Colorectal Cancer: Sailing with a T-Cell EMAST

During the past two decades, considerable progress has been made in understanding and defining the molecular basis of human colorectal cancer (CRC). The genetic heterogeneity of this disease is now well-established, and it has become clear that a distinct subgroup of CRC possesses a unique form of genetic instability, defined as microsatellite instability (MSI). The MSI phenotype is a hallmark of defective DNA mismatch repair (MMR), and inactivation of MMR genes permits increased instability and accumulation of genomic alterations in the sequences containing mono[e.g.(A)n] and di-nucleotide [e.g. (CA)n] microsatellite repeats. Approximately 12–15% of CRC exhibit high frequency MSI (MSI-H), which includes the majority of Lynch syndrome cancers with germline mutation of a MMR gene and about 12% of sporadic tumors due to methylation-induced transcriptional silencing of the MLH1 gene [1]. The remaining 85% of CRCs either possess very low levels of MSI (MSI-L) or are microsatellite stable (MSS); however, the molecular basis of these tumors remains poorly understood. Almost a decade ago, Sidransky and colleagues described a distinct form of genetic instability present in respiratory tumors, which was termed as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) [2]. In contrast to instability at the monoand di-nucleotide repeats seen in MSI CRCs, EMAST tumors are identified when the frameshift mutations occur at certain tetranucleotide repeat sequences [e.g. (AAAG)n or (ATAG)n]. Since its initial discovery in non-small cell lung cancers [2, 3], EMAST has subsequently been observed in several other human cancers, including skin [4], ovarian [5], endometrial [6], bladder [4, 7], prostate [8, 9] and colorectal [10–13]. Most microsatellite sequences (either mono-, dior tetra-nucleotide repeats) are present in the non-coding regions of DNA; however, small minorities of these tandem repeats exist within the coding sequences of growth regulatory genes that play a critical role in driving CRC pathogenesis. Frameshift mutations within this latter class of genes, such as observed with EMAST, have direct functional consequences for the growth and proliferation of tumor cells. The underlying molecular mechanism(s) causing EMAST remain unclear. The earliest reports in this regard proposed an association of EMAST with mutations in the p53 gene [3, 4]. It was suggested that exposure to environmental carcinogens may exacerbate this phenotype [14]. With the limited evidence at hand, EMAST appears to be distinct from the classic MSI signature that is frequently observed in Lynch syndrome and sporadic CRC. Whether EMAST contributes to tumor progression by specific geneinactivating mutations within repetitive coding sequences, as is the case with MSI-positive CRC, is a matter of ongoing investigation. Recently, it was shown that EMAST is present in the majority of sporadic CRCs [10]. Haugen et al. demonstrated that EMAST is associated with MSI-L and a deficiency in MSH3 protein expression in colorectal cell lines and tumor tissues [10]. Building upon this evidence, later on it was demonstrated that EMAST can be acquired during the adenoma to carcinoma transformation, as well as upon transformation of well-differentiated carcinomas to moderately and poorly differentiated CRCs [12]. Interestingly in this study, EMAST best correlated in CRCs with ulcerated features, and the authors suggested that inflammation may help drive EMAST [12]. A. Goel (&) Gastrointestinal Cancer Research Laboratory, Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, 3500 Gaston Avenue, Suite H-250, Dallas, TX 75246, USA e-mail: ajay.goel@baylorhealth.edu