The Truth about Public Genetic Databases

The vast majority (95%) of individuals pursuing BRCA testing receive one of two types of results: 1) negative results with no mutation or variant found or 2) a BRCA mutation detected. Both should be interpreted carefully by a certified genetic counselor in the context of that patient’s personal/family history.

However ~3-5% of individuals pursuing BRCA testing will learn that they carry a BRCA “variant of uncertain significance” or VUS, whose significance is not yet known. One commercial testing laboratory, that recently lost its patents on the BRCA1 and BRCA2 genes, has found new ways to leverage its product, including describing its variant classification and private database as “vastly superior” and a major differentiator among its competitors (1). Their newest claims call public databases into question (2). Upon recent return to their website, they have taken this page and video down. However, we aim to clarify this discussion.

This commercial laboratory has raised concerns about the “quality control” and “oversight” of public databases and the “safety and well-being of patients.”

This laboratory claims that its contributions to public databases stopped due to concerns over database curation, matching data formats and patient safety. However, several reports have emerged that this change in philosophy had more to do with hoarding trade secrets than patient care (3,4). Recently, executives at this laboratory acknowledged that their “competitors reliance on public databases with high VUS and error rates will further restrict patient access to life-saving medicine (5).” This statement was made in the context of PARP inhibitor eligibility.

Other laboratories, clinicians, scientist and patients have recognized that patients, clinicians and researchers will benefit from pooling of such mutation and variant data and have created or contributed to the Free the Data movement (http://www.free-the-data.org). With recognition of the greater good created from shared information, some patients have begun to request that their testing be performed only at a laboratory that shares their data. Data-sharing has become a selling point for laboratories competing for BRCA testing. As this movement gains greater attention and traction, creating public genetic databases that feature proper curation of data, transparency on how variant classification decisions are made, and open forums for discussion will be critical. Read more on this topic here: Choosing a BRCA Genetic Testing Laboratory: A Patient-Centric and Ethical Call to Action for Clinicians and Payer.

This lab also reports that they plan to publish a comparison showing wide disparities of over 2,000 variants in BRCA1 and BRCA2 among 5 public databases with their proprietary database. We look forward to an open discussion of their data but realize that this will likely be a one-sided conversation as it has been for many years. The few recent publications from this laboratory lack analytic algorithms and underlying sequence details that are necessary to validate and interpret their data independently (6–10). This is in contrast with national recommendations to include such data for validation (11, 12). For many years, this laboratory has had access to public databases and researchers work while not contributing anything themselves nor allowing access to their internal data. This relationship has created an inequity that relates to basic scientific and medical information. Cook-Deegan and colleagues concluded that this dynamic “changes the policy context, prompting a debate about keeping clinically relevant data proprietary when that secrecy makes independent verification of its medical significance impossible (3).”

In addition, ethical questions have been raised regarding this labs refusal to disclose mutation/variant classification information on genes that were initially discovered as a result of a large, international research collaboration, funded by government grants and then kept under lock-and-key by patents that have now been invalidated (1, 13-16).

It appears that the ultimate goal of retaining such data as a trade secret is to extend the life of their patents and continue to reap the financial windfall from their long held monopoly.

For more on this topic visit: http://www.ajmc.com/publications/evidence-based-oncology/2014/May-2014/Choosing-a-BRCA-Genetic-Testing-Laboratory-A-Patient-Centric-and-Ethical-Call-to-Action-for-Clinicians-and-Payers

References:
1. Pollack A. Despite gene patent victory, Myriad Genetics faces challenges. The New York Times. http://www.nytimes.com/2011/08/25/business/despite-gene-patent-victory-myriad-genetics-faces-challenges.html?pagewanted=all&module=Search&mabReward=relbias%3Ar Published August 24, 2011.

2. Myriad Pro “Public Variant Database Considerations” https://myriadpro.com/public-variant-database-considerations/?utm_source=hs_email&utm_medium=email&utm_content=13160318&_hsenc=p2ANqtz-9Hy2EyKDKSdFjrPHm_KZ_dJNRO5NUp-qg34AZtg2pobHjD5YCI0hHXqRurLUdsv0yUXd_UmiBS2e6V0NMzflCT8ptK3ds1rKIZcCTTQmTGYQpyWPI&_hsmi=13160318 Accessed June 13, 2014

3. Cook-Deegan R, Conley JM, Evans JP, Vorhaus D. The next controversy in genetic testing: clinical data as trade secrets. Eur J Hum Genet. 2013;21:585-588.

4. Ray T. In tackling the VUS challenge, are public databases the solution or a liability for labs? Pharmacogenomics Reporter. http://www.genomeweb.com/clinical-genomics/tackling-vuschallenge-are-public-databases-solution-or-liabilitylabs. Published February 12, 2014. Accessed February 27, 2014.

5. Seeking Alpha. Myriad Genetics’ (MYGN) CEO Peter Meldrum on Q3 2014 Results - Earnings Call Transcript. http://seekingalpha.com/article/2196503-myriad-genetics-mygn-ceopeter-meldrum-on-q3-2014-results-earningscall-transcript?page=3. Published May 6, 2014. Accessed May 7, 2014.

6. Easton DF, Deffenbaugh AM, Pruss D et al: A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet 2007; 81: 873–883.

7. Eisenbraun A, Wenstrup R, Hellerstedt B et al: Hereditary breast and ovarian cancer testing: integration and outcomes within community oncology practices. Commun Oncol 2010; 7: 75–81.

8. Hall MJ, Reid JE, Burbidge LA et al: BRCA1 and BRCA2 mutations in women of different ethnicities undergoing testing for hereditary breast-ovarian cancer. Cancer 2009; 115: 2222–2233.

9. Saam JBL, Bowles K, Roa B et al: Decline in rate of BRCA1/2 variants of uncertain significance: 2002-2008. 27th Annual Education Conference of the National Society of Genetic Counselors. Los Angeles, CA 2008.

10. Wu K, Hinson SR, Ohashi A et al: Functional evaluation and cancer risk assessment of BRCA2 unclassified variants. Cancer Res 2005; 65: 417–426.

11. Micheel CM, Nass SJ, Omenn GS (eds Evolution of Translational Omics: Lessons Learned and the Path Forward. National Academies Press, 2012.

12. National Research Council: Sharing Publication-Related Data and Materials: Responsibilities of Authorship in the Life Sciences. Washington, DC: National Academies Press, 2003.

13. Matloff E1, Caplan A. Direct to confusion: lessons learned from marketing BRCA testing. Am J Bioeth. 2008;8(6):5-8.

14. Williams-Jones, B. 2006. Be ready against cancer, now: direct-to-consumer advertising for genetic testing. New Genetics and Society, 25(1): 89–107.

15. Hall, J., Lee, M., Newman, B., Morrow, J. E., Anderson, L. A. and Huey, B. 1990. Linkage of early-onset familial breast cancer to chromosome 17q21. Science, 250(4988): 1684–1689.

16. Wooster, R., Neuhausen, S., Mangion, J., Quirk, Y., Ford, D. and Collins, N. 1994. Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science, 265(5181): 2088–2090.