Mestre-Escorihuela Cinta, Rubio-Moscardo Fanny, Richter Jose A, Siebert Reiner, Climent Joan, Fresquet Vicente, Beltran Elena, Agirre Xabier, Marugan Isabel, Marín Miguel, Rosenwald Andreas, Sugimoto Kei-Ji, Wheat Luise M, Karran E Loraine, García Juan F, Sanchez Lydia, Prosper Felipe, Staudt Louis M, Pinkel Daniel, Dyer Martin J S, Martinez-Climent Jose A
Center for Applied Medical Research (CIMA), University of Navarra, Avda Pio XII, 55, Pamplona 31008, Spain.
Blood. 2007 Jan 1;109(1):271-80. doi: 10.1182/blood-2006-06-026500. Epub 2006 Sep 7.
Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.
综合基因组和基因表达分析已在B细胞非霍奇金淋巴瘤（B-NHL）中鉴定出扩增的癌基因，但此类技术在纯合缺失区域定位肿瘤抑制基因的能力尚未得到探索。对来自不同B-NHL患者的48个细胞系进行基于阵列的比较基因组杂交（CGH）和基因表达微阵列分析，在7个染色体区域划定了20个纯合缺失，所有这些区域都包含肿瘤抑制基因靶点。进一步研究发现，只有一小部分原发性活检组织通过点突变或基因内缺失使这些基因失活，相反，其中一些基因经常因表观遗传机制而沉默。值得注意的是，B-NHL亚型之间遗传和表观遗传失活模式有所不同。因此，p53诱导的PIG7/LITAF在原发性纵隔B细胞淋巴瘤中因纯合缺失而沉默，在生发中心淋巴瘤中因启动子高甲基化而沉默；促凋亡的BIM基因在套细胞淋巴瘤中出现纯合缺失，在伯基特淋巴瘤中出现启动子高甲基化；仅含BH3结构域的促凋亡基因NOXA在弥漫性大B细胞淋巴瘤中发生突变并优先沉默；INK4c/P18在套细胞淋巴瘤中因双等位基因突变而沉默。我们的微阵列策略已鉴定出通过遗传和表观遗传机制失活的新型候选肿瘤抑制基因，这些机制在B-NHL亚型之间有很大差异。
