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The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333‐3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278‐1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants. [ABSTRACT FROM AUTHOR]

The cost reduction in sequencing and the extensive genomic characterization of a wide variety of cancers are expanding tumor sequencing to a wide number of research groups and the clinical practice. Although specific pipelines have been generated for the identification of somatic mutations, their results usually differ considerably, and a common approach is to use several callers to achieve a more reliable set of mutations. This procedure is computationally expensive and time-consuming, and it suffers from the same limitations in sensitivity and specificity as other approaches. Expert revision of mutant calls is therefore required to verify calls that might be used for clinical diagnosis. This step could take advantage of machine learning techniques, as they provide a useful approach to incorporate expert-reviewed information for the identification of somatic mutations. Here we present RFcaller, a pipeline based on machine learning algorithms, for the detection of somatic mutations in tumor-normal paired samples that does not require large computing resources. RFcaller shows high accuracy for the detection of substitutions and insertions/deletions from whole genome or exome data. It allows the detection of mutations in driver genes missed by other approaches, and has been validated by comparison to deep and Sanger sequencing., (© The Author(s) 2023. Published by Oxford University Press on behalf of NAR Genomics and Bioinformatics.)

Taxanes are the mainstay of treatment in triple-negative breast cancer (TNBC), with de novo and acquired resistance limiting patient's survival. To investigate the genetic basis of docetaxel resistance in TNBC, exome sequencing was performed on matched TNBC patient-derived xenografts (PDX) sensitive to docetaxel and their counterparts that developed resistance in vivo upon continuous drug exposure. Most mutations, small insertions/deletions, and copy number alterations detected in the initial TNBC human metastatic samples were maintained after serial passages in mice and emergence of resistance. We identified a chromosomal amplification of chr12p in a human BRCA1 -mutated metastatic sample and the derived chemoresistant PDX, but not in the matched docetaxel-sensitive PDX tumor. Chr12p amplification was validated in a second pair of docetaxel-sensitive/resistant BRCA1 -mutated PDXs and after short-term docetaxel treatment in several TNBC/ BRCA1 -mutated PDXs and cell lines, as well as during metastatic recurrence in a patient with BRCA1 -mutated breast cancer who had progressed on docetaxel treatment. Analysis of clinical data indicates an association between chr12p amplification and patients with TNBC/basal-like breast cancer, a BRCA1 mutational signature, and poor survival after chemotherapy. Detection of chr12p amplification in a cohort of TNBC PDX models was associated with an improved response to carboplatin. Our findings reveal tumor clonal dynamics during chemotherapy treatments and suggest that a preexisting population harboring chr12p amplification is associated with the emergence of docetaxel resistance and carboplatin responsiveness in TNBC/ BRCA1 -mutated tumors. SIGNIFICANCE: Chr12p copy number gains indicate rapid emergence of resistance to docetaxel and increased sensitivity to carboplatin, therefore sequential docetaxel/carboplatin treatment could improve survival in TNBC/ BRCA1 patients. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4258/F1.large.jpg., (©2019 American Association for Cancer Research.)

Proteases constitute up to 3% of all protein-coding genes in a vertebrate genome and participate in numerous physiological and pathological processes. The characterization of the degradome of one organism, the set of all genes encoding proteolytic enzymes, and the comparison to the degradome of other species have proved useful to identify genetic differences that are helpful to elucidate the molecular basis of diverse biological processes, the different susceptibility to disease, and the evolution of the structure and function of proteases. Here we describe the main procedures involved in the characterization of the degradome of an organism for which its genome sequence is available.