Identification of homozygous deletions at chromosome 16q23 in Aflatoxin B1 exposed hepatocellular carcinoma
Identification of homozygous deletions at chromosome 16q23 in Aflatoxin B1 exposed hepatocellular carcinoma
复制标题
黄曲霉毒素 B1 暴露肝细胞癌中染色体 16q23 纯合缺失的鉴定
作者：
M. Yakicier;P. Legoix;C. Vaury;L. Gressin;Emmanuel Tubacher;F. Capron;J. Bayer;C. Degott;C. Balabaud;J. Zucman‐Rossi
杂合性缺失（洛）是肝细胞癌（HCC）中最常见的遗传变异。染色体16 q是特别感兴趣的，因为它在29%的HCC肿瘤中表现出洛缺失，并且在乳腺癌、前列腺癌、卵巢癌和胃癌中经常丢失。我们对157例HCC肿瘤进行了16号染色体上17个微卫星标记的基因分型，并确定了位于标记D16 S518和D16 S504之间的一个共同的洛区域。通过细化两个间质性洛缺失和两个纯合性缺失的边界，将关键区域界定为D16 S3096和D16 S3029之间的180 kb。该区域位于WWOX/FOR基因的内含子8，但在27个HCC肿瘤和细胞系中搜索该基因的所有编码外显子的突变没有发现任何肿瘤体细胞改变。此外，通过RT-PCR，在9个肝癌细胞系中没有检测到该WWOX/FOR基因的异常转录本。最后，分析p53基因突变与所有肿瘤的临床参数显示，两个纯合性缺失发生在肿瘤中呈现R249 S突变。我们的数据显示，在患者暴露于黄曲霉毒素B1的肿瘤中，染色体16 q纯合缺失与R249 S p53突变之间存在相关性（P=0.002）。这些结果与黄曲霉毒素B1在染色体16 q脆性位点FRA 16 D处的不稳定性中的作用一致。然而，在肝癌发生过程中改变的特定基因的性质仍有待阐明。
Loss of heterozygosity (LOH) represents the most frequent genetic alteration observed in hepatocellular carcinoma (HCC). Chromosome 16q is of particular interest as it exhibits LOH in 29% of HCC tumors and is frequently lost in breast, prostate, ovarian and gastric carcinomas. We genotyped 157 HCC tumors for 17 microsatellite markers distributed on chromosome 16q and determined a common region of LOH localized between the markers D16S518 and D16S504. By refining the boundaries of two interstitial LOH and two homozygous deletions, the critical region was delimited to 180 kb between D16S3096 and D16S3029. This region is located in intron 8 of the WWOX/FOR gene, but a search for mutations in all coding exons of this gene in 27 HCC tumors and cell lines did not reveal any tumor somatic alterations. Furthermore, by RT–PCR, no abnormal transcripts of this WWOX/FOR gene was detected in nine HCC cell lines. Finally, analysis of the p53 gene mutations with the clinical parameters of all tumors revealed that the two homozygous deletions have occurred in tumors presenting a R249S mutation. Our data revealed a relationship between chromosome 16q homozygous deletions and R249S p53 mutations in tumors where the patient had been exposed to Aflatoxin B1 (P=0.002). These results are consistent with a role of Aflatoxin B1 in the instability of chromosome 16q at the fragile site FRA16D. However, the nature of the specific gene that is altered during hepatocarcinogenesis remains to be elucidated.
影响因子：
11.2
作者：
A. Bednarek;K. J. Laflin;R. Daniel;Q. Liao;K. A. Hawkins;Claudio Marcelo Aldaz
通讯作者：
A. Bednarek;K. J. Laflin;R. Daniel;Q. Liao;K. A. Hawkins;Claudio Marcelo Aldaz
影响因子：
4.4
作者：
Krummel, KA;Roberts, LR;Smith, DI
通讯作者：
Smith, DI