BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features.
BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: an aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features.
复制标题
DOI：
10.1097/pas.0b013e31824430d7
复制
发表时间：
2012-05
期刊：
影响因子：
--
通讯作者：
Pai RK
中科院分区：
文献类型：
--
作者：
Pai RK;Jayachandran P;Koong AC;Chang DT;Kwok S;Ma L;Arber DA;Balise RR;Tubbs RR;Shadrach B;Pai RK
BRAF V600 E突变与CpG岛甲基化表型（CIMP）和微卫星不稳定性（MSI）的存在之间的关联经常混淆BRAF突变状态和结直肠癌生存率的分析。我们评估了一系列连续的近端结肠腺癌的错配修复蛋白异常/MSI、BRAF V600 E突变和KRAS突变，试图确定这些异常的预后意义，并将组织病理学特征与分子改变相关联。在259例分析错配修复蛋白异常和/或MSI的近端结肠腺癌中，181例近端结肠腺癌通过MSI PCR（n = 78）、错配修复蛋白免疫组织化学（n = 91）或MSI PCR和错配修复免疫组织化学（n = 12）显示出熟练的DNA错配修复;对这些进行BRAF V600 E突变和KRAS突变的检测。与BRAF野生型腺癌相比，BRAF突变腺癌更常表现出不良的组织学特征，如淋巴管浸润（16/20，80% vs. 75/161，47%; P = 0.008），平均淋巴结转移数（4.5 vs. 2.2; P = 0.01）、神经周围浸润（8/20，40% vs. 13/161，8%; P = 0.0004）和高肿瘤出芽（16/20，80% vs. 83/161，52%; P = 0.02）。与KRAS突变和KRAS/BRAF野生型腺癌相比，BRAF突变腺癌经常包含粘液组织学（P = 0.0002）和印戒组织学（P = 0.03）区域。临床随访资料可用于173例具有熟练DNA错配修复的近端结肠腺癌。BRAF突变腺癌患者的中位生存期为12.3个月，1年生存概率为54%，1年无病生存率为56%。与BRAF突变腺癌患者相比，KRAS突变和KRAS/BRAF野生型腺癌患者的总生存率（分别为未校正的对数秩P = 0.03和未校正的对数秩P = 0.0002）和无病生存率（分别为未校正的对数秩P = 0.02和未校正的对数秩P = 0.02）显著改善。当调整肿瘤分期时，生存分析表明，与KRAS/BRAF野生型腺癌患者相比，BRAF突变腺癌患者的总生存期和无病生存期显著较差（风险比分别为6.63，95% CI，2.60-16.94;和6.08，95% CI，2.11-17.56）。KRAS突变型和KRAS/BRAF野生型腺癌患者的总体生存率或无病生存率无显著差异。我们的研究结果表明，BRAF突变的近端结肠腺癌与熟练的DNA错配修复有一个令人沮丧的预后与积极的临床过程，往往显示粘液分化，局灶性印戒组织学，和其他不良的组织学特征，如淋巴和神经浸润和高肿瘤出芽。
The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic ad-enocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n = 78), mismatch repair protein immunohistochemistry (n = 91), or both MSI PCR and mismatch repair immunohistochemistry (n = 12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P = 0.008), mean number of lymph node metastases (4.5 vs. 2.2; P = 0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P = 0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P = 0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P = 0.0002) and signet ring histology (P = 0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P = 0.03 and unadjusted log-rank P = 0.0002, respectively) and disease-free survival (unadjusted log-rank P = 0.02 and unadjusted log-rank P = 0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60–16.94; and 6.08, 95% CI, 2.11–17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.