Researchers have discovered the factors that may make breast and ovarian cancers associated with BRCA1 and BRCA2 gene mutations more likely to recur, according to new findings published by Shah et al in Nature Communications.
These mutations are known to strongly predispose women to breast and ovarian cancers that have a high risk of recurrence after initial treatment. In the new study, researchers compared a large set of tumors from patients with primary and recurrent BRCA1 or BRCA2 mutation–associated breast and ovarian cancers, and found multiple features associated with recurrence—including factors that would be expected to improve the tumors’ ability to repair treatment-caused DNA damage.
“These results suggest key biological features of therapy-resistant recurrences, which point to new possibilities for treating BRCA1- [and BRCA2]-mutat[ed] cancers,” said senior study author Katherine Nathanson, MD, the Pearl Basser Professor for BRCA-Related Research and Deputy Director of the Abramson Cancer Center, and the Director of Genetics at the Basser Research Center at the University of Pennsylvania Perelman School of Medicine.
Study Background
Female patients with inactivating mutations in the BRCA1 or BRCA2 genes may opt for mastectomies or oophorectomies to reduce their cancer risks, or may choose to undergo close monitoring aimed at detecting cancers at the earliest stages.
However, many patients learn that they have a BRCA1 or BRCA2 mutation only after breast or ovarian cancer has developed—often when the diseases are too advanced to be treated surgically. These BRCA1 and BRCA2 mutation–associated tumors may often go into remission with chemotherapy and radiation, which take advantage of the tumors’ lower DNA-repair capacity. But these tumors have a high risk of recurrence within a few years after patients complete their first-line therapy—and scientists know relatively little about the factors that drive recurrence.
Study Methods and Findings
In the study, the researchers examined 67 instances of primary and recurrent breast and ovarian tumors from BRCA1- and BRCA2-mutation carriers. For each instance, they compared the DNA mutations, gene activity patterns, and other cell features in the primary tumors to see how these factors differed from those of the recurrent tumors.
“We hypothesized that differences between paired tumors could point to possible mechanisms of tumor evolution allowing recurrence,” Dr. Nathanson said.
One novel observation was that, especially in BRCA1-mutation recurrent cancers, the tumor cells have often switched to expressing a specific isoform of the BRCA2 protein’s messenger RNA molecule—an isoform that is slightly shorter than the typical length of BRCA2 RNA. It is translated into the usual BRCA2 protein but is more stable than the normal BRCA2 messenger RNA, and thus, may be associated with an increased level of BRCA2 protein—and may be capable of boosting the tumor’s DNA-repair capability. In general, tumors treated with strong DNA-damaging drugs and/or radiation may survive that treatment better, and ultimately recur, when they can increase their ability to repair DNA damage. The researchers linked the presence of the shorter form of the BRCA2 RNA not only to cancer recurrence but also to significantly decreased survival.
Similarly, the researchers were surprised to find that the state of the tumor’s loss of heterozygosity could vary throughout its development. Loss of heterozygosity had been generally assumed to be necessary for development of breast and ovarian cancers in germline BRCA1- and BRCA2-mutation carriers, but the researchers’ findings have shown that it is not always needed. They have found that loss of heterozygosity can vary between primary and recurrent tumors in 25% of cases—a novel finding only possible with matched primary and recurrent tumors. Some tumors have been found to progress to a state of having heterozygosity from a state of initially lacking loss of heterozygosity as part of tumor progression. Other tumors go from initially having loss of heterozygosity to lacking it as a mechanism of therapeutic resistance.
In summary, the researchers discovered several novel markers of therapeutic resistance, which they say underscores the importance of profiling the tumors at the time of treatment. Dr. Nathanson and her colleagues are continuing to evaluate multiple other factors that contribute to therapeutic response and resistance in patients with BRCA1- and BRCA2-related tumors.
Disclosure: The research in this study was supported by the Basser Center for BRCA at the University of Pennsylvania, the Gray Foundation, the V Foundation for Cancer Research, the Breast Cancer Research Foundation, the Miguel Servet Programme, Asociación Española Contra el Cáncer, and the National Institutes of Health. For full disclosures of the study authors, visit nature.com.
