No matter how they come about, functional impairments in the DNA repair protein BRCA1 will hamper cells' ability to repair their genome, and increase the chances that a cell will become cancerous.

However, researchers from the Jackson Laboratory for Genomic Medicine reported in the July 6, 2022, issue of Science Translational Medicine that reduced BRCA1 activity that was due to methylation of its promoter differed from BRCA1 mutation in terms of its response to platinum chemotherapy.

"Unlike [BRCA-mutated] cancers, where BRCA loss is a genetically "fixed" deficiency state, [BRCA1-methylated] cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy." The findings add another layer of complexity to the therapeutic implications of BRCA1, which was originally identified in 1990. Since then, it has repeatedly served as an example for much broader trends in cancer research.

BRCA1 was originally identified as "the breast cancer gene" by Marie-Claire King. But since then, mutations in BRCA1 – and the related BRCA2 – have been identified as drivers in other tumor types, too, illustrating that molecular alterations can cut across anatomically defined tumors.

Poly (ADP-ribose) polymerase (PARP) inhibitors are approved for the treatment of BRCA-mutated breast, ovarian, prostate, and pancreatic tumors, and clinical studies have shown benefit in some other tumor types as well.

PARP inhibitors are highly innovative drugs, the first successful example of approaching a target via the concept of synthetic lethality.

Mutations are far more likely to be deleterious than to confer a selective advantage, so the ability to repair DNA damage is crucial for cells. As a result, there are redundant pathways dedicated to this function.

BRCA mutations damage one of those pathways. But due to the presence of redundant pathways, cells remain able to repair at least some of the damage to their DNA, and limp along rather than going into apoptosis.

PARP inhibitors work by shutting down a redundant pathway, rather than trying to alter the function of the pathway that is compromised by the BRCA mutations. The concept is called synthetic lethality, and is likely to yield more success stories.

In a 2019 review on "Synthetic lethality as an engine for cancer drug target discovery," the authors asserted that exploiting synthetic lethality has "broad potential to drive the discovery of the next wave of genetic cancer targets."

The approach could replace mutational analysis, which has "largely been exhausted as a strategy for the identification of new cancer targets that are druggable with conventional approaches."

Biopharma has been paying attention – synthetic lethality is one of the four "core focus areas" of GSK's oncology efforts.

Not all variants in the BRCA gene (or any other gene, for that matter) have the same effect on cells, though.

Some mutations are known to be pathogenic, some are known to be benign, and the "variants of unknown significance" (VUS) are the biggest headache from a clinical perspective, as it's unknown whether they raise the risk of cancer and so, whether preventive measures would be appropriate.

BRCA that has been silenced via methylation of its promoter presents a similar clinical conundrum. It is not, technically speaking, a VUS, because it is not a mutation in the gene. But there have been conflicting reports about whether promoter methylation affected the sensitivity of BRCA-driven tumors to platinum chemotherapy, which is usually a highly effective treatment strategy. And patients with ovarian or triple-negative breast cancers (TNBCs) that are driven by BRCA methylation do not have the same high overall survival rates that are typical of BRCA-mutated tumors.

In their experiments, the team compared the effects of methylation and mutation in impairing BRCA DNA repair. They showed that methylation and mutation led to the same genomic signature, in form of a high mutation rate.

The response to treatment, though, was a different matter.

"Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance," the authors wrote.

In other words, methylation, unlike mutation, can be changed in the face of selective pressure. Which is what happened with the methylated tumors.

The team also compared the value of two measures that are used to predict the response to therapy, immune scores and homologous recombination deficiency signatures.

They showed that high immune scores predicted better outcomes in tumors without BRCA mutations, but not in BRCA-driven tumors. And as might be expected from their insights into the reversible nature of BRCA methylation during chemotherapy, homologous recombination deficiency signatures predicted response to therapy in mutated but not in methylated tumors.