Abstract
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.
Highlights
Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death both in developed and developing regions [1]
We found a set of gene-centric alterations identified as pathogenic mutations in exomes from invasive breast carcinomas of ductal luminal subtype in a cohort of patients of Southwest Colombia
The mutations were correlated with exome mutations and genome-wide expression alterations detected in a larger set of tumor samples of the same breast cancer subtype from The Cancer Genome Atlas (TCGA)
Summary
Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death both in developed and developing regions [1]. The genetic complexity inherent to cancer is primarily attributable to variation across patients, who suffer different somatically acquired alterations in different genes and present different rates of accumulation of such alterations [8]. In this scenario, the development of large-scale omic techniques, allowing the simultaneous analysis of all active genes in tumor cells versus normal cells, provides a new comprehensive way to discover the genetic alterations that can drive the expression and regulatory changes in the complexity of malignant transformations [9]. In large genomic studies such as The Cancer Genome Atlas (TCGA) project, DNA sequencing (DNA-seq) is the main technique utilized for mutation detection, either using a gene panel sequencing approach or whole exome sequencing approach, while RNA sequencing (RNA-seq) is performed to measure gene expression (looking for coding or noncoding genes) and transcript use (sometimes including splicing analyses to detect isoforms) [10]
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