Exploring novel cancer-related genes within novel amplifications detected by CGH in gastrointestinal tumors

在胃肠道肿瘤中 CGH 检测到的新扩增中探索新的癌症相关基因

• 批准号: 13470252
• 负责人: INAZAWA Johji
• 金额: $ 8.83万
• 依托单位: Tokyo Medical & Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470252/
• 关键词: gastrointestinal cancer; gene amplification; CGH array; Cancer-related gene; Oncogene; personalized medicine; 染色体; ゲノム; 遺伝子; マイクロアレイ; CGH; がん; アポトーシスインヒビター; トランスレーショナルリサーチ

Accumulated evidence suggests that multiple genetic alterations occurring sequentially in a cell lineage, at the nucleotide levels as well as at the chromosome levels, underlie the carcinogenetic process in gastrointestinal tumors. Amplification of chromosomal DNA is one of the mechanisms capable of activating genes that are implicated in developing tumors. Oncogenes such as CCND1 (11q13) and MYC (8q24) are known to be activated by amplification in several types of cancer. Comparative genomic hybridization (CGH) studies is the powerful tool for exploring additional regions of amplification. Thus we perform extensive analysis of copy number aberration in solid tumors, especially in gastrointestinal tumors, to explore novel amplified regions and identify target genes within the amplicons. By using mis strategy, we have identified novel target genes including GASC1 (9p23), cIAP1 (11q22), TGIF2 (18p11.3), SNO and Evil (3q26-27), HNF2A (14q12-13), CEMPF and ATF3 (1q32), and IQGAP1 (15q26>. Furthermore, we have constructed high-density CGH array system as follows; (1) An array harboring 4500 BACs throughout a whole genome, (2) An array containing 800 cancer-related genes for "personalized medicine", and (3) An array harboring 212 BACs spanning the 20 Mb contig at chromosome 1p36. Our CGH array can open the window for exploring cryptic chromosome copy number aberrations relevant with molecular pathogenesis in gastrointestinal tumors.

越来越多的证据表明，在核苷酸水平和染色体水平上，细胞谱系中顺序发生的多种遗传改变是胃肠道肿瘤致癌过程的基础。染色体DNA的扩增是激活与肿瘤发生有关的基因的机制之一。已知在几种类型的癌症中，CCND1 （11q13）和MYC （8q24）等癌基因通过扩增被激活。比较基因组杂交（CGH）研究是探索其他扩增区域的有力工具。因此，我们对实体肿瘤，特别是胃肠道肿瘤的拷贝数畸变进行了广泛的分析，以探索新的扩增区域并在扩增子中识别靶基因。通过mis策略，我们发现了新的靶基因，包括GASC1 （9p23）、cIAP1 （11q22）、TGIF2 （18p11.3）、SNO和Evil （3q26-27）、HNF2A （14q12-13）、CEMPF和ATF3 （1q32）以及IQGAP1 （15q26>）。此外，我们构建了高密度CGH阵列系统如下：(1)在整个基因组中包含4500个BACs的阵列，(2)包含800个用于“个性化医疗”的癌症相关基因的阵列，以及(3)包含212个BACs的阵列，跨越1p36染色体上20 Mb的contig。我们的CGH阵列可以为探索与胃肠道肿瘤分子发病机制相关的隐性染色体拷贝数畸变打开窗口。

项目成果

Okamoto, R, Inazawa, J et al.: "Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract"Nature Medicine. 8. 1011-1017 (2002)

Okamoto, R, Inazawa, J 等人：“人胃肠道中骨髓衍生细胞再生的受损上皮细胞”《自然医学》。

Li QL, Ito K, Inazawa J, et al.: "Causal relationship between the loss of RUNX3 expression and gastric cancer"Cell. 109・1. 113-124 (2002)

Li QL、Ito K、Inazawa J 等：“RUNX3 表达缺失与胃癌之间的因果关系”Cell 109・1（2002）。

Imoto, I., Inazawa, J., et al.: "Expression of cIAPl, a target for 11q22 amplification, correlates with resistance of cervical cancers to radiotherapy"Cancer Res. 62. 4860-4866 (2002)

Imoto, I.、Inazawa, J.等人：“cIAP1（11q22 扩增的靶标）的表达与宫颈癌对放射治疗的抵抗力相关”Cancer Res。

Yokoi, S., Inazawa, J., et al.: "A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers"Am J Pathol. 161. 207-216 (2002)

Yokoi, S.、Inazawa, J. 等人：“5p13 扩增子中的一种新靶基因 SKP2，经常在小细胞肺癌中检测到”Am J Pathol。

Li, QL, Inazawa, J et al.: "Causal relationship between the loss of RUNX3 expression and gastric cancer"Cell. 109. 113-124 (2002)

Li, QL, Inazawa, J 等人：“RUNX3 表达缺失与胃癌之间的因果关系”细胞。