Posted: February 28, 2012
Association between BRCA1 and BRCA2 Mutations and Ovarian Cancer Survival Identified in part through TCGA Data Analysis
Pritty Patel Joshi
Approximately 22,000 women are expected to receive a new diagnosis of ovarian cancer this year, and 15,500 are estimated to die from this disease. The high mortality rate associated with ovarian cancer is attributed to a lack of early symptoms and inadequate screening tools. Recent findings from analyses of ovarian cancer datasets, including data from The Cancer Genome Atlas (TCGA), have the potential to enhance the clinical management of this deadly disease.
Physicians and scientists know that women who carry mutations in the DNA repair genes, BRCA1 and BRCA2, are at an increased risk for developing ovarian cancer. However, the association of these mutations with patient prognosis is unclear. Some studies have shown that ovarian cancer patients who harbor BRCA1 or BRCA2 mutations have a more favorable outcome compared to patients who do not carry these mutations. Others suggest there is no significant difference.
Two articles recently published in JAMA show how TCGA data have helped to illuminate the effect of BRCA1 and BRCA2 mutations on ovarian cancer prognosis. Although the authors of these two reports reached some contrasting conclusions, together their analyses provide important implications for the clinical management of women battling ovarian cancer.
Mutations in BRCA1 and BRCA2 Genes are Associated with Improved Survival
A team of scientists led by Wei Zhang, Ph.D. at the University of Texas MD Anderson Cancer Center analyzed the publicly available TCGA ovarian cancer dataset and published their results in October 2011. They found that of the two BRCA genes, only mutations in BRCA2 were associated with improved survival. Further analyses demonstrated that patients with BRCA2 mutations exhibited increased sensitivity to certain chemotherapeutic agents, such as cisplatin, that attack cells by inducing an overwhelming amount of DNA damage.
A second team of investigators, whose results were published in January 2012, recognized the small sample size limitations of previous studies investigating the effect of BRCA1 and BRCA2 mutations on ovarian cancer prognosis. Therefore, they examined ovarian cancer data from over 20 observational studies. Their combined analyses included data from more than 3,500 ovarian cancer cases with approximately eight percent of these data originating from TCGA.
The scientists confirmed the findings published by the Zhang group demonstrating an improved survival for patients harboring BRCA2 mutations. However, in contrast to the previous study, these researchers also revealed an improved prognosis for women with BRCA1 mutations. While BRCA2 carriers had the best prognosis with a 52 percent 5-year survival rate, the overall survival for BRCA1 carriers and noncarriers was 44 percent and 36 percent, respectively.
The authors of the January 2012 report suggest that the discrepancy in findings between these two studies is due to the moderate survival effect of BRCA1 mutations. The TCGA dataset alone, the scientists argue, was not large enough to reveal this difference. Notably, the combined dataset that revealed similar roles for BRCA1 and BRCA2 mutations as prognostic indicators was roughly ten times the size of the TCGA ovarian cancer dataset.
Resulting Implications Support the Stratification of Ovarian Cancer Patients Based on Their BRCA1 and BRCA2 Mutation Statuses
Together, these reports suggest that patients who harbor BRCA1 or BRCA2 mutations and noncarriers each develop tumors that exhibit unique molecular attributes such as differing levels of sensitivity to chemotherapeutics. These findings further suggest that BRCA1 and BRCA2 mutations may profoundly influence the biology of individual tumors. Consequently, the stratification of ovarian cancer patients based on their BRCA1 and BRCA2 mutation statuses may be justified prior to the initiation of specific treatment regimens for these women or prior to their enrollment in clinical trials.
Finally, these studies highlight the importance of validation in biomedical research. Differences in experimental design and methods used to analyze genomic datasets have the potential to influence research results. Thus, multiple independent analyses of genomic and functional datasets such as those provided by TCGA are necessary to ensure the development of accurate and practical applications of research findings to disease management.
Bolton, K.L., Chenevix-Trench, G., Goh, C., Sadetzki, S., Ramus, S.J., Karlan, B.Y., Lambrechts, D., Despierre, E., Barrowdale, D., McGuffog, L., et al (2012) Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer. JAMA. 307(4):382-390. Read the full article.
Yang, D., Khan, S., Sun, Y., Hess, K., Shmulevich, I., Sood, A.K. and Zhang, W. (2011) Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA. 306(14):1557-1565. Read the full article.