Bioinformatics and Functional Genomics Group, Cancer Research Center (CiC-IMBCC, CSIC/USAL/IBSAL), Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca (USAL), 37007 Salamanca, Spain.
Human Molecular Genetics Lab, Department of Biology, Universidad del Valle, 477027 Meléndez University City, Cali 25360, Colombia.
Biomolecules. 2020 Apr 30;10(5):698. doi: 10.3390/biom10050698.
Cancer is one of the leading causes of mortality worldwide. Breast cancer is the most frequent cancer in women, and in recent years it has become a serious public health problem in Colombia. The development of large-scale omic techniques allows simultaneous analysis of all active genes in tumor cells versus normal cells, providing new ways to discover the drivers of malignant transformations. Whole exome sequencing (WES) was obtained to provide a deep view of the mutational genomic profile in a set of cancer samples from Southwest Colombian women. WES was performed on 52 tumor samples from patients diagnosed with invasive breast cancer, which in most cases (33/52) were ductal luminal breast carcinomas (IDC-LM-BRCA). Global variant call was calculated, and six different algorithms were applied to filter out false positives and identify pathogenic variants. To compare and expand the somatic tumor variants found in the Colombian cohort, exome mutations and genome-wide expression alterations were detected in a larger set of tumor samples of the same breast cancer subtype from TCGA (that included DNA-seq and RNA-seq data). Genes with significant changes in both the mutational and expression profiles were identified, providing a set of genes and mutations associated with the etiology of ductal luminal breast cancer. This set included 19 single mutations identified as tumor driver mutations in 17 genes. Some of the genes (ATM, ERBB3, ESR1, TP53) are well-known cancer genes, while others (CBLB, PRPF8) presented driver mutations that had not been reported before. In the case of the CBLB gene, several mutations were identified in TCGA IDC-LM-BRCA samples associated with overexpression of this gene and repression of tumor suppressive activity of TGF-β pathway.
癌症是全球主要死亡原因之一。乳腺癌是女性最常见的癌症，近年来已成为哥伦比亚严重的公共卫生问题。大规模组学技术的发展使得能够同时分析肿瘤细胞与正常细胞中所有活跃的基因，为发现恶性转化的驱动因素提供了新的途径。进行了全外显子组测序（WES），以提供一组来自哥伦比亚西南部女性癌症样本中突变基因组特征的深入视图。对 52 名浸润性乳腺癌患者的肿瘤样本进行了 WES，其中大多数（33/52）为导管内乳癌（IDC-LM-BRCA）。计算了全局变异调用，并应用了六种不同的算法来过滤掉假阳性并识别致病性变异。为了比较并扩展在哥伦比亚队列中发现的体细胞肿瘤变异，对同一乳腺癌亚型的更大一组肿瘤样本进行了外显子突变和全基因组表达改变检测，这些样本来自 TCGA（包括 DNA-seq 和 RNA-seq 数据）。在突变和表达谱中都有显著变化的基因被鉴定出来，为导管内乳癌的病因提供了一组与基因和突变相关的基因。这组基因包括 17 个基因中的 19 个单突变，这些突变被鉴定为肿瘤驱动突变。其中一些基因（ATM、ERBB3、ESR1、TP53）是众所周知的癌症基因，而其他基因（CBLB、PRPF8）则存在以前未报道过的驱动突变。在 CBLB 基因的情况下，在 TCGA IDC-LM-BRCA 样本中鉴定出了几个与该基因过表达和抑制 TGF-β 途径肿瘤抑制活性相关的突变。
