Abstract
Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment, and sequencing-based approaches are often applied to identify MSI because of its fastness and efficiency. These approaches, however, may fail to identify MSI on one or more sub-clones for certain cancers with a high degree of heterogeneity, leading to erroneous diagnoses and unsuitable treatments. Besides, the computational cost of identifying sub-clonal MSI can be exponentially increased when multiple sub-clones with different length distributions share MSI status. Herein, this paper proposes "scMSI", an accurate and efficient estimation of sub-clonal MSI to identify the microsatellite status. scMSI is an integrative Bayesian method to deconvolute the mixed-length distribution of sub-clones by a novel alternating iterative optimization procedure based on a subtle generative model. During the process of deconvolution, the optimized division of each sub-clone is attained by a heuristic algorithm, aligning with clone proportions that adhere optimally to the sample's clonal structure. To evaluate the performance, 16 patients diagnosed with endometrial cancer, exhibiting positive responses to the treatment despite having negative MSI status based on sequencing-based approaches, were considered. Excitingly, scMSI reported MSI on sub-clones successfully, and the findings matched the conclusions on immunohistochemistry. In addition, testing results on a series of experiments with simulation datasets concerning a variety of impact factors demonstrated the effectiveness and superiority of scMSI in detecting MSI on sub-clones over existing approaches. scMSI provides a new way of detecting MSI for cancers with a high degree of heterogeneity.