BRCA Gene Mutations May Influence Survival, Treatment Response in Ovarian Cancer || NCI Cancer Bulletin for October 18, 2011 - National Cancer Institute

 

BRCA Gene Mutations May Influence Survival, Treatment Response in Ovarian Cancer

Women with ovarian cancer who have a mutated form of the BRCA2 gene may be more likely to respond to standard chemotherapy and have better overall and progression-free survival than women without the mutation, according to a new study published October 12 in JAMA. The findings also suggested that women with BRCA1 mutations had better overall and progression-free survival than women whose tumors lacked the mutations, but these latter findings were not statistically significant.

To conduct the observational study, Dr. Da Yang of the University of Texas M. D. Anderson Cancer Center and his colleagues analyzed genomic and clinical data from the tumors of 316 women with high-grade serous ovarian cancer. The data were made available in 2009 and 2010 from the NCI-supported The Cancer Genome Atlas (TCGA) program. Most of the women in the study (219) had nonmutated forms of the BRCA1 and BRCA2 genes. Only 27 women had BRCA2 mutations, and 35 had BRCA1 mutations.

Overall, 61 percent of women with BRCA2 mutations were alive after 5 years compared with 25 percent of women with non-mutated BRCA1 and BRCA2 genes and 44 percent of women with BRCA1 mutations. All of the women with BRCA2 mutations responded to chemotherapy, whereas 82 percent of women with wild-type BRCA genes and 80 percent of women with BRCA1-mutations responded.

“Our observations provide evidence that BRCA1 and BRCA2 mutations are differentially associated with patient survival compared with [non-mutated] BRCA and that this difference may be a result of distinct response to platinum-based treatment and different associations with genome instability,” the study authors wrote. Because of the relatively small size of the study, they acknowledged, more research is needed to validate the findings.

The study results provide “a major advance” in the understanding of how to test new treatments in women with ovarian cancer, wrote Drs. Victor Grann and Ramon Parsons of the Columbia University Medical Center in an accompanying editorial. They cited, for example, clinical trials that could test PARP inhibitors in women with ovarian cancer to test whether patients with BRCA1 or BRCA2 mutations respond differently.
A larger, NCI-led study presented earlier this year at the American Association for Cancer Research annual meeting had similar findings, including improved overall survival in women with ovarian cancer whose tumors had BRCA2 mutations.

Further reading: "Study Suggests How the BRCA1 Protein May Help Suppress Tumors"

NCI Cancer Bulletin for October 18, 2011 - National Cancer Institute

Study Suggests How the BRCA1 Protein May Help Suppress Tumors

Mutations in the BRCA1 gene are known to increase a woman’s lifetime risk of developing breast and ovarian cancers, but researchers are still investigating how the protein encoded by this gene helps suppress the formation of tumors. A study by Dr. Inder Verma and his colleagues at the Salk Institute for Biological Studies in the September 8 Nature offers some clues.

Using mice and human breast cancer cells, the researchers identified a series of abnormalities in cells lacking the BRCA1 protein. Taken together, the findings suggest that BRCA1 helps to preserve the integrity of a cell’s genome by “silencing” stretches of repetitive DNA that might harm the cell if “awakened,” or transcribed.

When BRCA1 is missing, the researchers found, certain chromosome regions are no longer maintained in a condensed state. Normally, these regions (known as constitutive heterochromatin) are bound tightly; as a result, certain stretches of repetitive DNA are silent. In the absence of BRCA1, however, cells may produce relatively large amounts of RNA from the repetitive regions.

This activity, in turn, may make the genome less stable and set the stage for cancer. “When cells make a lot of this noncoding RNA, it can lead to DNA damage,” said co-author Dr. Quan Zhu. “This kind of damage is thought to cause cancer.”

The maintenance of distinct chromosomal regions in a condensed state may underlie the tumor-suppressive effect of the protein, wrote Dr. Ashok Venkitaraman of the Hutchison/Medical Research Council Research Centre, Cambridge, UK, in an accompanying editorial. The finding, he added, “might herald a breakthrough” for the field.

Over the past decade and a half, many studies have proposed potential functions for the normal BRCA1 protein, such as repairing damaged DNA or helping with transcription. Dr. Verma and his colleagues believe their findings could provide a framework for understanding the role this protein plays in a number of cellular functions.

By and large, the researchers note, their observations in mice and in human cells are consistent with previous studies of BRCA1. “We observed all of the cellular problems that people have reported over the years related to the loss of BRCA1,” said co-author Dr. Gerald Pao.

The activation of repetitive DNA observed in this study was seen in mouse and human tumors. “Whether, and how, this event promotes cancer development in carriers of germline BRCA1 mutations is not yet evident,” Dr. Venkitaraman wrote. Nonetheless, the study “reveals an intriguing new pathway for tumor suppression,” he added.