Wielandt Ana María, Hurtado Claudia, Moreno C Mauricio, Villarroel Cynthia, Castro Magdalena, Estay Marlene, Simian Daniela, Martinez Maripaz, Vial Maria Teresa, Kronberg Udo, López-Köstner Francisco
Oncology and Molecular Genetics Laboratory, Coloproctology Unit, Clínica Las Condes, Santiago, Chile.
Coloproctology Unit, Clínica Las Condes, Santiago, Chile.
Tumour Biol. 2020 Jul;42(7):1010428320938492. doi: 10.1177/1010428320938492.
Molecular classification of colorectal cancer is difficult to implement in clinical settings where hundreds of genes are involved, and resources are limited. This study aims to characterize the molecular subtypes of patients with sporadic colorectal cancer based on the three main carcinogenic pathways microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and chromosomal instability (CIN) in a Chilean population. Although several reports have characterized colorectal cancer, most do not represent Latin-American populations. Our study includes 103 colorectal cancer patients who underwent surgery, without neoadjuvant treatment, in a private hospital between 2008 and 2017. MSI, CIN, and CIMP status were assessed. Frequent mutations in KRAS, BRAF, and PIK3CA genes were analyzed by Sanger sequencing, and statistical analysis was performed by Fisher's exact and/or chi-square test. Survival curves were estimated with Kaplan-Meier and log-rank test. Based on our observations, we can classify the tumors in four subgroups, Group 1: MSI-high tumors (15%) are located in the right colon, occur at older age, and 60% show a BRAF mutation; Group 2: CIN-high tumors (38%) are in the left colon, and 26% have KRAS mutations. Group 3: [MSI/CIN/CIMP]-low/negative tumors (30%) are left-sided, and 39% have KRAS mutations; Group 4: CIMP-high tumors (15%) were more frequent in men and left side colon, with 27% KRAS and 7% presented BRAF mutations. Three percent of patients could not be classified. We found that CIMP-high was associated with a worse prognosis, both in MSI-high and MSI stable patients (p = 0.0452). Group 3 (Low/negative tumors) tend to have better overall survival compared with MSI-high, CIMP-high, and CIN-high tumors. This study contributes to understanding the heterogeneity of tumors in the Chilean population being one of the few characterizations performed in Latin-America. Given the limited resources of these countries, these results allow to improve molecular characterization in Latin-American colorectal cancer populations and confirm the possibility of using the three main carcinogenic pathways to define therapeutic strategies.
在涉及数百个基因且资源有限的临床环境中，结直肠癌的分子分类难以实施。本研究旨在基于微卫星不稳定性（MSI）、CpG岛甲基化表型（CIMP）和染色体不稳定性（CIN）这三种主要致癌途径，对智利人群中散发性结直肠癌患者的分子亚型进行特征描述。尽管已有多篇报道对结直肠癌进行了特征描述，但大多数研究并不代表拉丁美洲人群。我们的研究纳入了2008年至2017年间在一家私立医院接受手术且未接受新辅助治疗的103例结直肠癌患者。评估了MSI、CIN和CIMP状态。通过桑格测序分析KRAS、BRAF和PIK3CA基因的常见突变，并采用Fisher精确检验和/或卡方检验进行统计分析。采用Kaplan-Meier法和对数秩检验估计生存曲线。基于我们的观察结果，我们可将肿瘤分为四个亚组，第1组：MSI高肿瘤（15%）位于右半结肠，发病年龄较大，60%显示BRAF突变；第2组：CIN高肿瘤（38%）位于左半结肠，26%有KRAS突变。第3组：[MSI/CIN/CIMP]低/阴性肿瘤（30%）位于左侧，39%有KRAS突变；第4组：CIMP高肿瘤（15%）在男性和左半结肠中更为常见，27%有KRAS突变，7%有BRAF突变。3%的患者无法分类。我们发现，在MSI高和MSI稳定的患者中，CIMP高均与较差的预后相关（p = 0.0452）。与MSI高、CIMP高和CIN高的肿瘤相比，第3组（低/阴性肿瘤）往往具有更好的总生存期。本研究有助于了解智利人群中肿瘤的异质性，是拉丁美洲为数不多的特征描述之一。鉴于这些国家资源有限，这些结果有助于改善拉丁美洲结直肠癌人群的分子特征描述，并证实利用三种主要致癌途径来确定治疗策略的可能性。
