Abstract
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.
Highlights
Telomeres are the essential capping structures of chromosomes with well-established roles in ageing and cancer
High molecular weight DNA was extracted from the saliva samples collected from the control and Lynch syndrome (LS) families described in Table 1 and Figure S1
Median telomere lengths were measured in saliva DNA from control and LS families using single telomere length analysis (STELA)
Summary
Telomeres are the essential capping structures of chromosomes with well-established roles in ageing and cancer. Short telomeres activate a DNA damage response and cells with one or a few dysfunctional telomeres enter a senescent state. Cancer cells usually acquire mutations that allow them to bypass this replication barrier but must eventually activate a telomere maintenance mechanism [1,2,3]. Heterozygous carriers of MLH1 or MSH2 mutations show a higher level of instability at short tandem repeat (STR). Loci ( known as microsatellite instability, MSI), with a bias towards deletions, than seen in their non-carrier relatives. This shows that heterozygous MMR+/− cells have a limited capacity for MMR arising from haplo-insufficiency [5,6,7]
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