Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage.
Spectrum of HNF1A somatic mutations in hepatocellular adenoma differs from that in patients with MODY3 and suggests genotoxic damage.
复制标题
DOI：
10.2337/db09-1819
复制
发表时间：
2010-07
期刊：
影响因子：
7.7
通讯作者：
Zucman-Rossi J
中科院分区：
文献类型：
--
作者：
Jeannot E;Mellottee L;Bioulac-Sage P;Balabaud C;Scoazec JY;Tran Van Nhieu J;Bacq Y;Michalak S;Buob D;Groupe d'étude Génétique des Tumeurs Hépatiques (INSERM Network);Laurent-Puig P;Rusyn I;Zucman-Rossi J
年轻3型成熟型糖尿病（MODY 3）是HNF 1A杂合种系突变的结果。肝细胞腺瘤（HCA）的一个亚型也是由双等位基因体细胞HNF 1A突变（H-HCA）引起的，罕见的HCA可能与MODY 3有关。为了更好地理解MODY 3和HCA之间的关系，我们比较了HNF 1A突变的种系和体细胞谱。我们比较了HCA中的151个体细胞HNF 1A突变与MODY 3中描述的364个种系突变。我们在HCA和周围肝组织中寻找遗传毒性和氧化应激特征。HNF 1A体细胞突变谱与MODY 3中的种系变化显著不同。在HCA中，我们在密码子206处发现了一个特定的热点，无义突变和移码突变主要发生在NH 2端部分，几乎所有的氨基酸替换都局限于POU-H结构域。主要在非转录DNA链上发现的高频率G至T转录表明存在遗传毒性机制。然而，在非肿瘤肝组织中没有观察到氧化应激的特征。最后，在少数MODY 3患者中，HNF 1A种系突变导致POU-H结构域以外的氨基酸取代，我们确定了一种不同的HCA亚型，具有gp 130和/或CTNNB 1激活突变。生殖系HNF 1A突变可能与HCA的不同分子亚型相关。H-HCA显示突变严重灭活肝细胞核因子-1 α功能;它们与遗传毒性特征相关，表明可能与遗传易感性相关的特定毒物暴露。
Maturity onset diabetes of the young type 3 (MODY3) is a consequence of heterozygous germline mutation in HNF1A. A subtype of hepatocellular adenoma (HCA) is also caused by biallelic somatic HNF1A mutations (H-HCA), and rare HCA may be related to MODY3. To better understand a relationship between the development of MODY3 and HCA, we compared both germline and somatic spectra of HNF1A mutations. We compared 151 somatic HNF1A mutations in HCA with 364 germline mutations described in MODY3. We searched for genotoxic and oxidative stress features in HCA and surrounding liver tissue. A spectrum of HNF1A somatic mutations significantly differed from the germline changes in MODY3. In HCA, we identified a specific hot spot at codon 206, nonsense and frameshift mutations mainly in the NH2-terminal part, and almost all amino acid substitutions were restricted to the POU-H domain. The high frequency of G-to-T tranversions, predominantly found on the nontranscribed DNA strand, suggested a genotoxic mechanism. However, no features of oxidative stress were observed in the nontumor liver tissue. Finally, in a few MODY3 patients with HNF1A germline mutation leading to amino acid substitutions outside the POU-H domain, we identified a different subtype of HCA either with a gp130 and/or CTNNB1 activating mutation. Germline HNF1A mutations could be associated with different molecular subtypes of HCA. H-HCA showed mutations profoundly inactivating hepatocyte nuclear factor-1α function; they are associated with a genotoxic signature suggesting a specific toxicant exposure that could be associated with genetic predisposition.
登录
查看更多内容
影响因子：
29.4
作者：
Bacq, Y;Jacquemin, E;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
8
作者：
Denissenko, MF;Pao, A;Tang, MS
通讯作者：
Tang, MS
影响因子：
64.8
作者：
BRESSAC, B;KEW, M;OZTURK, M
通讯作者：
OZTURK, M
影响因子：
30.8
作者：
Bluteau, O;Jeannot, E;Zucman-Rossi, J
通讯作者：
Zucman-Rossi, J
影响因子：
7.7
作者：
Bellanne-Chantelot, Christine;Carette, Claire;Timsit, Jose
通讯作者：
Timsit, Jose