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Incidence of BRCA1 and BRCA2 Mutations in Young Korean Breast Cancer Patients

From the Departments of Therapeutic Radiology, Genetics, and Pathology, Yale University School of Medicine, New Haven, CT; and the Department of Surgery, Soonchunhyang University, Seoul, Korea.

Address reprint requests to Bruce G. Haffty, MD, Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520-8040; e-mail: bruce.haffty{at}yale.edu

	ABSTRACT

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PURPOSE: The prevalence of BRCA-associated breast carcinoma in the Korean population has not been evaluated extensively.

METHODS: Sixty Korean women who developed breast cancer by age 40 years were studied. Lymphocyte specimens from peripheral blood were processed for BRCA1 and BRCA2 by complete sequencing. Family history through three generations was obtained. Available paraffin-embedded tissue blocks were processed for immunohistochemical staining.

RESULTS: In the cohort of 60 patients, nine patients with 11 deleterious mutations (six in BRCA1 and five in BRCA2) and seven missense mutations of unknown significance were found. Two patients had deleterious mutations in both BRCA1 and BRCA2 (double mutant). One half of the mutations were novel, and no founder mutations were observed in this cohort. Most of the BRCA-associated patients had no family history of breast and/or ovarian cancer. The expression of HER-2/neu, cyclin D1, and hormone receptors was less common, and p53 overexpression was more common in BRCA-associated tumors.

CONCLUSION: The prevalence of BRCA1 and BRCA2 mutations in Korean women with breast cancer at a young age was high. However, the penetrance, as evidenced by the low frequency of breast and ovarian cancers in family members, appears to be low. These data suggest that there may be different genetic and etiologic factors affecting transmission and penetrance of the BRCA genes in Korean patients with breast cancer diagnosed at a young age.

	INTRODUCTION

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Breast cancer is the most common noncutaneous malignancy in females, occurring in approximately one in eight women in Western countries.¹ The age-adjusted incidence of invasive breast cancer for non-Hispanic white women is four times as high as that for the lowest Korean-American group in the Surveillance, Epidemiology, and End Results regions and 4% to 8% of total cases in Western countries occur in patients younger than 40 years.² However, approximately 25% of invasive breast cancer cases in Korea occur in patients younger than 40 years.² The median age of Korean women with breast cancer is 45 years—approximately 15 years younger than the median age of white women with breast cancer in the United States.³ Breast cancer is usually a disease of premenopausal women in Korea compared with a disease of postmenopausal women in United States.

Studies of large families, many of whose members have cancer, have led to the identification of mutations in two genes that contribute to the development of breast cancer, BRCA1 and BRCA2.^4,5 The occurrence of early-onset breast cancer has been associated with mutations in these genes.^6–8 Previous studies on BRCA1 and BRCA2 mutations in breast cancer patients have been confined largely to Western countries. The prevalence rates have been approximately 20% among selected populations,^6,9–12 in which highly recurrent founder mutations account for the majority of all mutations, whereas rates decreased to between 5% and 10% among less isolated populations.^13–23 The majority of breast cancer patients found to have BRCA1 or BRCA2 also reveal a family history of breast and/or ovarian cancer in at least one first-degree relative.^6,7,16,24 To assess the contribution of BRCA1 and BRCA2 mutations to breast cancer in young Korean women, a hospital-based study was undertaken. We analyzed a sample of young breast cancer patients who were treated at the Soonchunhyang University Hospital (Seoul, Korea). Patients were selected solely because they had a diagnosis of breast cancer at a young age and were observed in our clinics, and were not selected on the basis of family history. Complete sequencing for germline mutations in BRCA1 and BRCA2 was undertaken and available tissue specimens also were stained for molecular markers.

	METHODS

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Study Patients
From 1995 to 2000, patients with invasive breast cancer diagnosed at age 40 or younger who were surgically treated at the Soonchunhyang University Hospital were asked to provide a blood sample for the sole purpose of genetic testing for this study. Sixty consecutive patients who met the selection criteria of having breast cancer at age 40 or younger, who presented to our follow-up clinics between October 2000 and February 2001, were invited to participate. All invited patients agreed to the genetic testing with the understanding that they would receive the results and would be counseled regarding the implications. None of the patients were selected on the basis of a family history of breast or ovarian cancer. Twenty-seven patients underwent breast-conserving surgery and radiotherapy, and 33 patients underwent modified mastectomy or skin-sparing mastectomy. All of the patients received postoperative chemotherapy. One patient had bilateral breast cancer.

The study was approved by an institutional review board and informed consent was obtained from all subjects. Patients were interviewed for information on family history of any cancers, with specific reference to any history of breast or ovarian cancer. They were informed of the possibility that testing could lead to psychological distress and family disruption. Patients were informed of the potential implications of results. However, patients also were informed of the benefits of identifying those at risk, which would warrant increased surveillance or preventive options that might result in improved health care. All of the patients were promised confidentiality, with the results stored in coded files and not included in their clinical records. All patients who participated elected to receive their results.

Additional details of other cancers in first-, second-, or third-degree relatives was obtained during the initial intake, renewed contact, and/or on notifying the patients of test results. A majority of these patients are from close-knit families. In addition, the treating physicians were involved in the recruitment of patients and in eliciting family history information, reducing the likelihood of missing or underreporting of family history information. For occurrences of cancers diagnosed and treated in other family members, the information regarding the type of cancer was verified from the medical record.

Blood samples were obtained from phlebotomy in two tubes from each patient. We attempted to retrieve paraffin-embedded primary tumor specimens for immunohistochemical staining of pertinent molecular markers, and of the 60 patients, 31 paraffin-embedded tissue blocks were available from the hospital archives.

Genetic Testing
Genomic DNA was isolated from peripheral-blood lymphocytes. All analyses of BRCA1 and BRCA2 were performed by direct gene sequencing at Myriad Genetics Laboratories (Salt Lake City, UT). Aliquots of patients' DNA were each subjected to polymerase chain reaction (PCR), an amplification of the entire coding region and intron-exon boundaries (35 reactions for BRCA1, 47 reactions for BRCA2). The amplified products were each directly sequenced in forward and reverse directions using fluorescent dye–labeled sequencing primers. A chromatographic tracing of each amplicon was analyzed by proprietary sequence analysis software followed by visual inspection and confirmation. Genetic variants were detected by comparison with a consensus wild-type sequence constructed for each gene and were confirmed by repeated analysis, including PCR amplification of the indicated gene regions and sequence determination.

Immunohistochemistry
Five-micrometer sections cut from paraffin blocks were dried at 60°C for 1 hour. The sections were dewaxed in xylene and rehydrated through graded alcohols to distilled water. Antigen retrieval was performed in a steam bath at 97°C for 20 minutes for determination of estrogen receptor (ER), progesterone receptor (PR), p53, cyclin D1, and HER-2/neu status. An autostainer (DAKO, Glostrup, Denmark) was used for the staining and no blocking steps were required. The sections were incubated in primary antibody at various dilutions for 30 minutes at room temperature. Secondary antigen retrieval was performed using detection kits (Envision for ER and PR, DAKO Lsab+ for p53 and cyclin D1, and HercepTest [DakoCytomation, Glostrup, Denmark] for HER-2/neu). All sections were counterstained with hematoxylin, dried, and coverslipped.

Statistical Analysis
All of the patient data, including clinical, immunologic, and BRCA mutations testing, were entered into the PRODAS computerized database management system (Conceptual Software Inc, Houston, TX). Differences in categoric variables between wild-type and mutations were compared using standard ² analysis or Fisher's exact test, as appropriate.

	RESULTS

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The characteristics of the 60 patients with or without BRCA mutations are summarized in Table 1. Only the patients with deleterious mutations in BRCA1 or BRCA2 are classified as carriers. Patients with normal sequencing and those with variants of unclear significance are classified as noncarriers. Infiltrating ductal carcinoma was the prominent histology in both cohorts (BRCA carriers and BRCA noncarriers). Of note, the three medullary carcinomas in the study belonged to women without deleterious mutations. The patient with bilateral disease and all of the primary tumors larger than 5.0 cm were also in women without mutations. Only a marginally significant statistical difference in family history of cancers was found between the two groups of BRCA carriers and sporadic patients (Table 1).

Three patients had more than two sequence variants, including two patients with deleterious mutations in both BRCA1 and BRCA2 (Table 2). Patient 60071, who was diagnosed at age 33, had two deleterious mutations without a family history of breast cancer. Peripheral blood samples were collected from all of her first-degree relatives and sequencing for the two mutation sites showed that the proband's mother had the same two mutations and other first-degree relatives have one or none of the mutations (Fig 1). The proband's mother had stomach cancer at the age of 62 years, which is the most prevalent cancer in both men and women in Korea. None of the sisters carrying one of the mutations had cancers.

View larger version (12K): [in this window] [in a new window]   Fig 1. Family pedigree of patient with two deleterious mutations, with all first-degree relatives tested.

	DISCUSSION

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As opposed to other populations with relatively high prevalence rates of BRCA1 or BRCA2, no recurrent founder mutations were observed in this study. There were two ethnic populations in which a higher prevalence of BRCA-associated cancers was reported compared with the current study. Studies carried out in isolated populations, such as Ashkenazi Jews^6,9 or Icelanders,^11,12 showed that the prevalence of BRCA-associated breast tumors in young patients may be as high as 30% for Ashkenazi Jews and approximately 25% for Icelanders (Table 5). In those isolated selected populations, highly recurrent founder mutations account for the majority of mutations. More than 2% of Ashkenazi Jews carry mutations in BRCA1 (185delAG, 5382insC) and BRCA2²⁵ (6174delT), and about 0.5% of Icelanders^11,12 have 999del5 in the BRCA2 gene. Among Ashkenazi Jews, BRCA1 mutations appear to provide a greater contribution to breast cancer in young women than do BRCA2 mutations. Conversely, in Iceland, BRCA2 accounts for a major proportion, whereas BRCA1 makes a small contribution. In other studies of unselected populations, the prevalence rate of BRCA1 and BRCA2 mutations lies between 6% and 12%^13–23 (Table 5). Mutations in the two genes make approximately equal contributions to breast cancer in our study. This is consistent with other results.^{13,14,17,18,26} One study had a large proportion of the BRCA1 mutation because researchers included missense mutations in the analysis, and all of the missense mutations were detected in the BRCA1 gene.²⁰ BRCA2 gene mutations contributed more than BRCA1 mutation to breast cancer in the Philippines.²³

One of the most important findings of this study is that most of the patients with deleterious BRCA mutations do not have a family history of breast or ovarian cancer. We observed only two of nine patients with a family history of cancer: one whose mother had breast cancer and one with a paternal aunt with breast cancer. The observation that seven of nine carriers do not have a relative with breast or ovarian cancer is clearly not in accordance with previous studies evaluating family histories in BRCA1 and BRCA2 mutation carriers. Family history is observed in more than 80% of patients in the Ashkenazi and Icelander populations,^6,12 and 40% to 90% in the other populations.^14–20,23 Only one study with ethnic Chinese had a family history pattern similar to this study.²² One might speculate that the Asian cultures would be less likely to report family history information. However, in the current study a majority of patients come from close-knit families, in which sharing of information regarding family illnesses is not believed to be a cultural barrier. Furthermore, the physicians involved in the study were well acquainted with the patients and involved directly in eliciting the information. Therefore, underreporting of family history information is unlikely in our study. However, underreporting of additional family members with breast cancer cannot be totally excluded and must be acknowledged as a potential limitation in interpretation of these data.

The family history of breast and/or ovarian cancers of 13% in this study is significantly lower than that of most studies and not different from the 11.9% of family history of breast cancers in the general population of the United States.²⁹ This likely is a reflection of the fact that our patients were not selected from high-risk clinics, and were selected solely on the basis of a diagnosis of breast cancer at a young age. The lower incidence of a family history of breast and ovarian cancers, even among those patients with deleterious mutations in our study, suggests the possibility of a lower penetrance of the gene among Korean women compared with other populations studied. This possibly is attributable to genetic and environmental modifying effects.³⁰ One possible environmental effect might be attributed to the Asian diet or caloric intake. Breast cancer may be reduced by diets with less animal fat and more fruits and vegetables.³¹ Indeed, a recent study on twins suggests that inherited genetic factors make a minor contribution to sporadic breast cancers (27%).³² Studies of Asian women suggest that those who consume a traditional diet high in soy products have a low incidence of breast cancer because circulating levels of ovarian hormones are decreased³³ and expression of the epidermal growth factor receptor is upregulated.³⁴

The significance of the lower incidence of breast and ovarian cancers in Korean BRCA carriers remains unclear and warrants additional investigation. It could mean that mutations observed in Korean or Chinese confer a lower penetrance than previously estimated in Western countries, especially in the Ashkenazi population. ^26,35 A recently published study from Kang et al,³⁶ however, screened 21 Korean families with two or more affected members with breast and/or ovarian cancer. They observed deleterious mutations in nine of these families, suggesting a relatively high penetrance pattern in these families. Early studies of families with multiple members with breast and ovarian cancer suggested that BRCA1 mutation carriers may have a lifetime risk for breast cancer of up to 84% and a risk for ovarian cancer of up to 44%.^26,37 However, studies of women not selected for family history have suggested that the risk may be somewhat lower than those initial estimates,²⁵ and the penetrance of the BRCA2 mutation is lower than that of the BRCA1 mutation, especially in the Jewish population.³⁸

Another distinct pattern in this study is that Korean patients with breast cancers at a young age have a high frequency of double mutations in the BRCA genes. Two patients had two known deleterious mutations (each with one in BRCA1 and one in BRCA2). Since Ramus et al³⁹ first reported such a patient, subsequent case reports mostly have been in Ashkenazi populations.^39–42 Frank et al⁴² found 10 patients with both mutations in BRCA1 and BRCA2 of 10,000 patients, which was significantly lower than the expected 30 patients from an equilibrium population of 2,539 Ashkenazi women. Friedman et al⁴⁰ also found only three patients of approximately 1,500 breast or ovarian cancer patients, and they postulated that there may be some selection against mutations in each BRCA1 and BRCA2 as well. The unexpected finding of two patients with deleterious mutations in both BRCA1 and BRCA2 gene in nine carriers observed in this relatively small sample size of just 60 women is significantly higher than expected.

One patient classified as deleterious carried the IVS17+1G T in BRCA1. This mutation is suspected to be deleterious because nucleotides at this position are highly conserved and necessary for proper mRNA processing.⁴³ Furthermore, biochemical analysis demonstrates that similar mutations in other genes are usually deleterious. One of the missense mutations, L1780P is located in the BRCA1 C-terminal domain to which a transactivation function has been ascribed.^44,45 On the basis of its location at conserved residues in functionally important domains and the occurrence of this alteration in a woman with a positive family history of breast cancer, L1780P may be considered to be deleterious. However, we have not classified this as disease-associated in the current study.

Results from this study for immunohistochemistry are not different from other studies. BRCA mutation carriers' tumors are typically ER-negative, PR-negative, cyclin D1-negative, HER-2/neu-negative, and p53-positive in all age groups for patients with a family history,^6,46,47 but similar results have been observed in early-onset breast cancer regardless of family history and mutation sites.^22,48 These data suggest that neither hormone receptor nor HER-2/neu stimulation seem to be important in the pathogenesis of cancers arising in mutation carriers. A reasonable explanation for these results is that p53 loss rescues the proliferative deficiency of BRCA mutant cells at the expense of genetic instability.⁴⁹

In summary, Korean patients with breast cancer diagnosed at a young age have characteristics of high prevalence of BRCA mutations, minimal family history of breast and ovarian cancer, and frequent occurrence of double mutations. Although we can make no definitive recommendations from this study regarding implications for genetic testing in Korean women, it is clear that the prevalence of BRCA mutations in this population of young Korean women is high. The data also suggest a low penetrance, evidenced by the low frequency of breast and ovarian cancers in family members. It is difficult to ascertain the clinical implications of these data, given our limited sample size. Whether Korean women with BRCA mutations have similar risks of breast and/or ovarian cancer or second malignancies of the contralateral breast, and their potential benefit from prophylactic strategies remains to be seen. Large population-based screening studies are needed to establish the frequency, penetrance, and significance of the broad spectrum of variations in the sequence of BRCA1 and BRCA2 genes. Only then will it be possible to offer reliable results and meaningful counseling to Korean women with breast cancer who choose to have such testing.

Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by Greenwich Breast Cancer Alliance and the Ethel F. Donaghue Women's Health Investigator Program at Yale University School of Medicine.

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

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Submitted April 25, 2003; accepted February 12, 2004.

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