Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome.
Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome.
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MLH1中C.1852_1853AA> GC的分类的证据作为Lynch综合征的中性变体。
DOI：
10.1186/1471-2350-12-12
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发表时间：
2011-01-19
影响因子：
--
通讯作者：
Soto JL
中科院分区：
文献类型：
--
作者：
Castillejo A;Guarinos C;Martinez-Canto A;Barbera VM;Egoavil C;Castillejo MI;Perez-Carbonell L;Sanchez-Heras AB;Segura A;Ochoa E;Lazaro R;Ruiz-Ponte C;Bujanda L;Andreu M;Castells A;Carracedo A;Llor X;Clofent J;Alenda C;Paya A;Jover R;Soto JL
Lynch综合征（LS）是一种常染色体显性遗传性癌症综合征，其特征是结肠直肠、子宫内膜和其他肿瘤的早发性癌症。LS患者中很大比例的DNA变异是未分类的。关于MLH 1基因的c.1852_1853AA>GC（p.Lys618Ala）变体的致病性的报道是相互矛盾的。在这项研究中，我们提供了新的证据表明，这种变异对LS没有显着的影响。以下方法用于评估p.Lys618Ala变体的临床意义：对照人群中的频率、病例对照比较、p.Lys618Ala变体与致病性突变的共现、与疾病的共分离以及变体携带者肿瘤中的微卫星不稳定性。我们对1034名个体进行p.Lys618Ala基因分型（373名散发性结直肠癌[CRC]患者，250名来自疑似LS家族的索引受试者[修订的Bethesda指南]和411名对照）。三个充分表征的LS家庭，满足阿姆斯特丹II标准，并包括与p.Lys618Ala变异的成员，以评估共同出现和共同分离。使用5种单核苷酸标记物对17例携带p.Lys618Ala变异的患者的结直肠肿瘤DNA样本子集进行微卫星不稳定性筛查。27例患者为p.Lys618Ala变异杂合子; 9例为散发性CRC（2.41%），7例疑似遗传性CRC（2.8%），11例为对照组（2.68%）。在病例-对照和病例-病例研究中没有显著的相关性。p.Lys618Ala变异与两个无关LS家族的致病性突变共存。在一个家系中，致病性和未分类的变异的等位基因分布是在反式，在另一个家庭的致病性变异中检测到的MSH 6基因，只有有害的变异与疾病共分离在两个家庭。在p.Lys618Ala携带者的肿瘤中仅检测到两例微卫星不稳定性阳性病例（2/17，11.8%），表明该变体在CRC患者MLH 1的功能失活中不起作用。p.Lys618Ala变体应被视为LS的中性变体。这些发现对大肠癌先证者及其亲属的临床管理具有重要意义。
Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co-segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co-occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives.
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影响因子：
5.3
作者：
Liu, T;Tannergård, P;Lindblom, A
通讯作者：
Lindblom, A
HMLH1和HMSH2中的遗传变异与丹麦种群中零星大结直肠癌的发展之间的关联。
影响因子：
--
作者：
Christensen, Lise Lotte;Madsen, Bo E.;Wikman, Friedrik P.;Wiuf, Carsten;Koed, Karen;Tjonneland, Anne;Olsen, Anja;Syvanen, Ann-Christine;Andersen, Claus L.;Orntoft, Torben F.
通讯作者：
Orntoft, Torben F.
影响因子：
--
作者：
Peltomäki P;Vasen H
通讯作者：
Vasen H
影响因子：
5.2
作者：
Belvederesi, Laura;Bianchi, Francesca;Porfiri, Emilio
通讯作者：
Porfiri, Emilio
DOI：
10.1073/pnas.0407187101
发表时间：
2004-11-09
影响因子：
11.1
作者：
Fearnhead, NS;Wilding, JL;Bodmer, WF
通讯作者：
Bodmer, WF