of somatic ATBF1 mutations and no role for the C609T NQO1 polymorphism.
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DOI：
10.1186/1471-2407-8-105
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发表时间：
2008-04-16
期刊：
影响因子：
3.8
通讯作者：
Cornelisse, Cees J.
中科院分区：
文献类型：
--
作者：
Cleton-Jansen, Anne-Marie;van Eijk, Ronald;Lombaerts, Marcel;Schmidt, Marjanka K.;Van't Veer, Laura J.;Philippo, Katja;Zimmerman, Rhyenne M. E.;Peterse, Johannes L.;Smit, Vincent T. B. H. M.;van Wezel, Tom;Cornelisse, Cees J.
染色体16 q的杂合性丢失（洛）在乳腺癌中是常见的，提示该位点可能存在一个或多个靶肿瘤抑制基因（TSGs）。然而，详细定位洛缺失的最小区域还没有发现16号染色体上的TSG。因此，本研究试图使用基于mRNA表达的方法来鉴定TSGs。构建了16 q区域的cDNA微阵列，并使用来自39个已知16 q洛状态的乳腺肿瘤的RNA样品进行分析。与没有洛的肿瘤相比，在16 q处具有洛的肿瘤中鉴定出5个基因显示较低的表达。鉴于NAD（P）H脱氢酶醌（NQO1）和AT结合转录因子1（ATBF 1）的潜在TSG功能，进一步研究了它们的基因。NQO1由于其在醌解毒和p53稳定中的作用而与致癌作用有关。NQO1的一种失活的多态性变体编码显示酶活性降低的产物。然而，我们没有发现在16 q处有洛的肿瘤中优先靶向活性NQO 1等位基因。对354例浸润性乳腺肿瘤的免疫组化分析显示，NQO1蛋白在乳腺肿瘤的一个亚组中的表达高于正常上皮，这与其作为抑癌基因的作用相矛盾。ATBF 1被认为是前列腺癌16 q洛缺失的靶点。我们分析了48个乳腺肿瘤的整个编码序列，但没有发现体细胞序列的变化。我们确实发现了几个框内插入和缺失，其中两个变体被报道为前列腺癌的体细胞致病突变。在这里，我们发现这些变异也存在于550名乳腺癌患者的2.5%和175名健康对照的2.9%的生殖细胞中。这表明这些变异的频率在乳腺癌患者中没有增加。此外，在乳腺肿瘤中没有野生型等位基因的优先洛缺失。在乳腺癌16 q的两个可能的候选TSGs，NQO 1和ATBF 1，在这里被鉴定为在具有16 q洛的肿瘤中显示出降低的表达，但是进一步的分析表明它们不是洛的靶基因。此外，我们的研究结果对先前报道的ATBF 1基因致病变体的有效性提出了质疑。
Loss of heterozygosity (LOH) at chromosome arm 16q is frequently observed in human breast cancer, suggesting that one or more target tumor suppressor genes (TSGs) are located there. However, detailed mapping of the smallest region of LOH has not yet resulted in the identification of a TSG at 16q. Therefore, the present study attempted to identify TSGs using an approach based on mRNA expression. A cDNA microarray for the 16q region was constructed and analyzed using RNA samples from 39 breast tumors with known LOH status at 16q. Five genes were identified to show lower expression in tumors with LOH at 16q compared to tumors without LOH. The genes for NAD(P)H dehydrogenase quinone (NQO1) and AT-binding transcription factor 1 (ATBF1) were further investigated given their functions as potential TSGs. NQO1 has been implicated in carcinogenesis due to its role in quinone detoxification and in stabilization of p53. One inactive polymorphic variant of NQO1 encodes a product showing reduced enzymatic activity. However, we did not find preferential targeting of the active NQO1 allele in tumors with LOH at 16q. Immunohistochemical analysis of 354 invasive breast tumors revealed that NQO1 protein expression in a subset of breast tumors is higher than in normal epithelium, which contradicts its proposed role as a tumor suppressor gene. ATBF1 has been suggested as a target for LOH at 16q in prostate cancer. We analyzed the entire coding sequence in 48 breast tumors, but did not identify somatic sequence changes. We did find several in-frame insertions and deletions, two variants of which were reported to be somatic pathogenic mutations in prostate cancer. Here, we show that these variants are also present in the germline in 2.5% of 550 breast cancer patients and 2.9% of 175 healthy controls. This indicates that the frequency of these variants is not increased in breast cancer patients. Moreover, there is no preferential LOH of the wildtype allele in breast tumors. Two likely candidate TSGs at 16q in breast cancer, NQO1 and ATBF1, were identified here as showing reduced expression in tumors with 16q LOH, but further analysis indicated that they are not target genes of LOH. Furthermore, our results call into question the validity of the previously reported pathogenic variants of the ATBF1 gene.
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影响因子：
11.2
作者：
Kumar, R;Neilsen, PM;Callen, DF
通讯作者：
Callen, DF
影响因子：
2.6
作者：
Miura, Y;Kataoka, H;Okada, H
通讯作者：
Okada, H
影响因子：
11.4
作者：
Berx, G;CletonJansen, AM;vanRoy, F
通讯作者：
vanRoy, F
影响因子：
3.7
作者：
Smith, Paula;McGuffog, Lesley;Easton, Douglas F;Mann, Graham J;Pupo, Gulietta M;Newman, Beth;Chenevix-Trench, Georgia;Szabo, Csilla;Southey, Melissa;Renard, Helene;Odefrey, Fabrice;Lynch, Henry;Stoppa-Lyonnet, Dominique;Couch, Fergus;Hopper, John L;Giles, Graham G;McCredie, Margaret R E;Buys, Saundra;Andrulis, Irene;Senie, Ruby;Goldgar, David E;Oldenburg, Rogier;Kroeze-Jansema, Karin;Kraan, Jaennelle;Meijers-Heijboer, Hanne;Klijn, Jan G M;van Asperen, Christi;van Leeuwen, Inge;Vasen, Hans F A;Cornelisse, Cees J;Devilee, Peter;Baskcomb, Linda;Seal, Sheila;Barfoot, Rita;Mangion, Jon;Hall, Anita;Edkins, Sarah;Rapley, Elizabeth;Wooster, Richard;Chang-Claude, Jenny;Eccles, Diana;Evans, D Gareth;Futreal, P Andrew;Nathanson, Katherine L;Weber, Barbara L;Rahman, Nazneen;Stratton, Michael R
通讯作者：
Stratton, Michael R
影响因子：
4
作者：
de Bock, GH;Schutte, M;Klijn, JGM
通讯作者：
Klijn, JGM