Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.
Telomere Instability in Lynch Syndrome Families Leads to Some Shorter Telomeres in MSH2+/- Carriers.
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DOI：
10.3390/life10110265
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发表时间：
2020-10-31
期刊：
影响因子：
--
通讯作者：
Royle NJ
中科院分区：
文献类型：
--
作者：
Garrido-Navas MC;Tippins F;Barwell J;Hoffman J;Codd V;Royle NJ
林奇综合征（LS）是一种遗传性的各种癌症的早期发病倾向，由DNA错配修复（MMR）基因突变引起。在杂合子MMR+/−携带者中，野生型等位基因的体细胞突变、缺失或沉默增加了突变率，促进了MMR缺陷型癌症的发生。这些癌症的特征在于短串联重复序列（STR）和端粒DNA的不稳定性。我们研究了LS和对照家庭唾液DNA中的端粒长度，使用XpYp和12 q处的单个端粒分析和通过qPCR测量总端粒DNA。单端粒分析显示，与MLH 1 +/−携带者或对照相比，MSH 2 +/−携带者的XpYp端粒有缩短的趋势，但这在总端粒DNA的比较分析中被掩盖了。家庭内年龄调整后的端粒长度比较显示，MSH 2 +/−或MLH 1 +/−儿童的端粒都没有比他们的MMR+/−父母更短或更长，这表明端粒长度不存在代际效应。然而，出乎意料的是，在MSH 2突变的家庭中，野生型儿童的XpYp端粒比他们的MMR+/−父母显着更长。总之，我们的数据表明，MMR不足，特别是在MSH 2 +/−携带者中，在LS突变携带者的寿命期间增加端粒不稳定性和体细胞更新，但对种系中端粒长度的影响最小。
Lynch syndrome (LS) is an inherited predisposition to early onset of various cancers, caused by mutation in a DNA mismatch repair (MMR) gene. In heterozygous MMR+/− carriers, somatic mutation, loss or silencing of the wild type allele increases the mutation rate, facilitating the initiation of MMR-defective cancers. These cancers are characterized by instability at short tandem repeats (STRs) and in telomeric DNA. We have investigated telomere length in saliva DNA from LS and control families, using single telomere analysis at XpYp and 12q and by qPCR to measure total telomeric DNA. Single telomere analysis showed a trend for shorter XpYp telomeres in MSH2+/− carriers compared to MLH1+/− carriers or controls, but this was masked in the comparative analysis of total telomeric DNA. Comparison of age-adjusted telomere length within families showed that neither MSH2+/− or MLH1+/− children had consistently shorter or longer telomeres than their MMR+/− parent, indicating the absence of an inter-generational effect on telomere length. Unexpectedly however, wildtype children in families with MSH2 mutations, had significantly longer XpYp telomeres than their MMR+/− parent. Altogether our data suggest that MMR insufficiency, particularly in MSH2+/− carriers, increases telomere instability and somatic cell turnover during the lifetime of LS mutation carriers but has minimal consequences for telomere length in the germline.
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DOI：
10.1016/j.mrfmmm.2011.04.003
发表时间：
2012-02-01
影响因子：
2.3
作者：
Aubert, Geraldine;Hills, Mark;Lansdorp, Peter M.
通讯作者：
Lansdorp, Peter M.
影响因子：
13.1
作者：
通讯作者：
--
影响因子：
14.9
作者：
Mendez-Bermudez A;Hills M;Pickett HA;Phan AT;Mergny JL;Riou JF;Royle NJ
通讯作者：
Royle NJ
影响因子：
9.8
作者：
Baird, DM;Coleman, J;Royle, NJ
通讯作者：
Royle, NJ
影响因子：
11.4
作者：
BAIRD, DM;JEFFREYS, AJ;ROYLE, NJ
通讯作者：
ROYLE, NJ