Breast and ovarian cancers with a BRCA mutation are known to recur at a high rate after initial treatment. Now, a team of researchers at the University of Pennsylvania have discovered factors that may predispose breast and ovarian cancers associated with BRCA1/2 gene mutations that make them more likely to recur.
According to the new report, published in the journal Nature Communications by investigators from the Basser Center for BRCA at the Abramson Cancer Center at UPenn, their comparison of tumors from women with primary and recurrent BRCA1/2 ovarian and breast cancer uncovered multiple factors that led to recurrence, even some that would have been expected to repair DNA damage that result from treatment.
BRCA1 and BRCA2 proteins are important for DNA-repair and their functional loss leaves some cells highly vulnerable to DNA damage—damage that in some cases may lead to cancer. Women with inactivating mutations in the BRCA1 or BRCA2 genes have very high lifetime risks of breast cancer, as well as high risks of ovarian cancer.
In the new study, a team of researchers led by Katherine Nathanson, MD, the Pearl Basser Professor for BRCA-Related Research in Penn’s Perelman School of Medicine, examined 67 sets of primary and recurrent breast and ovarian tumors from BRCA1/2 mutation carriers. For each set, they compared the DNA mutations, gene activity patterns, and other tumor cell features in the primary tumor to see how these features differed from the recurrent tumor. The hope was that by examining the difference between the tumor cell features in primary tumors with those in recurrent tumors, the team could uncover the mechanisms of tumor evolution that leads to recurrent disease.
One indicator of recurrence uncovered by the researchers was especially noted in recurrent cancers with a BRCA1 mutation, was tumor cells switching to expressing a specific isoform of the BRCA2 protein’s messenger-RNA molecule. Slightly shorter than normal BRCA2 RNA, the shorter version still translated into the usual BRCA2 protein, but is more stable than the normal BRCA2 messenger-RNA. Because of this, it would be expected to be associated with an increased level of BRCA2 protein—plausibly as a way of boosting DNA-repair capability.
Prior research has shown, broadly, that when tumor that can increase their ability to repair DNA damage caused by drugs or radiation during treatment are likely to better survive and ultimately recur. The UPenn researchers say the shorter form of the BRCA2 RNA is linked not only to cancer recurrence but also to significantly decreased patient survival times.
A surprising discovery in the research was that a tumor’s loss of the normal copy of the BRCA1 or BRCA2 gene— or loss of heterozygosity—could vary through the tumor’s development. Prior to this research it was believed that loss of heterozygosity was necessary for the development of cancer in BRCA1/2 mutation carriers. The UPenn showe this is not always the case, and report that in 25% of cases loss of heterozygosity can vary between primary and recurrent tumors—a finding that was only possible by examining matched primary and recurrent tumors.
Some tumors progress to not having loss of heterozygosity from having it, as part of tumor progression, while other tumors go from having loss of heterozygosity to not having it, presumably as a mechanism of therapeutic resistance.
“These results suggest key biological features of therapy-resistant recurrences, which point to new possibilities for treating BRCA1/2-mutation cancers,” said Nathanson, who is also the deputy director of the Abramson Cancer Center, and director of genetics at the Basser Center for BRCA.