Laboratorio Investigación, Hospital Universitario Elche, Elche, Spain.
BMC Med Genet. 2011 Jan 19;12:12. doi: 10.1186/1471-2350-12-12.
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.
林奇综合征（LS）是一种常染色体显性遗传的癌症综合征，其特征为结直肠、子宫内膜和其他肿瘤的早期发病。LS 患者的大量 DNA 变异尚未分类。关于 MLH1 基因 c.1852_1853AA>GC（p.Lys618Ala）变异的致病性报告存在争议。本研究提供了新的证据，表明该变异与 LS 无关。
采用以下方法评估 p.Lys618Ala 变异的临床意义：在对照组中的频率、病例对照比较、与致病性突变的共发生、与疾病的共分离以及携带变异的肿瘤中的微卫星不稳定性。我们对 1034 名个体（373 名散发性结直肠癌 [CRC] 患者、250 名疑似 LS 家族的索引受试者 [修订后的贝塞斯达指南] 和 411 名对照）进行了 p.Lys618Ala 基因分型。纳入了三个符合阿姆斯特丹 II 标准且包含携带 p.Lys618Ala 变异的成员的 LS 家系，以评估共发生和共分离。从携带 p.Lys618Ala 变异的 17 名 CRC 患者的肿瘤 DNA 样本中筛选了五个单核苷酸标记的微卫星不稳定性。
27 名个体为 p.Lys618Ala 变异的杂合子；9 名患有散发性 CRC（2.41%），7 名疑似遗传性 CRC（2.8%），11 名是对照（2.68%）。病例对照和病例病例研究均无显著关联。p.Lys618Ala 变异与两个不相关的 LS 家系中的致病性突变共存。在一个家系中，致病性和未分类变异的等位基因分布为反式，在另一个家系中，致病性变异存在于 MSH6 基因中，只有有害变异与疾病在两个家系中共同分离。仅在携带 p.Lys618Ala 变异的患者的肿瘤中检测到 2 例微卫星不稳定性阳性病例（2/17，11.8%），表明该变异在 CRC 患者中不会导致 MLH1 的功能失活。
p.Lys618Ala 变异应被视为 LS 的中性变异。这些发现对 CRC 先证者及其亲属的临床管理具有重要意义。
