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Originally published as JCO Early Release 10.1200/JCO.2008.17.8228 on September 29 2008 © 2008 American Society of Clinical Oncology. Clinically Applicable Models to Characterize BRCA1 and BRCA2 Variants of Uncertain Significance
From the Departments of Biology and Pathology; Clinical Cancer Genetics Program, Comprehensive Cancer Center; Division of Human Genetics, Department of Internal Medicine; and Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; University of California, San Francisco Cancer Risk Program, San Francisco, CA; and the Departments of Oncology and Laboratory Medicine and Pathology, Mayo Clinic School of Medicine, Rochester, MN Corresponding author: Amanda Ewart Toland, PhD, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Division of Human Cancer Genetics, 998 Biomedical Research Tower, 460 W 12th Ave, Columbus, OH 43210; e-mail: Amanda.toland{at}osumc.edu
Purpose Twenty percent of individuals with a strong family and/or personal history of breast and ovarian cancer carry a deleterious mutation in BRCA1 or BRCA2. Identification of mutations in these genes is extremely beneficial for patients pursuing risk reduction strategies. Approximately 7% of individuals who have genetic testing of BRCA1 and BRCA2 carry a variant of uncertain significance (VUS), making clinical management less certain. The majority of identified VUS occur only in one to two individuals; these variants are not able to be classified using current classification models with segregation analysis components. Methods To develop a clinically applicable method that can predict the pathogenicity of VUS that does not require familial information or segregation analysis, we identified characteristics of breast or ovarian tumors that distinguished sporadic tumors from tumors with BRCA1 or BRCA2 mutations. Study participants included individuals with known deleterious mutations in BRCA1 or BRCA2 and individuals with classified or unclassified BRCA variants. Results We applied the models to 57 tumors with 43 different deleterious BRCA mutations and 57 tumors with 54 unique classified and unclassified BRCA variants. Of the 33 previously unclassified VUS studied, we found evidence of neutrality for 21. Conclusion Our models showed 98% sensitivity and 76% specificity for predicting classified DNA changes. We classified 64% of unknown variants as neutral. Classification of VUS as neutral will have immediate benefit for those individuals and their family members. These models are adaptable for the clinic and will be useful for individuals with limited available family history.
Mutations in BRCA1 and BRCA2 confer a greatly increased lifetime risk for breast and ovarian cancer. The number of individuals who have had genetic testing of BRCA1 and BRCA2 in the United States now exceeds 70,000.1 Individuals who carry a mutation in BRCA1 or BRCA2 can increase the likelihood of detecting cancers at an earlier stage by more stringent surveillance and can decrease their chance of developing cancer through the use of prophylactic surgery and/or chemopreventive agents. Of the high-risk individuals who have had mutation analyses through Myriad Genetic Laboratories (Salt Lake City, UT), approximately 7% have a variant of uncertain significance (VUS) in BRCA1 or BRCA2.2-4 VUS are typically missense or potential splice site changes of uncertain biologic or clinical relevance. They are more frequent in the minority ethnic populations.3 More than 1,500 VUS have been identified; most have only been reported in one to two individuals. Through prediction studies, some BRCA VUS have been classified as neutral polymorphisms, and a small number of BRCA VUS have been classified as likely deleterious. Many of the predicted deleterious VUS are located in highly conserved functional domains or affect transcript start or splice sites. Still, the majority of variants have yet to be classified.4-11 Several of the algorithms used to characterize VUS use familial segregation analysis or study variants in multiple unrelated individuals to provide evidence for or against causality. One difficulty with this approach is that the vast majority of reported VUS have been observed in only one or two individuals, which makes them ineligible for segregation analysis. Also, population-based studies in BRCA carriers have shown that more than 50% of BRCA-positive individuals may not have a close family member with a BRCA-related cancer who would be available for segregation analysis.12 Finally, some individuals with BRCA VUS have BRCA-related cancers segregating on both sides of the family. Thus, it is important to develop additional means to classify VUS that do not rely on segregation and can be applied in various clinical settings. To address this need, we developed four BRCA VUS classification models that use clinical information typically available from pathology and mutation testing reports combined with protein prediction model data, cancer type, and tumor loss of heterozygosity (LOH) data. We applied these models to 57 tumors with deleterious BRCA mutations and 57 tumors with classified and/or unclassified variants.
Human Samples Studies were approved by local institutional review boards. All study participants signed informed consent for this research. Paired normal and tumor tissues were ascertained through one of the following three sources: The Ohio State University Comprehensive Cancer Center Clinical Cancer Genetics Program, the Mayo Clinic Familial Cancer Program, and the University of California, San Francisco Familial Risk Shared Resource. Eligibility criteria included a diagnosis of breast or ovarian cancer, available normal and tumor DNA, available pathology records, and a BRCA testing report showing a BRCA1 and/or BRCA2 deleterious mutation, VUS, or a reclassified variant. Hematoxylin and eosin slides from tumors were reviewed by a pathologist, and areas comprising greater then 70% tumor cells were microdissected from sections or were cored. Normal DNA was isolated from blood or histologically normal breast tissue. Lymphoblastoid cell lines were established on a subset of individuals. Genomic DNA was isolated from fixed archival tissue by removal of paraffin using xylene and ethanol washes. Protein was removed by proteinase K treatment for 48 hours at 55°C in nucleic acid lysis buffer. Samples were phenol/chloroform extracted and ethanol precipitated.
Allele-Specific LOH
Evolutionary Conservation
Splicing Studies
Observation With a Deleterious Mutation
Model Phenotypes
Statistical Methods To derive odds of pathogenicity for each variant, we used a modified multifactorial approach that combines the odds of causation of independent variables.4,5,7,9 Odds for each independent variable were determined from frequencies reported in the literature or published odds, with the exception of truncating mutations and splice site alterations for which we calculated odds of being deleterious of 1,000:1 if splicing defects or truncating mutations were identified and odds of 0.01 if splicing defects were not observed. The product of the likelihoods of independent variables was obtained to provide an overall odds of pathogenicity for each sequence alteration (additional details are in Appendix). On the basis of previous studies, we used a cutoff of 1,000:1 in favor of being deleterious and a cutoff of 100:1 in favor of being neutral for final classification status.4,5 When two independent tumors with the same sequence alteration were identified, independent factors for both were combined and considered in the final data interpretation. We calculated odds both with and without LOH data because LOH data may not be typically available clinically and the frequency of LOH in neutral BRCA variants has not been well documented. If a prediction of variant status was only significant in the combined odds using LOH data, we scored the variant as suspected neutral or suspected deleterious accordingly.
Identification of Study Criteria for the Models We collected tumor and normal tissue and histopathologic and clinical data from the medical records and mutation reports of 102 individuals with BRCA mutations or characterized or uncharacterized variants (Table 2). The study group consisted of 57 tumors with 43 unique deleterious mutations and 57 tumors with 54 unique variants (Tables 2, 3, and 4; Appendix Tables A2 and A3, online only).
LOH One characteristic of BRCA1 and BRCA2 mutation tumors that has been used previously to assess pathogenicity of BRCA VUS is tumor LOH.5,11,25 LOH occurs more frequently in BRCA mutation–positive tumors than sporadic tumors and is thought to occur predominantly on the nonmutated chromosome (Table 1).5,11,25,26,28 LOH in tumors with a neutral BRCA1 or BRCA2 variant is predicted to be random for loss of variant or wild-type allele; however, LOH in this group has not been well studied. To determine whether our observed rates of LOH were comparable to published rates, we successfully conducted allele-specific LOH studies on 56 of 57 tumors from carriers of known deleterious mutations. We detected LOH of the wild-type BRCA1 allele in 85% of breast tumors (28 of 33 tumors) and 100% of ovarian tumors (three of three tumors; Tables 3 and 4; Appendix Tables A2 and A3). We observed LOH of the wild-type BRCA2 allele in 63% of breast tumors (10 of 16 tumors) and 25% of ovarian tumors (one of four tumors). We also observed loss of the mutant allele in one BRCA1 breast tumor and in one BRCA2 breast tumor (Appendix Table A2). The BRCA1 frequencies of LOH are similar to published rates. However, the BRCA2 frequencies of loss were slightly lower than expected and lower than the frequencies used in other studies.5 We were also surprised by the high observed frequency of LOH of the mutant allele in breast tumors (one of 33 tumors for BRCA1 and one of 16 tumors for BRCA2). On the basis of our data and previous published reports, we used a frequency of LOH to generate likelihood ratios of the wild-type allele of 79% and 69% for BRCA1- for BRCA2-positive breast tumors, respectively, and 89% and 79% for BRCA1- and BRCA2-positive ovarian tumors, respectively, in our prediction models (Appendix Table A1). For deleterious mutations, we assumed that 1% of the time there would be loss of the mutant allele, as has been suggested in the literature.5,11,25,26,28 We successfully assessed allele-specific LOH in 55 of 57 tumors with BRCA VUS (Tables 2 and 3; Appendix Tables A2 and A3). Twenty-nine percent of tumors (six of 21 tumors) with BRCA1 VUS showed LOH of the wild-type allele, 14% of tumors (three of 21 tumors) showed LOH of the variant allele, and 57% of tumors (12 of 21 tumors) showed no imbalance. For BRCA2, 26% of breast tumors (nine of 34 tumors) showed wild-type allele loss, 23% of tumors (eight of 34 tumors) showed variant allele loss, and 50% of tumors (17 of 34 tumors) showed no imbalance. Variants BRCA1 IVS2-14 C>T, S127N, and V1804D and BRCA2 A1170V, E2856A, H1966Y, I2285V, M784V, N1878K, and Y42C were lost in tumors providing evidence for neutrality.
Sequence-Based Methods to Determine Pathogenicity
Splicing Studies Using ESEfinder and SpliceSiteFinder, none of the missense variants were predicted to affect splicing (Appendix Tables A4 and A5). To study splicing defects of intronic variants, we isolated RNA from lymphoblastoid cell lines for four individuals with unclassified intronic VUS and from one individual with an intronic variant classified as deleterious. cDNA from 11 individuals not carrying the variants and genomic DNA from the carriers were used as controls. None of the four VUS studied (BRCA1 IVS2-14 C>T and IVS20-14 C>G and BRCA2 IVS23+9 C>T and IVS8-12delTA) showed splicing defects in contrast to the intervening sequence variant previously classified as deleterious (BRCA1 IVS5-11 G>T; data not shown).
Prediction of Deleterious Status
We developed four models for the prediction of BRCA VUS that do not require family history information or segregation analysis. To our knowledge, we describe the first models for the characterization of BRCA VUS that use ovarian tumor histopathology to characterize VUS. Using these models, we characterized 21 BRCA VUS as neutral. Of known deleterious mutations, none were incorrectly classified as neutral, and of predicted neutral variants, none were incorrectly classified as deleterious. For known or predicted deleterious mutations, our models showed 98% sensitivity. No VUS in this study were predicted to be deleterious. In our study, one known deleterious truncating BRCA1 mutation was not classified as deleterious or suspected deleterious. The tumor sample was from a 75-year-old woman. It did not show LOH and had pathologic characteristics (estrogen receptor [ER] positive and progesterone receptor [PR] positive) more typical of a non-BRCA1, sporadic tumor observed in women of this age. It is possible that this tumor is a phenocopy and not a result of the patient's inherited BRCA1 mutation. A few VUS, such as BRCA2 IVS13+5 G>C and BRCA1 L1764P, showed odds of greater than 20:1 in favor of being deleterious and warrant additional studies for characterization. L1764P has shown suggestive odds for being deleterious in other studies.4,58 A number of VUS were close to a cutoff of 100:1 in favor of a neutral classification. These are likely to be neutral; however, further studies are needed to clarify their status. These models can be readily adapted for use in the clinical setting or for an online clinical prediction tool because all of the weighting factors, except for LOH, are available from mutation and pathology reports, online programs, and published resources. Thus, these models offer a significant advantage over other models currently used to predict VUS status. Recently, a study by the kConFab group proposed a similar model using tumor histopathology as one feature to classify BRCA VUS.63 The main differences between our models and the kConFab model are that the kConFab model included segregation analysis, a different protein prediction method, and immunohistochemical staining of basal cytokeratins. Their model also did not evaluate VUS found in ovarian tumors. One advantage of our model over other models is that it does not require segregation analysis or additional laboratory analysis. For example, basal cytokeratin staining is not yet commonly used in many pathology laboratories for breast cancer diagnosis purposes. However, ER, PR, and human epidermal growth factor receptor 2 staining are part of routine practice for breast cancer pathology. In addition, a recent article suggests that, although basal cytokeratins can help to predict BRCA1 mutation–positive tumors, cytokeratin staining itself was not as good a predictor as age of onset and ER, PR, and human epidermal growth factor receptor 2 status.42 Seventy-two percent of the 20 VUS in the kConFab study, including some previously characterized variants, and 64% of the 33 unclassified VUS in our study were classified. Together, these studies demonstrate that inclusion of histopathology can be powerful for the characterization of BRCA VUS. Individuals and their at-risk family members who carry a BRCA VUS often delay making decisions about their cancer risk management or make management decisions based on uncertain information. These individuals are also not able to take full advantage of prevention and therapeutic strategies typically offered to deleterious mutation carriers. Classification of 21 previously unclassified VUS using the models described here has the potential to help the individuals who carry these variants. Our models should also be useful for the classification of additional BRCA VUS in individuals from whom limited family history is available.
The author(s) indicated no potential conflicts of interest.
Conception and design: Andrew D. Spearman, Fergus J. Couch, Amanda Ewart Toland Financial support: Amanda Ewart Toland Administrative support: Kevin Sweet Provision of study materials or patients: Kevin Sweet, Xiao-Ping Zhou, Jane McLennan, Fergus J. Couch Collection and assembly of data: Andrew D. Spearman, Amanda Ewart Toland Data analysis and interpretation: Andrew D. Spearman, Amanda Ewart Toland Manuscript writing: Andrew D. Spearman, Kevin Sweet, Amanda Ewart Toland Final approval of manuscript: Andrew D. Spearman, Kevin Sweet, Xiao-Ping Zhou, Jane McLennan, Fergus J. Couch, Amanda Ewart Toland
Variants of Uncertain Significance Characterization Models We created four models to characterize BRCA1 and BRCA2 variants of uncertain significance, one each for BRCA1 breast cancer, BRCA1 ovarian cancer, BRCA2 breast cancer, and BRCA2 ovarian cancer. The models differ only in the input variables and the weighted odds associated with each variable. The input characteristics and their weighted odds are listed for each model in Appendix Table A1. The overall likelihood odds of causality for each variant were calculated by obtaining the product of the combined independent variables. When nonindependent variables were present (eg, estrogen receptor status and estrogen receptor status/grade), the variable with the highest odds for being deleterious was used in the calculation. When data from multiple tumors with the same variant were combined, the odds for align grantham variation, grantham deviation/mutation, splice site, age at diagnosis, and in trans with mutation were used only once in the combined odds. We developed models with and without loss of heterozygosity (LOH) data because LOH data may not readily be available clinically, and we wished to determine whether the models would perform well without these data. A sequence change was considered to be deleterious if the odds without LOH data were 1,000:1 or higher. A sequence change was considered to be suspected deleterious if the odds were 1,000:1 or higher for the odds including the LOH data but the odds not including the LOH data were lower than 1,000:1. A sequence change was considered to be neutral if the odds of deleterious without LOH data were 0.01:1 or lower. A sequence change was considered to be suspected neutral if the odds of deleterious with LOH data were 0.01 or lower but the odds of deleterious without LOH data were higher. Sequence changes falling between odds of deleterious of 1,000:1 and 0.01:1 were scored as uncertain. The concordance in calls between the odds with and without the LOH data was 79% for deleterious mutations (34 of 43 mutations) and 90% for previously predicted neutral variants (19 of 21 variants). These data suggest that these models will perform well with or without the LOH data.
Sensitivity and Specificity of Models
We thank Drs. S. Barsky, R. Jimenez, M. Abdel-Rahman, and B.-M. Ljung for reviewing pathology. J. Ziegler, B. Crawford (University of California, San Francisco [UCSF] Familial Risk Shared Resource), C. Reeder (The Ohio State University [OSU] Comprehensive Cancer Center [CCC] Tissue Procurement Shared Resource), K. Chew (UCSF Tissue Shared Resource), K. Gault, M. Means, A. D’Souza, I. Comeras (OSU Clinical Cancer Genetics), and S. Nagy, (OSU Human Cancer Genetics Sample Bank) were instrumental in sample ascertainment and preparation. Finally, we thank the OSU CCC Nucleic Acids Shared Resource for sequencing support.
published online ahead of print at www.jco.org on September 29, 2008 Supported by the National Institutes of Health, National Cancer Institute, Bay Area Breast Spore Career Development Award No. P50 CA582017 [GenBank] (A.E.T.), Mayers Summer fellowships (A.D.S.), and internal funds from the Ohio State University Comprehensive Cancer Center (A.E.T.). Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Spurdle AB, Lakhani SR, Healey S, et al: Clinical classification of BRCA1 and BRCA2 DNA sequence variants: The value of cytokeratin profiles and evolutionary analysis—A report from the kConFab Investigators. J Clin Oncol 26:1657-1663, 2008 Submitted April 24, 2008; accepted July 14, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
