Editorial
Pros and Cons for Population Screening BRCA Mutation Carriers
San Ming Wang*
University of Nebraska Medical Center, Omaha, USA
*Corresponding author: San Ming Wang, University of Nebraska Medical Center, Omaha, USA
Published: 13 Dec, 2016
Cite this article as: Wang SM. Pros and Cons for
Population Screening BRCA Mutation
Carriers. Clin Oncol. 2016; 1: 1161.
Editorial
Breast cancer is the most common cancer among women worldwide. About 10-15% of breast
cancer is caused by hereditary genetic predisposition [1]. The most penetrate predisposition is the
germline mutation in BRCA1 and BRCA2 (BRCA) [2-5], which is responsible for 20-30% of hereditary
breast cancer [6]. Women carrying the predisposition in BRCA1 have 55-65% and in BRCA2 45-
47% risk of developing breast cancer by age 70, comparing to the rates in general population of 12%
and 1.4%, respectively [7,8]. Besides breast cancer, BRCA mutation also causes other types of cancer
including ovarian cancer, prostate cancer, melanoma, and pancreatic cancer. With the known cause
for the disease, the effective treatment options of blocking cancer development through enhanced
cancer screening [9], chemoprevention [10], and preventive surgery [11], identification of germline BRCA1 mutation carriers becomes the key for early prevention of hereditary breast cancer.
In the developed countries, BRCA mutation test is applied routinely in clinical practice through
the family history-based approach. Here, a physician first determines if a breast cancer patient has
familial history of this disease. If yes, the patient is referred for BRCA test. If the result is positive,
family members of the affected person (proband) are referred to take the same test [12-14]. However,
this approach misses the majority of the mutation carriers, due to factors of the smaller size of
modern nuclear family that prevents tracking family history, lack of the mutation information if
it is inherited from the father who has much lower probability of developing breast cancer, lack of
insurance coverage for BRCA test, and lack of awareness of the disease in both medical professionals
and general public [15]. In the United States, only 19% of the estimated half-million BRCA carriers
have been tested [16]; in Israel, the test rate is about only 35% even with the awareness for the high
prevalence of BRCA predisposition in Ashkenazi Jewish population, the well-developed genetic
testing system and the smaller population size [17]. The failure in identifying mutation carriers
misses the best time for early prevention. As a result, these mutation carriers missed the test will
only be identified after they develops breast cancer, and their family members will only be tested for
the same mutation after the proband developed breast cancer. "To identify a woman as a carrier only
after she develops cancer is a failure of cancer prevention" [18].
To overcome the dilemma situation, Dr. King et al. [18] recently proposed a revolutionary
concept for prevention of BRCA predisposition-caused breast cancer. That is, using population
screening approach to determine the BRCA status for every woman once in her life. This concept
is built upon the deep understanding for the roles of BRCA predisposition in breast cancer after
decades’ extensive study, and the next-generation DNA sequencing (NGS)-based technology
development that enables population screening practically possible for the first time.
The proposed population screening concept triggered public and academic debates to address
various related issues [19-20]:
• Scientific issue. Although the prevalence of BRCA carriers in general population is
believed to be 1 in 200-400, the actual rate is largely unknown as the estimates are largely based on
the data from breast cancer patient population rather than cancer-free general population [21-23];
• Cost-effectiveness issue. Studies demonstrated that population screening is more costeffective
than family history-based approach does to control BRCA mutation-caused breast cancer
[24-26]. However, screening a population over multi-millions is still costly although sequencing
cost has dramatically decreased;
• Psychological issue for the identified mutation carriers. A study concluded that no longterm
psychological effects exist in these identified as the mutation carriers [27];
• Ethics issue for privacy protection [28];
• Over-diagnosis issue.
• Policy issue. These include ethics guideline for implementing
population-level genetic screening, and changing insurance policy to
cover the screening cost for individuals without cancer symptom.
A proof-of-principal population screening study was performed
in Israel [17]. The study analyzed three hot-spot predispositions
(BRCA1: 185delAG, 5382insC; BRCA2: 6174delT) in 8,195 Ashkenazi
Jewish individuals, and identified 178 mutation carriers (2.17%). Fifty
percent of families harbored the mutations had no family history of
cancer. Further test in 629 family relatives of the identified mutation
carriers identified 211 female mutation carriers (33.5%). In 2015,
Hudson Alpha Institute in Alabama, USA initiated a voluntary-based
screening project with 23 cancer genes including BRCA1 and BRCA2
for the women in Madison county with a population size of 334,811,
Alabama. Of the 1,500 screened in the first phase study, 44 cases (3%)
were identified as the carriers with mutations in one of the genes.
The study is expanded into phase two in 2016 by offering test for all
voluntary female and male over 19 years old [29]. In 2016, the Moon
shot Cancer Program selected the hereditary breast and ovarian
cancer (HBOC, the majorities are caused by BRCA mutation) as one
of the two demonstration projects for cancer prevention and plan
to identify 7,000 HBOC proband and their 28,000 family member
carriers out of the estimated 250,000-450,000 HBOC cases [30].
As indicated above, screening a population over multi-millions
is still too costly. Restricted by this single factor, it is unlikely that
population screening for BRCA mutation carriers will be applied
for breast cancer prevention in countries with large population size,
such as China (1.35 billion), USA (300 million), Japan (126 million),
and even Singapore (5 millions). Therefore, the family history-based
system will likely remain as the major tool to identify BRCA mutation
carriers in the populations in these countries, in which two third of
the BRCA mutation carriers are predicted to remain unidentified
before cancer occurs in them. In the near term, however, population
screening does provide a powerful tool to reach comprehensive
identification of the BRCA mutation carriers in the populations with
smaller size, such as the population at specific geographically isolated
region like the Iceland population, specific ethnic group like certain
American Indian tribes, specific group with hot-spot predisposition
like the Ashkenazi population. The results from these populations
will also provide valuable information to know better the prevalence
of BRCA mutations in human population and to screen in larger
population in future when the obstacles are overcome.
In short, the population-based screening indicates a direction for
eradicating hereditary cancer at the population level.
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