Novel mutations in breast cancer patients from southwestern Colombia.

Breast cancer is the leading cause of death by cancer among women in less developed regions. In Colombia, few published studies have applied next-generation sequencing technologies to evaluate the genetic factors related to breast cancer. This study characterized the exome of three patients with breast cancer from southwestern Colombia to identify likely pathogenic or disease-related DNA sequence variants in tumor cells. For this, the exomes of three tumor tissue samples from patients with breast cancer were sequenced. The bioinformatics analysis identified two pathogenic variants in Fgfr4 and Nf1 genes, which are highly relevant for this type of cancer. Specifically, variant FGFR4-c.1162G>A predisposes individuals to a significantly accelerated progression of this pathology, while NF1-c.1915C>T negatively alters the encoded protein and should be further investigated to clarify the role of this variant in this neoplasia. Moreover, 27 novel likely pathogenic variants were found and 10 genes showed alterations of pathological interest. These results suggest that the novel variants reported here should be further studied to elucidate their role in breast cancer.

Exomes of Ductal Luminal Breast Cancer Patients from Southwest Colombia: Gene Mutational Profile and Related Expression Alterations.

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-ß pathway.

Mutational analysis of BRCA1 and BRCA2 genes in women with familial breast cancer from different regions of Colombia.

PURPOSE: The main risk factor for familial breast cancer is the presence of mutations in BRCA1 and BRCA2 genes. The prevalence of mutations in these genes is heterogeneous and varies according to geographical origin of studied families. In Colombia mutations in these genes have been mainly studied on patients from Andean region. Bogotá and Medellin presented its own battery of mutations. This study aims to identify mutations in BRCA1-2 genes in women with familial breast cancer from different regions of Colombia. METHODS: One hundred four families with a history of breast cancer were sampled in different regions of Colombia, and the BRCA1 gene and exon 11 of the BRCA2 gene were sequenced. To predict the possible effects of sequence alterations found in protein function, different bioinformatics tools were used. RESULTS: A total of 33 variants were found; 18 in BRCA1 and 15 in BRCA2, of which 15 are unique variants of Colombia. In silico analysis established that alterations p.Thr790Ala, p.Arg959Lys and p.Glu1345Lys in the BRCA1 gene and variants p.Leu771Phe, p.Asn818Lys, p.Val859Ser*22 and p.Lys1032Ile in the BRCA2 gene are considered likely pathogenic. Both the mutations as the variants of unknown clinical significance, in their great majority, presented a specific region distribution and they were different from those reported in previous studies. CONCLUSIONS: In this study we report the BRCA1 and BRCA2 spectrum of mutations and their distribution by regions in Colombia. Our results may help to design a diagnostic test including recurrent mutations for screening high risk to breast cancer families in Colombia.