Abstract
We developed a sensitive sequencing approach that simultaneously profiles microsatellite instability, chromosomal instability, and subclonal structure in cancer. We assessed diverse repeat motifs across 225 microsatellites on colorectal carcinomas. Our study identified elevated alterations at both selected tetranucleotide and conventional mononucleotide repeats. Many colorectal carcinomas had a mix of genomic instability states that are normally considered exclusive. An MSH3 mutation may have contributed to the mixed states. Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.
Highlights
Microsatellites are composed of short tandem repeats (STRs) and are present throughout the human genome
After indexing based on the probe sequence in Read 2, we evaluate reads to determine whether both the expected 5′ and 3′ Short tandem repeats (STRs)-flanking sequences are present in Read 1
Evaluating diverse microsatellite classes and cancer drivers We developed a cancer sequencing approach to identify somatic alterations for the major classes of tandem repeat motifs (i.e., microsatellite instability (MSI) and elevated microsatellite alterations at selected tetranucleotide repeats (EMAST)) and to simultaneously characterize other genomic instability features, such as copy number alterations and clonal architecture (Fig. 1a)
Summary
Microsatellites are composed of short tandem repeats (STRs) and are present throughout the human genome. STRs have different classes of motifs that include mono, di-, tri-, and tetranucleotide sequences. In colorectal carcinoma (CRC), somatic mutations or methylation of DNA mismatch repair (MMR) genes (i.e., MSH2, MLH1, PMS2, MSH6) lead to increased mutation rates, in microsatellites. Somatic inactivation of the remaining wildtype allele of an MMR gene leads to inactivation of this DNA repair pathway and increased risk of developing tumors. Tumors with MMR loss display hypermutability in microsatellite sequences. This phenomenon is referred to as microsatellite instability (MSI) and is characterized by the accrual of insertions or deletions (indels) in either coding or noncoding microsatellite sequences. MSI occurs in all classes of microsatellite repeats. Most published studies have exclusively focused on the presence of microsatellite
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