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BRCA1 and BRCA2 Genetic Testing in Hispanic Patients: Mutation Prevalence and Evaluation of the BRCAPRO Risk Assessment Model

Kristen J. Vogel, Deann P. Atchley, Julie Erlichman, Kristine R. Broglio, Kaylene J. Ready, Vicente Valero, Christopher I. Amos, Gabriel N. Hortobagyi, Karen H. Lu, Banu Arun

From the Center for Medical Genetics, Evanston Northwestern Healthcare, Evanston, IL; Departments of Breast Medical Oncology, Gynecologic Oncology, Biostatistics, and Epidemiology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX; and the University of Pennsylvania Abramson Cancer Center, Philadelphia, PA

Address reprint requests to Banu Arun, MD, The University of Texas M.D. Anderson Cancer Center, Department of Breast Medical Oncology, Unit 1354, 1515 Holcombe Blvd, Houston, TX, 77030; e-mail: barun{at}mdanderson.org

	ABSTRACT

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Purpose The BRCAPRO model, used to predict a family's likelihood of carrying a BRCA1 or BRCA2 mutation, was designed using mutation frequencies of white and Ashkenazi Jewish populations, and may not be applicable to other populations. BRCAPRO was recently validated in African Americans, although has yet to be examined in Hispanics. This retrospective study reports the mutation frequency and spectrum of BRCA1 and BRCA2 mutations in a Hispanic population and evaluates the BRCAPRO model in Hispanics.

Patients and Methods A descriptive analysis of mutation frequency and spectrum was performed for Hispanic patients who underwent BRCA1 and BRCA2 genetic testing at a single institution. For comparative analysis of the BRCAPRO risk model, Hispanic patients who underwent comprehensive analysis were compared with white controls using area under the receiver operating characteristic curves (AUROC).

Results Fourteen Hispanic individuals who underwent comprehensive analysis were identified to carry a mutation in BRCA1 or BRCA2 (17.9%; 95% CI, 10.2% to 28.3%) and seven individuals had a variant of uncertain significance (9.0%; 95% CI, 12.0% to 30.8%). A total of eight different mutations and three variants were observed within the entire Hispanic population. When evaluating the performance of the BRCAPRO model, the AUROC for Hispanics was 0.774 (95% CI, 0.63 to 0.90), compared with the AUROC of 0.770 (95% CI, 0.65 to 0.89) for whites.

Conclusion Deleterious BRCA1 and BRCA2 mutations occur at considerable frequency within the Hispanic population, many of which have been identified previously in other ethnic populations. The BRCAPRO model appears to perform equally well in Hispanics as in whites.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Approximately 7% to 10% of breast cancer and 10% to 15% of ovarian cancer is hereditary, arising from mutations in highly penetrant cancer susceptibility genes.^1-5 The majority of individuals with hereditary breast and ovarian cancer have mutations in the BRCA1 and BRCA2 genes.^6,7

Mutations in BRCA1/BRCA2 confer a 43% to 84% risk of breast cancer and a 27% to 39% risk of ovarian cancer by age 70 years in women.^6-9 Risk factors include personal/family history of early-onset breast cancer, ovarian cancer, multiple family members with breast/ovarian cancer, male breast cancer, multiple primary breast/ovarian cancers in one individual, and Ashkenazi Jewish ancestry.^2,10-13

Mutations in BRCA1/BRCA2 are not unique to any one race or ethnicity, and have been identified worldwide.^14-22 Despite the diverse mixture of ethnic backgrounds within the United States, the majority of individuals who have undergone BRCA1/BRCA2 genetic testing have been of European or Ashkenazi Jewish decent.¹¹

Disparities in access to health care are well documented.²³ Genetics services are no exception.^24,25 As we work to decrease disparities, the hope is to increase uptake of genetics services in minority populations. Information about the Hispanic American's experience with BRCA1/BRCA2 genetic testing is limited. The primary aim of existing studies has been to describe mutation prevalence.^26-28 However, no study has examined the quality of the risk assessment provided.

In providing genetic counseling to individuals at risk for carrying BRCA1/BRCA2 mutations, tools have been developed to aid in providing risk assessments. Such tools include BRCAPRO, Myriad II, BOADICEA, UPenn, and UPennII, among others. Although it varies by institution, BRCAPRO is commonly used in clinical practice and is the primary tool used at our institution. The accuracy of mutation detection using BRCAPRO was evaluated at three clinical sites and compared various tools. Results showed similar accuracy for BRCAPRO, BOADICEA, and Myriad II, with other methods providing less accurate results.²⁹

The BRCAPRO Bayesian probability model (accessed through CancerGene [http://www3.utsouthwestern.edu/cancergene/]) is a computer-based program that predicts the likelihood of identifying a BRCA1/BRCA2 mutation, given family history. This model was developed using mutation rates of Ashkenazi Jewish and other European populations.^30,31 Nanda et al¹² reported that BRCAPRO was as sensitive for African Americans as it was for Ashkenazi and European controls. However, no study to date has looked at BRCAPRO sensitivity in Hispanics to our knowledge. Therefore, using a single-institution cohort of Hispanic patients, we retrospectively report the prevalence and mutation spectrum of BRCA1/BRCA2 mutations as well as the sensitivity of BRCAPRO in evaluating our patient population.

	PATIENTS AND METHODS

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Study Population
The University of Texas M.D. Anderson Cancer Center's Clinical Cancer Genetics Program offers genetic risk assessment for individuals at risk of a hereditary cancer syndrome. Individuals are referred at their physician's discretion because of a personal and/or family history of cancer. If patients are referred to discuss hereditary breast and ovarian cancer, they are counseled regarding their risk to carry a BRCA1/BRCA2 mutation, as well as the risks and benefits of genetic testing. On the basis of this information, patients decide whether to pursue genetic testing.

This study was approved by the University of Texas M.D. Anderson Cancer Center institutional review board. The Clinical Cancer Genetics patient database was queried for all self-identified Hispanic patients who were evaluated between February 1997 and July 2006. "Hispanic" was defined as individuals of Latin American or Spanish descent. Medical records were then reviewed to determine which families had been evaluated for hereditary breast and ovarian cancer.

In addition to our Hispanic participants, a random selection of whites was used as a control to test the sensitivity of BRCAPRO. We randomly selected 79 Non-Ashkenazi whites who had undergone comprehensive analysis of BRCA1/BRCA2 and were the first individuals in their families to undergo testing. Although it would have been ideal to include all whites, it was not feasible to include the entire population of more than 900 individuals.

Mutation Detection
All individuals who opted to undergo genetic testing had testing completed through Myriad Genetic Laboratories (MGL; Salt Lake City, UT). Comprehensive analysis was completed for individuals who were the first family member to undergo testing. Single-site testing was completed for individuals with a familial mutation. Also, 6.4% (five of 78) of Hispanics and 6.3% (five of 79) of whites were tested before MGL added the large rearrangement panel to their clinical testing in 2002.

Personal History and Family History Information
Medical records were reviewed for all participants. For individuals with a personal history of cancer, pathology reports were used to confirm cancer diagnoses and ages at diagnosis, when available. Family history information was retrieved from genetic consult notes and/or from pedigrees. Medical records were gathered when possible, although most family members' diagnoses had never been confirmed

BRCAPRO Calculation
Data are often entered into BRCAPRO slightly differently between users, both between and within institutions. Therefore, criteria were established to eliminate user variability. BRCAPRO was calculated only for individuals who were the first in their family to undergo testing. Information on all first- and second-degree relatives of the proband (current ages/ages of death, breast/ovarian cancer diagnoses, and ages at diagnosis) was entered into BRCAPRO (CancerGene version 4b) for the side of the family that was most suggestive of carrying a mutation. If this was unclear, then each side of the family was calculated independently and the larger risk value was taken.

Not all individuals had complete family history information, and therefore, the following rules were used for entering incomplete information into BRCAPRO. If the age/age at death of an unaffected individual was unknown, that individual was excluded. If the age/age at death of an affected individual was unknown, then the age at diagnosis was used. If the age at a cancer diagnosis was unknown, the age of 55 was used for breast cancer and the age of 65 was used for ovarian cancer, unless the individual had died before age 55 or 65 respectively, and then the age at death was used as the age at diagnosis. BRCAPRO takes into account only invasive breast cancers, but to account for ductal carcinoma in situ (DCIS), individuals were entered into the model as having had invasive breast cancer 10 years after the DCIS diagnosis.

We used release 1.3.1 of BRCAPRO. This release incorporates updated estimates of penetrance for breast and ovarian cancer that were obtained after a study of 1,948 families collected from the Cancer Genetics Network.⁸

Statistical Analysis
The prevalence of BRCA1/BRCA2 mutations in each group was calculated along with the exact binomial two-sided 95% CI. The distribution of BRCAPRO scores in each group was described by the median and range. The performance of BRCAPRO was compared between groups by visually assessing the receiver operating characteristics (ROC) curves and by calculating the area under the curve (AUC). The AUC is equal to the value of the Wilcoxon-Mann-Whitney test statistic and can be interpreted as the probability that BRCAPRO will have a higher score for a BRCA1/BRCA2 mutation-positive (BRCA+) patient than for a BRCA1/BRCA2 mutation-negative (BRCA–) patient.

To estimate the 95% CI of the AUC, we generated 10,000 bootstrap samples and calculated the 2.5% and 97.5% quartiles. The performance of BRCAPRO was assessed for different risk ranges by dividing the patients into quartiles on the basis of BRCAPRO scores and comparing the predicted probability from BRCAPRO to the observed prevalence of mutations.

We compared the number of relatives with breast cancer, number of relatives with ovarian cancer, presence of bilateral breast cancer, presence of both breast and ovarian cancer, age at diagnosis of breast cancer diagnosis, and age at diagnosis of ovarian cancer diagnosis between groups using Wilcoxon rank sum test, the Kruskal-Wallis rank sum test, or Fisher's exact test, as appropriate. Analyses were performed using R (R Foundation for Statistical Computing; http://www.R-project.org) and the contributed package ROCR.³³

	RESULTS

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Study Population
A total of 204 self-identified Hispanic individuals had been seen during our study period. However, 109 patients declined genetictesting for a variety of reasons including but not limited to: not the ideal test candidate in the family, lack of insurance coverage for genetic testing, low pretest probability of finding a mutation, not interested in genetic testing, and so on. The remaining 95 individuals elected to undergo BRCA1/BRCA2 genetic testing. Of these 95, 80% had a personal history of cancer and 78% had a family history of breast and/or ovarian cancer (Table 1). Seventy-eight of the 95 individuals had undergone comprehensive analysis because they were the first individual in their family to undergo genetic testing, four individuals had undergone single-site testing because another family member had been found to carry a mutation at an outside institution, and 13 individuals had undergone single-site testing because they were family members of mutation-positive patients we had seen previously.

BRCAPRO Assessment
ROC curves for the two groups are shown in Figure 1. Both groups include only individuals who were the first in their family to have undergone genetic testing. The area under the ROC curves (AUROC curve) was 0.774 (95% CI, 0.63 to 0.90) in Hispanics and 0.770 (95% CI, 0.65 to 0.89) in whites. Table 4 shows the median, mean, and range of the BRCAPRO predicted probability and the observed prevalence of BRCA1/BRCA2 mutations. In both groups, the observed prevalence tended to be higher than the median predicted probability in the lower quartiles, but lower than the predicted probabilities in the upper quartiles. Also, the prevalence of mutations was greater than the median predicted probability of detecting a mutation, for both populations.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Receiver operating characteristics curves for the BRCAPRO model.

	DISCUSSION

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Various mutations have been reported as having elevated mutation frequency in Hispanics, of which BRCA1 187delAG appears to be the most prevalent.^{10,16,17,20,27,28,34,35} The 187delAG mutation is a founder mutations in the Ashkenazi Jewish population, with a carrier frequency of 0.9%.³⁶ However, this mutation is not unique to Ashkenazi Jewish individuals; approximately 30% of individuals with this mutation self-report being of another ethnicity (MGL, personal communication, October 2006).

Of the individuals who have completed genetic testing with MGL, 63 individuals of Latin American or Caribbean descent have tested positive for BRCA1 187delAG, which accounts for approximately 15% of the mutations found in individuals of Latin American or Caribbean descent (extrapolated from data reported by MGL on October 31, 2006). This percentage is substantially lower than published studies on Spanish or Latin American high-risk families, in which up to 60% of mutation-positive individuals have this mutation.^16,27,34,35 These elevated mutation frequencies may be inaccurate due because of small sample sizes. It is also possible that the mutation frequency is much higher in individuals of Spanish descent than in Hispanic individuals as a group. Regardless, the 187delAG mutation is by far the most frequent mutation observed in this population, which is consistent with our result of 28.6% of mutation-positive Hispanics having the BRCA1, 187delAG mutation.

Unlike the BRCA1, 187delAG mutation, the other mutations and variants occurred in only one or two families each. The majority of these mutations and variants had Western European ancestry reported as the predominant ancestry. The fact that the majority of mutations were not unique to Hispanic individuals may explain why the mutation frequency did not differ significantly between whites and Hispanics in our population. The similarity of mutation frequencies is also important when evaluating BRCAPRO as a risk assessment tool in the Hispanic population.

BRCAPRO was first developed by statisticians at Duke University (Durham, NC),^31,37 and was validated in 2002, with an estimated sensitivity of 85%.³⁰ The model takes into account carrier frequency and penetrance rates of mutations, and then uses Bayesian probability to estimate the likelihood of being a mutation carrier, given personal and family history of cancer. The model uses a carrier frequency that is based on whites. The only instance in which the model adjusts for carrier frequency is for Ashkenazi Jewish individuals.^31,37,38 However, the mutation frequencies of other ethnic groups are not taken into account, mostly because these values are unknown. Hence, the concern arises as to whether the model is accurate in other populations.

Determining BRCA1/BRCA2 carrier frequencies of various ethnic groups are essential first steps in updating risk assessment models so that they may be used accurately in diverse populations. However, given the under-representation of minorities within genetic clinics, we are not close to gathering these data. In the interim, health professionals are left with the current BRCAPRO model that uses carrier frequency data from whites.³⁹ Our study evaluated the use of BRCAPRO in Hispanics, despite possible differences in mutation frequencies.

Previous studies have used AUROC curves to evaluate BRCAPRO.^12,40 The AUROC curve is consistent with the probability that an individual who has a mutation will have a greater mutation probability than an individual chosen at random who has no mutation. Euhus et al⁴⁰ found that in a population of 148 primarily white and Ashkenazi Jewish individuals, the median AUROC curve was 0.712 (95% CI, 0.706 to 0.720) for BRCAPRO.

A similar calculation was performed by Nanda et al¹² in a population of 43 African Americans and 103 controls. They found that the AUROC curve for African American patients was 0.77 (95% CI, 0.61 to 0.88) and for white/Ashkenazi patients, 0.70 (95% CI, 0.60 to 0.79). On the basis of these data, they concluded that BRCAPRO performs equally in both populations.

In our comparison of Hispanics and whites, we found that the AUROC was 0.774 (95% CI, 0.63 to 0.90) in Hispanics and 0.770 (95% CI, 0.65 to 0.89) in whites. These values are consistent with those of the aforementioned studies.

There are limitations when comparing these various studies. For instance, our study used a more recent version of CancerGene, whereas Nanda et al¹² used version 3.31 and Euhus et al⁴⁰ did not specify which version was used. Although there were no significant updates between versions 3.31 and 4b that would affect the BRCAPRO risk estimations, there may be significant differences between the version that Euhus et al⁴⁰ used and the version we used, which would limit comparison.

Additionally, we modified the use of BRCAPRO several ways. We included only one side of the family in our calculation, because, theoretically, a mutation would be inherited from only one parent. Secondly, the BRCAPRO model only includes individuals with invasive cancer; we included individuals with DCIS by adding 10 years to their age at diagnosis. The rational behind this choice is that is has been suggested that it takes up to 9 years for a DCIS lesion to become an invasive lesion.⁴¹ Our methods, although not validated, tend to maximize risk, but may overestimate risk. Therefore, the variability of use of BRCAPRO limits cross-study comparisons.

A multi-institutional study would be needed to determine whether our results would apply to a population-based sample. Parmigiani et al⁴² compared the accuracy of BRCA1/2 mutation prediction using samples from both clinic- and population-based samples. Surprisingly, population-based samples provided more accurate predictions in mutation-positive individuals. They suggested that the wider range of estimates from the population-based studies provided better discrimination among high- and low-risk families than could be obtained from clinical populations that include primarily high-risk families.⁴² Although results from our current study should generalize to other clinical populations, they may yield a less sensitive performance if applied in the context of a population-based study.

Breast cancer is the most commonly diagnosed cancer in Hispanic women, and is the leading cause of cancer death among this population.⁴³ Given the cancer burden and the appreciable frequency of BRCA1/BRCA2 mutations, it is important that high-risk Hispanic families be targeted for genetic counseling and testing. Our study provides evidence that it is appropriate to use BRCAPRO in the risk assessment of Hispanic families.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Kristen J. Vogel, Banu Arun

Administrative support: Deann P. Atchley, Christopher I. Amos, Gabriel N. Hortobagyi

Provision of study materials or patients: Kristen J. Vogel, Kaylene J. Ready, Vicente Valero, Karen H. Lu, Banu Arun

Collection and assembly of data: Kristen J. Vogel, Julie Erlichman, Kaylene J. Ready, Christopher I. Amos

Data analysis and interpretation: Kristen J. Vogel, Deann P. Atchley, Kristine R. Broglio, Gabriel N. Hortobagyi, Banu Arun

Manuscript writing: Kristen J. Vogel, Kristine R. Broglio, Banu Arun

Final approval of manuscript: Kristen J. Vogel, Deann P. Atchley, Julie Erlichman, Kristine R. Broglio, Kaylene J. Ready, Vicente Valero, Christopher I. Amos, Gabriel N. Hortobagyi, Karen H. Lu, Banu Arun

	NOTES

 
Presented in part at the 5th Annual American Association for Cancer Research International Conference: Frontiers in Cancer Prevention Research, November 12-15, 2006, Boston, MA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted December 21, 2006; accepted July 23, 2007.

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