Abstract
Microsatellite instability (MSI) is characterized by the expansion or contraction of DNA repeat tracts as a consequence of DNA mismatch repair deficiency (MMRD). Accurate detection of MSI in cancer cells is important since MSI is associated with several cancer subtypes and can help inform therapeutic decisions. Although experimental assays have been developed to detect MSI, they typically depend on a small number of known microsatellite loci or mismatch repair genes and have limited reliability. Here, we report a novel genome-wide approach for MSI detection based on the global detection of insertions and deletions (indels) in microsatellites found in expressed genes. Our large-scale analyses of 20 cancer cell lines and 123 normal individuals revealed striking indel features associated with MSI: there is a significant increase of short microsatellite deletions in MSI samples compared to microsatellite stable (MSS) ones, suggesting a mechanistic bias of repair efficiency between insertions and deletions in normal human cells. By incorporating this observation into our MSI scoring metric, we show that our approach can correctly distinguish between MSI and MSS cancer cell lines. Moreover, when we applied this approach to primal tumor samples, our metric is also well consistent with diagnosed MSI status. Thus, our study offers new insight into DNA mismatch repair system, and also provides a novel MSI diagnosis method for clinical oncology with better reliability.
Highlights
In normal cells, mismatch repair (MMR) system provides a highly efficient mechanism for correcting errors that occur during DNA replication
We determined the proportion of microsatellites altered by indels located in 59 UTR, coding sequence, 39 UTR or non-coding RNAs, and determined whether these proportions are significantly different between Microsatellite instability (MSI) and HapMap samples and between microsatellite stable (MSS) and HapMap samples
We observed a significant increase in the proportion of indels in MSI samples’ coding sequences (p = 1e–5, Student’s t-test; Figure 3a) when compared to HapMap samples, while the proportion remained similar in MSS samples (p = 0.15, Student’s t-test)
Summary
Mismatch repair (MMR) system provides a highly efficient mechanism for correcting errors that occur during DNA replication. E.g. through inactivation of human mismatch repair genes such as MLH1, MSH2 and MSH3, mismatch repair deficiency leads to uncorrected insertions/ deletions (indels), in microsatellites where a short sequence unit (one to six nucleotides long) is repeated multiple times [1]. Microsatellite instability (MSI) refers to the genetically aberrant condition in which microsatellite alleles in genome gain or lose repeat units at much higher frequency than in normal cells. Widespread MSI usually indicates mismatch repair deficiency (MMRD), which can cause accumulation of mutations in cancer-related genes and lead to carcinogenesis and tumor progression. MSI generates significant genetic heterogeneity and can be used for other purposes such as the isolation of drug resistant clones and the subsequent characterization of drug resistance mechanisms [4]
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