Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York.
JAMA Netw Open. 2021 Dec 1;4(12):e2136913. doi: 10.1001/jamanetworkopen.2021.36913.
Accurate clinical staging is important in rectal cancer because it determines the appropriate treatment and prognosis. Despite the use of multiple diagnostic imaging tools, it is sometimes difficult to clinically distinguish stage I tumors from stage II or III locally advanced disease. Identification of differentiating microRNAs (miRNAs) between these 2 groups may improve the clinical diagnostic power and provide insight into the biology of tumor progression.
To investigate differences in the expression of miRNAs in stage I vs stage II or III rectal cancers and integrate matched mRNA profiling data to identify possible functional roles of these miRNAs.
DESIGN, SETTING, AND PARTICIPANTS: The primary tumor specimens from patients who were enrolled in 2 prospective clinical trials between March 24, 2004, and November 16, 2012 (American College of Surgeons Oncology Group [ACOSOG] Z6041 and Timing of Rectal Cancer Response to Chemoradiation [TIMING]) were sequenced to arrive at a set of 127 cases (41 stage I and 86 stage II or III tumors) with matched miRNA and messenger RNA (mRNA) profiling data. These findings were also evaluated in an independent cohort of 127 patient specimens (29 stage I and 98 stage II or III tumors) from The Cancer Genome Atlas Rectum Adenocarcinoma (TCGA-READ) that also had matched miRNA and mRNA data. Data analysis was performed from September 1, 2019, to September 1, 2020.
Alterations in miRNA expression between stage I and stage II or III tumors and their potential gene targets.
A total of 254 pretreatment rectal adenocarcinoma specimens were analyzed in this study as 2 distinct cohorts: 127 samples in the ACOSOG/TIMING (stage I group: 27 [66%] male; mean [SD] age, 64.4 [10.8] years; stage II or III group: 47 [55%] male; mean [SD] age, 57.0 [11.4] years), and another 127 samples from TCGA-READ (stage I group: 17 [59%] male; mean [SD] age, 63.6 [12.0] years; stage II or III group: 48 [49%] male; mean [SD] age, 64.5 [11.4] years). A total of 19 miRNAs were overexpressed in stage II or III vs stage I tumors in both cohorts. This miRNA signature had an excellent discriminative value for distinguishing stage II or III from stage I rectal tumors (area under the curve, 0.88; 95% CI, 0.83-0.94 in ACOSOG/TIMING cohort and area under the curve, 0.84; 95% CI, 0.77-0.91 in the TCGA-READ cohort). Integrative analysis revealed 3 miRNA-mRNA pairs that exhibited significant correlations in both cohorts: miR-31-5p-SATB2, miR-143-3p-KLF5, and miR-204-5p-EZR.
This diagnostic study found that many of the dysregulated miRNAs in stage II or III vs stage I rectal cancers have biological implications for tumor progression. The results of this study suggest that these miRNAs could assist as diagnostic biomarkers to better identify patients with locally advanced rectal cancer.
准确的临床分期在直肠癌中很重要，因为它决定了适当的治疗和预后。尽管使用了多种诊断影像学工具，但有时仍难以临床区分 I 期肿瘤与局部进展期 II 期或 III 期疾病。鉴定这 2 组之间的差异表达 microRNAs（miRNAs）可能会提高临床诊断能力，并深入了解肿瘤进展的生物学特性。
研究 I 期与 II 期或 III 期直肠肿瘤之间 miRNA 的表达差异，并整合匹配的 mRNA 谱数据，以确定这些 miRNA 的可能功能作用。
设计、设置和参与者：在 2004 年 3 月 24 日至 2012 年 11 月 16 日之间进行的两项前瞻性临床试验（美国外科医师学院肿瘤学组 [ACOSOG] Z6041 和直肠癌对放化疗反应的时间 [TIMING]）中，对患者的原发肿瘤标本进行测序，得出了一组 127 例病例（41 例 I 期和 86 例 II 期或 III 期肿瘤），这些病例具有匹配的 miRNA 和信使 RNA（mRNA）谱数据。这些发现也在来自癌症基因组图谱直肠腺癌（TCGA-READ）的 127 例患者标本（29 例 I 期和 98 例 II 期或 III 期肿瘤）中进行了评估，这些标本也具有匹配的 miRNA 和 mRNA 数据。数据分析于 2019 年 9 月 1 日至 2020 年 9 月 1 日进行。
I 期和 II 期或 III 期肿瘤之间 miRNA 表达的变化及其潜在的基因靶标。
本研究共分析了 254 例直肠腺癌标本，分为 2 个独立队列：ACOSOG/TIMING 队列中的 127 例样本（I 期组：27[66%]例男性；平均[SD]年龄，64.4[10.8]岁；II 期或 III 期组：47[55%]例男性；平均[SD]年龄，57.0[11.4]岁）和 TCGA-READ 队列中的另 127 例样本（I 期组：17[59%]例男性；平均[SD]年龄，63.6[12.0]岁；II 期或 III 期组：48[49%]例男性；平均[SD]年龄，64.5[11.4]岁）。两个队列中，共有 19 个 miRNA 在 II 期或 III 期肿瘤中表达过度。该 miRNA 特征对区分 II 期或 III 期与 I 期直肠肿瘤具有极好的鉴别价值（ACOSOG/TIMING 队列的曲线下面积为 0.88[95%CI，0.83-0.94]，TCGA-READ 队列的曲线下面积为 0.84[95%CI，0.77-0.91]）。综合分析显示，在两个队列中都有 3 个 miRNA-mRNA 对存在显著相关性：miR-31-5p-SATB2、miR-143-3p-KLF5 和 miR-204-5p-EZR。
这项诊断研究发现，II 期或 III 期与 I 期直肠癌中许多失调的 miRNA 具有肿瘤进展的生物学意义。这项研究的结果表明，这些 miRNA 可以作为辅助诊断生物标志物，以更好地识别局部进展期直肠癌患者。
