PO.SHP01.01 · 科学与健康政策
一例MSI-H/EMAST非裔美国结直肠癌患者从I期快速进展至IV期的病例
A case of rapid progression from Stage I to Stage IV in an MSI-H/EMAST African American colorectal patient
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌（CRC）仍是癌症死亡的主要原因之一。虽然大多数病例为散发性，但家族风险约占30%，凸显了在筛查期间评估家族史的必要性。微卫星不稳定性（MSI）是一个公认的诊断和预后生物标志物，但选定四核苷酸重复序列的微卫星改变升高（EMAST）仍缺乏充分表征，尤其是在非裔美国患者中。我们报告一例59岁非裔美国女性，患有高血压、高脂血症以及先天性听力和言语障碍，因直肠出血就诊。结肠镜检查发现横结肠一处7 cm肿块和一处15 mm乙状结肠腺瘤。病理确诊为I期（pT2N0M0）腺癌，并在一年内快速进展为伴肝转移的IV期。免疫组化显示MLH1和PMS2缺失，MSH2和MSH6保留；MSI检测为MSI高（BAT26），EMAST对RBM47呈阳性。全基因组测序揭示MSH3中密集的内含子插入缺失簇，提示与EMAST一致的MutSbeta功能障碍。我们还在DNA修复、免疫和转录通路中识别出21个有害的错义变异（例如ZAP70、MSH4、ESR1、ACVR1B、LMNA）。拷贝数变异（CNV）增益富集于富含重复的位点，如11p15.5、11q14、13q31-q22和20q11-q13，与致癌基因簇（IGF2/H19、DNMT3B、SRC、BCL2L1、E2F1）重叠。此外，19个移码和终止获得突变（例如GRIK2、NOS3、WNT16）引入了提前终止密码子。STR分析显示在46个内含子位点上存在双向不稳定性——18个扩增和28个收缩——证实了由MSH3缺陷驱动的普遍EMAST模式。该病例展示了一例罕见、侵袭性的MSI-H/EMAST CRC，伴有快速进展、广泛的基因组不稳定性以及MSI-EMAST双重特征。研究结果凸显了MSI-H/EMAST联合肿瘤的生物学侵袭性，并强调了在代表性不足人群中开展遗传咨询、分子监测和靶向精准策略的必要性。
查看英文原文 English abstract
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.
利益披露 Disclosure
M. Rashid, None..
H. Brim, None..
R. Zafar, None..
C. Nembhard,, None..
S. Varma, None..
H. Ashktorab, None.