Department of Pathology, West China Hospital, Sichuan University, No.37 GuoXueXiang, Chengdu, 610041, Sichuan, China.
Department of Abdominal Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
Virchows Arch. 2019 Jul;475(1):39-47. doi: 10.1007/s00428-019-02576-y. Epub 2019 May 6.
Our study was done in order to identify novel molecular markers to predict which locally advanced rectal cancers (LARCs) might be resistant to neoadjuvant chemoradiotherapy (nCRT). Seventy-four patients with LARCs treated with nCRT were collected. Pathological evaluation after nCRT was performed according to the tumor regression grading (TRG) system. Next-generation sequencing kit including 279 exons of 59 genes was performed on Illumina Miseq Platform. Sanger sequencing was performed to confirm some mutations. Four of the tumors (4/74, 5.4%) had BRAF mutation, which presented in one TRG 2 tumor and three TRG 3 tumors but was not observed in TRG 0-1 tumors. Higher mutational frequency of BRAF gene in TRG 3 tumors (3/12, 25%) was found in comparison with the TRG 0-2 tumors (1/62, 1.6%; p = 0.012). Eight tumors (8/74, 10.8%) harbored SMAD4 mutations, which was mutated across all TRG groups. However, SMAD4 mutated more in TRG 3 tumors (4/12, 33.3%) compared with that in TRG 0-2 tumors (4/62, 6.5%; p = 0.020). The patients with BRAF-mutated LARCs had shorter progression-free survival (PFS) (p = 0.045) and shorter overall survival (OS) (p = 0.000) than the BRAF wild-type (WT) ones. The patients with SMAD4-mutated tumors had shorter PFS than the WT cases (p = 0.008). BRAF and SMAD4 genetic mutations might be important molecular markers to predict resistance to nCRT and poor prognosis in LARCs. More cases are needed to confirm these findings in the near future.
我们的研究旨在确定新的分子标志物，以预测哪些局部晚期直肠癌（LARC）可能对新辅助放化疗（nCRT）有抵抗作用。我们收集了 74 例接受 nCRT 治疗的 LARC 患者。根据肿瘤消退分级（TRG）系统对 nCRT 后的病理评估进行评估。在 Illumina Miseq 平台上进行了包括 59 个基因的 279 个外显子的下一代测序试剂盒。对一些突变进行了 Sanger 测序以确认。其中 4 例肿瘤（4/74，5.4%）存在 BRAF 突变，其中 1 例为 TRG 2 肿瘤，3 例为 TRG 3 肿瘤，但在 TRG 0-1 肿瘤中未观察到。与 TRG 0-2 肿瘤（1/62，1.6%；p=0.012）相比，TRG 3 肿瘤中 BRAF 基因突变的频率更高（3/12，25%）。8 例肿瘤（8/74，10.8%）存在 SMAD4 突变，其突变发生在所有 TRG 组中。然而，与 TRG 0-2 肿瘤（4/62，6.5%；p=0.020）相比，TRG 3 肿瘤中 SMAD4 突变更多。携带 BRAF 突变的 LARC 患者的无进展生存期（PFS）（p=0.045）和总生存期（OS）（p=0.000）更短，与 BRAF 野生型（WT）患者相比。携带 SMAD4 突变肿瘤的患者的 PFS 短于 WT 病例（p=0.008）。BRAF 和 SMAD4 基因突变可能是预测 LARC 对 nCRT 抵抗和不良预后的重要分子标志物。在不久的将来需要更多的病例来证实这些发现。
