NEW YORK (GenomeWeb) – A new genomic study focused on triple-negative breast cancers (TNBC) has identified a subset that contains features resembling those in tumors from individuals with pathogenic BRCA1 mutations.
Using a combination of genome, exome, and/or transcriptome sequencing, a team from Japan profiled mutation, structural variants (SVs), and expression patterns in TNBCs from three dozen individuals. The data revealed subsets of tumors with several different mutation signatures — including signatures consistent with BRCA gene mutation or other homologous repair defects — as well as mutations in specific cancer-related genes such as TP53.
As they reported in PLOS Genetics, the researchers also saw suspicious structural changes in the TNBC tumors, ranging from amplifications affecting known oncogenes and tumor suppressors to recurrent SVs falling in an enhancer region for a TGFA gene coding for an epidermal growth factor receptor-binding protein.
"Although TGFA expression is known to be elevated in a subset of TNBC tumors, this is the first report of the mechanistic basis of this phenomenon," corresponding author Masahito Kawazu, a medical genomics researcher at the University of Tokyo, and his co-authors wrote. "It is of particular importance considering that anti-EGFR agents are possible therapeutic options for TNBC patients."
They also noted that their study revealed "several features associated with 'BRCAness,' which is critical for identification of patients who may be responsive to platinum agents and/or poly ADP-ribose polymerase inhibitors."
Poly ADP-ribose polymerase, or PARP, inhibitors have shown promise for treating a subset of TNBCs, the team wrote. Such drugs are expected to show activity in tumors with BRCA1/2 mutations and expected to have an effect on those with other homologous recombination pathway problems, prompting the researchers' interest in finding and characterizing tumors with alterations affecting this process.
"At present, only tumors with mutations in BRCA1 or BRCA2 have been shown to be responsive to PARP inhibitors," they said. "Thus, identification of biomarkers that distinguish responders to PARP inhibitors is required."
With that in mind, the researchers used Illumina HiSeq 2000 or 2500 instruments to sequence protein-coding sequences captured from 36 resected TNBC tumor samples and matched normal tissue from the same individuals. They also did RNA sequencing on 23 of the tumors, along with deep whole-genome sequencing on 16 of the tumors.
Sifting through these data, the team narrowed in on tumors with mutations signatures associated with BRCA mutations, age, or APOBEC activity. And by delving into features found in the BRCA mutation-like tumors, it identified a range of mutations, structural changes, or BRCA1 or RAD51C promoter methylation shifts that appeared to prompt homologous recombination problems.
The investigators also used variant allele frequency to explore the clonality in the TNBC tumors and took a closer look at potential TNBC driver mutations in mouse fibroblast cells. From analyses of the tumors' SV landscape and parts of the genome most frequently impacted by these structural alterations, meanwhile, they noted that such variants may provide more clues to understanding and treating the disease than previously appreciated.
"[T]o reveal the pathogenesis of TNBC and identify the ideal therapeutic target," the authors wrote, "more attention should be focused on SVs that affect not only protein-coding sequences, but also non-coding regulatory elements."