A case of rapid progression from Stage I to Stage IV in an MSI-H/EMAST African American colorectal patient

Colorectal cancer (CRC) remains a leading cause of cancer mortality. While most cases arise sporadically, familial risk contributes to about 30%, underscoring the need to assess family history during screening. Microsatellite instability (MSI) is a well-established diagnostic and prognostic biomarker, but elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) remain poorly characterized, particularly among African American patients.We report a 59-year-old African American female with hypertension, hyperlipidemia, and congenital hearing and speech impairment who presented with rectal bleeding. Colonoscopy revealed a 7 cm mass in the transverse colon and a 15 mm sigmoid adenoma. Pathology confirmed a stage I (pT2N0M0) adenocarcinoma that rapidly progressed to stage IV with liver metastasis within one year. Immunohistochemistry showed loss of MLH1 and PMS2 with retained MSH2 and MSH6; MSI testing was MSI-high (BAT26), and EMAST was positive for RBM47.Whole-genome sequencing revealed dense intronic indel clusters in MSH3 , suggesting MutSbeta dysfunction consistent with EMAST. We also identified 21 deleterious missense variants across DNA-repair, immune, and transcriptional pathways (e.g., ZAP70, MSH4, ESR1, ACVR1B, LMNA ). CNV gains were enriched in duplication-rich loci such as 11p15.5, 11q14, 13q31-q22, and 20q11-q13, overlapping oncogenic clusters ( IGF2/H19, DNMT3B, SRC, BCL2L1, E2F1 ). Additionally, 19 frameshift and stop-gain mutations (e.g., GRIK2, NOS3, WNT16 ) introduced premature termination codons.STR profiling demonstrated bidirectional instability-18 expansions and 28 contractions across 46 intronic loci-confirming a pervasive EMAST pattern driven by MSH3 deficiency. This case illustrates a rare, aggressive MSI-H/EMAST CRC with rapid progression, extensive genomic instability, and dual MSI-EMAST features. Findings highlight the biological aggressiveness of combined MSI-H/EMAST tumors and emphasize the need for genetic counseling, molecular surveillance, and targeted precision strategies in underrepresented populations.