Performance of BRCA1/2 Mutation Prediction Models in Asian Americans

Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305-5405, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 09/2008; 26(29):4752-8. DOI: 10.1200/JCO.2008.16.8310
Source: PubMed


There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.
We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.
BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P > or = .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P < or = 3 x 10(-7)). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 x 10(-30)); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.
Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.

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    • "Several studies have found a tendency of BRCA1/2 mutation prediction models to underestimate the risk of BRCA1/2 mutations in Asian populations [32,41,60-62]. In a study of Asian Americans, the BRCAPRO and Myriad II models underestimated the proportion of Asian BRCA1/2 mutation carriers by two-fold. "
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    ABSTRACT: Breast cancer is the most prevalent cancer in Asian females, and the incidence of breast cancer has been increasing in Asia. Because Asian patients develop breast cancer at a younger age than their Caucasian counterparts, the contributions of BRCA1 and BRCA2 (BRCA1/2) mutations in Asians are expected to be different than in Caucasians. The prevalence of BRCA1/2 mutations in the Asian population varies among countries and studies. Most Asian studies have reported more frequent mutations in BRCA2 than in BRCA1, with the exception of studies from India and Pakistan. In addition, the contribution of large genomic rearrangements of BRCA1/2 genes is relatively small in Asian populations in comparison to other ethnic populations. Various statistical models for the prediction of BRCA1/2 mutations have underestimated the risk of having these genetic mutations in Asians, especially in predicting BRCA2 gene mutation. Until recently, BRCA1/2 mutation analyses in Asia were mostly conducted by independent single institutions with different patient selection criteria and using various genotyping methods. However, a couple of Asian groups have initiated nationwide studies collecting BRCA1/2 mutational data. These national collaborative studies will help a comprehensive understanding of the prevalence of BRCA1/2 mutations in the Asian population.
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    • "The most widely used models are the Myriad II [23], BRCAPRO [24], Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm [25], and Manchester [26] models, which were developed using data obtained from Caucasians. BRCAPRO and Myriad II were validated for various races, and these models underestimated the proportion of BRCA1/2 mutation carriers among Asians [27]. "
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    ABSTRACT: Most studies related to BRCA mutations have been performed in Western populations, and only a few small studies have been conducted in Korean populations. In 2007, the Korean Hereditary Breast Cancer (KOHBRA) Study was established to obtain evidence for the accurate risk assessment and management of hereditary breast and ovarian cancer (HBOC) in Korea. Between May 2007 and May 2010, the first phase of the KOHBRA Study was performed to estimate the prevalence of BRCA1/2 mutations among patients and their families at risk for HBOC. Between June 2010 and May 2013, the second phase of the KOHBRA Study was performed to identify the clinical characteristics and prognostic indicators of BRCA-related breast cancer and environmental and genetic modifiers of BRCA mutations and to develop a Korean BRCA risk calculator and nationwide genetic counseling network for HBOC. Herein, we review the results of the KOHBRA Study and describe the future perspectives of the study.
    Full-text · Article · Sep 2013 · Journal of Breast Cancer
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    • "However, the reliance on family history and recruitment through the genetics clinics poses significant challenges in many Asian countries, particularly low and middle income countries such as Malaysia. Clinical genetics services are relatively new and underdeveloped and, moreover, our data and data from Asian Americans have shown that risk assessment models for BRCA1 and BRCA2, which were largely built on families with multiple cancers, underestimate the number of BRCA carriers in Asians compared to Caucasians [12,13]. We have previously found that family history is poorly reported in Asian families in Malaysia, in part due to the stigma associated with cancer in Asian families, significant geographical dispersal of families and the lack of robust cancer registries [12,14]. "
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    ABSTRACT: Germline TP53 mutations cause an increased risk to early-onset breast cancer in Li-Fraumeni syndrome (LFS) families and the majority of carriers identified through breast cancer cohorts have LFS or Li-Fraumeni-like (LFL) features. However, in Asia and in many low resource settings, it is challenging to obtain accurate family history and we, therefore, sought to determine whether the presence of early-onset breast cancer is an appropriate selection criteria for germline TP53 testing. A total of 100 patients with early-onset breast cancer (≤ 35 years) treated at University Malaya Medical Centre between 2003 and 2009, were analyzed for germline mutations in BRCA1, BRCA2 and TP53 by full DNA sequencing. Of the mutations identified, we examined their likely pathogenicity on the basis of prevalence in a case-control cohort, co-segregation analyses and loss of heterozygosity (LOH) in tumor tissues. We identified 11 BRCA1 (11%) and 6 BRCA2 (6%) germline carriers among early-onset breast cancer patients. Of the 83 BRCA-negative patients, we identified four exonic variants and three intronic variants in TP53. Of these, two exonic variants are clinically relevant (E346X and p. G334_R335dup6) and two novel missense mutations (A138V and E285K) are likely to be clinically relevant, on the basis of co-segregation and loss of heterozygosity (LOH). Notably, E285K was found in two unrelated individuals and haplotype analyses suggest a founder effect. Two of the three intronic variants are likely benign based on their prevalence in a control population. Clinically relevant TP53 germline mutations were identified in three of the four patients (75%) with a family history of at least two LFS-linked cancers (breast, bone or soft tissue sarcoma, brain tumors or adrenocortical cancer); 1 of the 17 patients (6%) with a family history of breast cancer only, and 1 of the 62 patients (< 2%) with no family history of breast or LFS-linked cancers. Our study reports germline BRCA1, BRCA2 and TP53 mutations are found in early-onset breast cancer patients at 11%, 6% and 5% respectively, suggesting that TP53 mutation screening should be considered for these patients. However, we find that even in low resource Asian settings where family history is poorly reported, germline TP53 mutations are found predominantly among breast cancer patients with a family history of LFS-linked cancers.
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