SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer
SMAD4 alteration associates with invasive-front pathological markers and poor prognosis in colorectal cancer
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DOI：
10.1111/his.13805
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发表时间：
2019-05-01
期刊：
影响因子：
6.4
通讯作者：
Wakai, Toshifumi
中科院分区：
文献类型：
--
作者：
Oyanagi, Hidehito;Shimada, Yoshifumi;Wakai, Toshifumi
SMAD 4是一种肿瘤抑制因子，SMAD 4的缺失与结直肠癌（CRC）患者的预后不良相关。虽然下一代测序（NGS）使我们能够在一次检测中检测到许多遗传变异，但用NGS检测到的SMAD 4变异的临床意义尚未得到充分研究。本研究的目的是探讨SMAD 4基因在结直肠癌中的临床病理特征及临床意义。方法和结果我们回顾性研究了201例I-IV期结直肠癌患者，使用415个基因面板。为了分析SMAD 4改变与其他临床病理特征之间的关系，我们评估了临床病理变量，包括侵袭性前沿病理标志物：肿瘤出芽、低分化簇和克罗恩样淋巴反应。五十六例患者（28%）有SMAD 4改变：分别有24例和32例患者有SMAD 4突变和缺失。SMAD 4改变与T分类（P = 0.027）、N分类（P = 0.037）、M分类（P = 0.028）和浸润前沿病理标记物显著相关，如低分化簇3级（P = 0.020）和无克罗恩样淋巴反应（P = 0.004）。免疫组化显示SMAD 4改变与SMAD 4丢失显著相关（P = 0.023）。在90例I-III期患者中，SMAD 4改变与无复发和总生存率的不良预后显著相关（分别为P = 0.047; P = 0.022）。相反，在111例IV期疾病患者中，SMAD 4改变与总生存率无显著相关性。结论SMAD 4基因异常与I ~ III期结直肠癌患者的浸润前沿病理标志物及不良预后相关。
Aims SMAD4 acts as a tumour suppressor, and the loss of SMAD4 is associated with poor prognosis in colorectal cancer (CRC) patients. Although next-generation sequencing (NGS) enabled us to detect numerous genetic alterations in a single assay, the clinical significance of SMAD4 alteration detected with NGS has not been fully investigated. The aim of this study was to evaluate the clinicopathological characteristics and clinical significance of SMAD4 alteration detected with NGS in CRC. Methods and results We retrospectively investigated 201 patients with stage I-IV CRC, by using a 415-gene panel. To analyse the relationship between SMAD4 alteration and other clinicopathological characteristics, we evaluated clinicopathological variables, including invasive-front pathological markers: tumour budding, poorly differentiated cluster, and Crohn-like lymphoid reaction. Fifty-six patients (28%) had SMAD4 alteration: 24 and 32 patients had SMAD4 mutation and deletion, respectively. SMAD4 alteration was significantly associated with T category (P = 0.027), N category (P = 0.037), M category (P = 0.028), and invasive-front pathological markers, such as poorly differentiated cluster grade 3 (P = 0.020) and absence of Crohn-like lymphoid reaction (P = 0.004). Immunohistochemistry revealed that SMAD4 alteration was significantly associated with loss of SMAD4 (P = 0.023). In 90 patients with stage I-III disease, SMAD4 alteration was significantly associated with poor prognosis for relapse-free and overall survival (P = 0.047; P = 0.022, respectively). Conversely, in 111 patients with stage IV disease, SMAD4 alteration was not significantly associated with overall survival. Conclusion SMAD4 alteration is associated with invasive-front pathological markers and poor prognosis in stage I-III CRC patients.