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From: HubMed - breast cancer <rssfwd@rssfwd.com>
Date: Fri, Feb 22, 2008 at 10:18 AM
Subject: Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.
To: mesothelioma77@gmail.com
[1]Breast Cancer Res. 2008 Feb 19; 10(1): R19
Lee E, McKean-Cowdin R, Ma H, Chen Z, Van Den Berg D, Henderson BE, Bernstein L, Ursin G
ABSTRACT: INTRODUCTION: Efforts are ongoing to determine the significance of unclassified variants (UVs) in the breast cancer susceptibility genes BRCA1/2, but no study has systematically assessed whether women carrying the suspected deleterious UVs have characteristics commonly seen among women carrying known deleterious or disease-causing mutations in BRCA1/2. METHODS: We sequenced BRCA1/2 genes in 1,469 population-based female breast cancer patients diagnosed between the ages of 20-49. We used existing literature to classify variants into known deleterious mutations, polymorphic variants, and UVs. The UVs were further classified as high or low risk based on 5 methods: allele frequency, Polyphen, sequence conservation, Grantham scores, and a combination of the Grantham score and sequence conservation. Furthermore, we examined whether patients who carry the variants classified as ahigh riska using these methods have risk characteristics similar to patients with known deleterious BRCA1/2 mutations (early age at diagnosis, family history of breast or ovarian cancer, and negative ER/PR). RESULTS: We identified 262 distinct BRCA1/2 variants, including 147 UVs, in our study population. The BRCA1 UV carriers, but not BRCA2 UV carriers, who were classified as high risk using each classification method were more similar to the deleterious mutation carriers with respect to family history than those classified as alow riska. For example, the odds ratio (OR) of having a first-degree family history for the ahigh-riska women classified using Polyphen was 3.39 (95%CI=1.16-9.94) compared to normal/polymorphic BRCA1 carriers. The corresponding OR of low-risk women was 1.53 (95%CI=1.07-2.18). The OR for high-risk women defined by allele frequency was 2.00 (95%CI=1.14-3.51), and that of alow-riska women was 1.30 (95%CI=0.87-1.93). CONCLUSIONS: The results suggest that the 5 classification methods yielded similar results. Polyphen was particularly better at isolating BRCA1 UV carriers likely to have a family history, and may therefore help to classify BRCA1 UVs. Our study suggests that these methods may not be as successful in classifying BRCA2 UVs.
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Source: http://www.hubmed.org/display.cgi?uids=18284688
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From: HubMed - breast cancer <rssfwd@rssfwd.com>
Date: Fri, Feb 22, 2008 at 10:18 AM
Subject: Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients.
To: mesothelioma77@gmail.com
[1]Breast Cancer Res. 2008 Feb 19; 10(1): R19
Lee E, McKean-Cowdin R, Ma H, Chen Z, Van Den Berg D, Henderson BE, Bernstein L, Ursin G
ABSTRACT: INTRODUCTION: Efforts are ongoing to determine the significance of unclassified variants (UVs) in the breast cancer susceptibility genes BRCA1/2, but no study has systematically assessed whether women carrying the suspected deleterious UVs have characteristics commonly seen among women carrying known deleterious or disease-causing mutations in BRCA1/2. METHODS: We sequenced BRCA1/2 genes in 1,469 population-based female breast cancer patients diagnosed between the ages of 20-49. We used existing literature to classify variants into known deleterious mutations, polymorphic variants, and UVs. The UVs were further classified as high or low risk based on 5 methods: allele frequency, Polyphen, sequence conservation, Grantham scores, and a combination of the Grantham score and sequence conservation. Furthermore, we examined whether patients who carry the variants classified as ahigh riska using these methods have risk characteristics similar to patients with known deleterious BRCA1/2 mutations (early age at diagnosis, family history of breast or ovarian cancer, and negative ER/PR). RESULTS: We identified 262 distinct BRCA1/2 variants, including 147 UVs, in our study population. The BRCA1 UV carriers, but not BRCA2 UV carriers, who were classified as high risk using each classification method were more similar to the deleterious mutation carriers with respect to family history than those classified as alow riska. For example, the odds ratio (OR) of having a first-degree family history for the ahigh-riska women classified using Polyphen was 3.39 (95%CI=1.16-9.94) compared to normal/polymorphic BRCA1 carriers. The corresponding OR of low-risk women was 1.53 (95%CI=1.07-2.18). The OR for high-risk women defined by allele frequency was 2.00 (95%CI=1.14-3.51), and that of alow-riska women was 1.30 (95%CI=0.87-1.93). CONCLUSIONS: The results suggest that the 5 classification methods yielded similar results. Polyphen was particularly better at isolating BRCA1 UV carriers likely to have a family history, and may therefore help to classify BRCA1 UVs. Our study suggests that these methods may not be as successful in classifying BRCA2 UVs.
___
Source: http://www.hubmed.org/display.cgi?uids=18284688
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