Is it time for BRCA1/2 mutation screening in the general adult population?: impact of population characteristics

Abstract

Two recent linked publications present perspectives on routine population-based screening for breast cancer using BRCA1/2 mutations in different populations.1,2 In the United States, an estimated 235,000 new breast cancer cases are diagnosed annually, resulting in more than 40,000 deaths.3 From an epidemiological viewpoint, the strongest factors associated with breast cancer are being female and advancing age. However, more than 60 years ago, it was clear that some families had higher than expected rates of breast and ovarian cancer; researchers theorized that this might be due to an inherited predisposition. A family history of breast/ovarian cancer or a personal history of early-onset cancer are strong risk factors for breast cancer, and systematic criteria for a positive family history have been established by professional organizations and/or government agencies (e.g., US Preventive Services Task Force, 4 National Comprehensive Cancer Network 5 ). Less strongly related risk factors include oral contraceptive use, weight, alcohol intake, and reproductive history. In 1994 and 1995, the tumor suppressor genes BRCA1 (ref. 6) and BRCA2 (ref. 7) were identified. Since then, the scientific community has extensively explored both the personal and population impact of carrying a deleterious mutation in these genes. Any new population-based screening test, such as testing for BRCA1 and BRCA2 mutations, requires consideration of key performance characteristics that evaluate both strengths and shortcomings before its introduction. 8,9 The relationship between deleterious mutations in BRCA1/2 and breast cancer at the population level can be described by answering four epidemiologic questions: (i) What percentage of all women in the population carry a deleterious mutation? (ii) What percentage of women with breast cancer in the population carry one of these mutations? (iii) What percentage of women with a mutation develop breast cancer? (iv) What percentage of women will develop cancer by a given age, regardless of mutation status? Shorthand phrases for these four parameters are the carrier rate, the clinical sensitivity, the penetrance, and the population cumulative incidence, respectively. These four factors are interrelated; knowing three will allow the fourth to be computed. 10 As an example, three founder mutations account for the majority of deleterious BRCA1/2 mutations in the Ashkenazi Jewish population, allowing an inexpensive molecular test to be used. A reasonably confident estimate of the carrier rate in this population is about 1 in 40 (2.5%; range, 1 in 33 to 1 in 56).11 The proportion of all breast cancer cases attributable to these founder mutations (clinical sensitivity) is about 10% by age 70 (higher rates are found in younger women). The general cumulative incidence of breast cancer in the Ashkenazi population is also about 10% by age 70 (lower rates are found in younger women). Penetrance is more difficult to establish; published estimates (ranging from 30% to 70%) are usually based on women with stron...

The spectrum of BRCA mutations and characteristics of BRCA‐associated breast cancers in China: Screening of 2,991 patients and 1,043 controls by next‐generation sequencing

“…Clinic‐based screening indicated that the BRCA1/2 mutation frequency was approximately 9.1% in breast cancer patients with at least one risk factor from the five categories. Community‐based screening revealed that the BRCA1/2 mutation frequency was approximately 0.38% in unselected healthy people, much lower than the rate in healthy Ashkenazi Jewish women while approximately equal to that in American women . The prevalence rates of BRCA1 and BRCA2 mutations in our entire breast cancer cohort were 3.7 and 4.5% separately, comparable to data across other Asian countries .…”

Second primary cancer after female breast cancer: Familial risks and cause of death

“…High risks for contralateral BC are well known and associate with familial BC although many such patients lack a family history of BC . Gene mutations in BRCA1/2 constitute the dominant germline cause for heritable BC; these mutations are estimated to account for 1.4% of all BCs in European and African American populations . They also confer a high risk of ovarian cancer and a smaller but still increased risk of many other cancers .…”

“…5 Gene mutations in BRCA1/2 constitute the dominant germline cause for heritable BC; these mutations are estimated to account for 1.4% of all BCs in European and African American populations. 6 They also confer a high risk of ovarian cancer and a smaller but still increased risk of many other cancers. 7 Although population-level data on higher order multiple cancers (third, fourth etc primary cancers) should increase along with SPCs, they are often associated with genetic predisposition in the context of cancer syndromes.…”

Ovarian Cancer Prevention in High-risk Women

“…Two reasons make universal genetic testing amongst Ashkenazi Jewish women feasible: the high prevalence of BRCA1/2 mutations amongst Ashkenazi Jewish women (2.5% compared to the general population prevalence of 0.002-0.006%); and the specificity of testing because the founder mutations in the population are very well-characterized (70). Universal genetic testing in an unselected population remains controversial for several reasons, including the resulting need for more comprehensive testing technologies for screening, which would be expensive, and the identification of variants of unknown significance (71-73). …”