Mary-Claire King, PhD, the researcher who identified BRCA1's linkage to hereditary breast and ovarian cancer, was announced as the winner of the 2014 Lasker~Koshland Special Achievement Award in Medical Science.
Mary-Claire King, PhD, the researcher who identified theBRCA1gene locus and its linkage to hereditary breast and ovarian cancer, was announced as the winner of the 2014 Lasker~Koshland Special Achievement Award in Medical Science in early September, 2014, honoring her contributions to the field of genetics and medical research.
King’s discovery has greatly altered the view of how genes influence cancer. Coupled with recent findings by others in the field, her work may contribute to drastic changes in clinical guidelines for ovarian cancer screening. King is professor of Genome Sciences and of Medicine (Medical Genetics) at the University of Washington in Seattle.
The current understanding is that loss-of-function mutations inBRCA1andBRCA2indicate a hereditary predisposition to breast and ovarian cancer. Nearly 40% of women with aBRCA1mutation and approximately 25% of women with aBRCA2mutation will develop ovarian cancer by the age of 70.1
Maurie Markman, MD, on the Role of Molecular Testing in Gynecologic Cancers
Markman is the National Director for Medical Oncology at Cancer Treatment Centers of America.
Published inSciencein 1990, King’s seminal paper enrolled 23 extended families with early-onset breast cancer, using linkage analysis to map the likelihood of coinheritance to a specific region on chromosome 17q21.2This finding led to the sequencing ofBRCA1, mapping and sequencing of the sister gene,BRCA2, and the development of tests to screen forBRCA1/2mutations in high-risk patients.
Nearly two and a half decades later, with over 20 years of research supporting the role ofBRCA1andBRCA2in breast and ovarian cancer, genetic screening for these mutations is still largely restricted to patients with a family history of disease. However, King called for an amendment to these practices. “To identify a woman as a carrier [of inherited mutations inBRCA1orBRCA2] only after she develops cancer is a failure of cancer prevention,” King and colleagues wrote in an opinion piece published earlier this month inJAMA.3
The Lasker winner proposed that widespread genetic testing forBRCA1andBRCA2should be offered to all women at or above the age of 30, regardless of background. By identifying carriers of these cancer-predisposing mutations early, women could begin counseling to develop a prevention plan before being diagnosed with disease.
Mixed responses were raised to this call for action, given that knowledge of a genetic predisposition to cancer is challenging for some patients to accept. Other experts in the field, including Michael Watson, PhD, executive director of the American College of Medical Genetics, acknowledge that genetic screening in healthy individuals is on the horizon, but caution that there are “still gaps in our system to be able to do that effectively.”4
Earlier this year, the US Preventive Services Task Force (USPSTF) recommended that in asymptomatic women without a cancer diagnosis, genetic screening forBRCA1andBRCA2should be restricted to those with a family history of breast, ovarian, tubal, or peritoneal cancer.5Their recommendation against widespread genetic testing was based on a lack of evidence for risks associated with BRCA mutations in the general population.
Since that time, a study published in the Proceedings of the National Academy of Sciences presented evidence supportingBRCA1andBRCA2genetic testing for all women, regardless of family history. In this population-based screening study in the Ashkenazi Jewish population in Israel, genetic testing was offered to all female relatives of the 175 men identified as carriers ofBRCA1orBRCA2mutations.6
The authors found that 50% of the families harboring BRCA gene mutations had no clinically relevant history of breast or ovarian cancer. “Female mutation carriers from these low-cancer-incidence families had similar cancer risks to female carriers from families with high cancer incidence,” the authors wrote.3
Moving forward, as a number of mutations inBRCA1andBRCA2have been elucidated, including many variants of unknown significance (VUS) that may be benign, the decision of whichBRCA1/2mutations to include in a widespread genetic testing approach will be a critical barrier to overcome.
In addition, the advent of next-generation sequencing, which allows for cost-effective screening of multiple genes simultaneously, may detect other gene mutations associated with an increased risk of breast and ovarian cancer that might also warrant inclusion in genetic testing. At this point, King and colleagues recommend that initial testing focus specifically on the loss-of-function mutations inBRCA1andBRCA2with severe, unambiguous effects on cancer risk.
Due to the amount of evidence available for these gene loci versus more recently identified heritable factors, such as PALB2, they propose that onlyBRCA1/2mutations should be included in an initial population-wide screen. Women with a high familial incidence of breast and ovarian cancer should then receive additional screening for all known related genes.
“As population-based screening forBRCA1andBRCA2among adult women becomes a routine part of clinical practice, other genes are expected to be phased into the process,” King pointed out.3
Overall, it is estimated that between 1 in 300 and 1 in 500 US women carry medically actionable mutations in BRCA genes. According to King, this translates to between 250,000 and 415,000 individuals, “for whom breast and ovarian cancer is both highly likely and potentially preventable.”3
Once a high-risk mutation has been identified, bilateral salpingo-oophorectomy is a common avenue of prophylaxis. Additionally, removing the ovaries may also reduce the risk of breast cancer in high-risk women.
“Why should women be protected from information that will empower them and allow them to control their lives?” King asked in a recent interview.4“Women do not benefit by practices that ‘protect’ them from information regarding their own health…waiting for a perfect test denies women excellent resources that are now available.”3