Translational Genomics of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) does not respond to receptor targeted treatments because they do not possess the ligands to bind to these receptors. Thus, more research needs to be explored in terms of the translational modifications that genes undergo during this disease.

Summary of Research

Triple-negative breast cancers (TNBCs) present an unresolved clinical dilemma. Many TNBC cases have homologous DNA repair defects associated with BRCA1 or BRCA2 mutations. This homologous recombination deficiency (HRD) is characterized by increases in copy number variations (CNV) and high response rates to DNA damage and repair targeting therapies. The striking resemblance of the CNV data between BRCA1/2 mutant (mt) and subsets of BRCA1/2 wild type (wt) cases suggests that the HRD phenotype can result from mutations in genes other than BRCA1/2. We investigated key genetic alterations targeting DNA repair and assessed their associations with immune checkpoint regulators, PD-1 and PD-L1, in TNBC patients.

Thirteen TNBC samples including 8 HRD-positive cases underwent whole-exome sequencing. Strikingly, 7 of the HRD-positive TNBCs were BRCA wt. We identified non-synonymous mutations in DNA repair genes (e.g. DCLRE1C, BRIP1, CHEK2) in the BRCA wt HRD-positive cases. In contrast, all 5 HRD-negative TNBC patients did not harbor mutations in DNA repair genes. Thus, HRD-positive patients, including BRCA1/2 wt, may be responsive to DNA damage and repair targeting agents. However, there was no correlation with HRD-phenotype and PD- 1/PD-L1 expression. These data will help identify subsets of TNBC patients who may or may not derive benefit from DNA damage and repair targeting therapies and immunotherapy.

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Translational Genomics of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) does not respond to receptor targeted treatments because they do not possess the ligands to bind to these receptors. Thus, more research needs to be explored in terms of the translational modifications that genes undergo during this disease.

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