The role of financial factors in acceptance of clinical BRCA genetic testing

Many women who are offered BRCA genetic testing by genetics professionals do not have the test, possibly for financial reasons. We explored financial factors implicated in non-uptake of BRCA testing in women who had received genetic counseling in a clinical setting. Specifically, we described financial factors (affordability, health insurance, other) involved with BRCA testing; compared nonfinancial factors (disease, sociodemographic, risk assessment) in women who did not have BRCA testing (nontesters) with women who had the test (testers); showed associations of financial and nonfinancial factors with BRCA testing; and identified predictors of non-uptake of BRCA testing. The sample of 100 women (64 nontesters and 36 testers) completed an anonymous mailed survey on financial factors; 52 of the nontesters answered questions about nonfinancial factors. Testers had significantly better affordability and insurance coverage (p < 0.001), more diagnoses of breast or ovarian cancer (p < 0.05) and higher rates of receiving post-counseling risk estimates (p < 0.05), than nontesters. Non-uptake was 5.5-fold more likely in women that could not afford full or partial payment for the test and was 15.5-fold more likely in women that did not recall receiving risk estimates post-counseling. For many women having risk factors for breast/ovarian cancer, affordability of BRCA testing and insurance coverage for the test remain problematic. Post-counseling reminders of risk estimates may contribute to uptake of testing.     

Screening for 185delAG in the Ashkenazim.

A study was initiated to assess interest, educational effectiveness, and implications of genetic testing for the common BRCA1 mutation, 185delAG, in the Ashkenazim. Of 333 individuals who attended group sessions, 309 (92%) participated in the study. Participants were categorized as having negative family history (67%), positive family history (defined, by a relaxed criterion, as one first-degree relative or two second-degree relatives with breast [premenopausal] or ovarian cancer) (22%), positive personal history (7%), and both positive personal history and positive family history (4%). Group education was effective, as shown by the improvement in participant scores from pre- to posteducation tests. For the 289 individuals (94%) who requested testing, the major reasons included concern for their own risk, concern for the risk of their children, and desire to learn about surveillance options. The most common reason given by participants who declined testing was concern about health insurance. Six participants found to be heterozygous for the 185delAG mutation received results and were offered genetic counseling. Participants had consented for additional testing without receiving results and were screened for the 6174delT mutation in BRCA2, and seven were found to be positive. All identified carriers reported at least one first- or second-degree relative with a history of breast or ovarian cancer, although they did not all meet our study criteria for positive family history. Given these outcomes, we conclude that screening for breast and ovarian cancer susceptibility is most appropriate for individuals with a positive personal or positive family cancer history. We propose a guideline for future studies designed to identify individuals who may benefit from genetic testing for inherited breast and ovarian cancer.     

Frequency and carrier risk associated with common BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer patients.

Based on breast cancer families with multiple and/or early-onset cases, estimates of the lifetime risk of breast cancer in carriers of BRCA1 or BRCA2 mutations may be as high as 85%. The risk for individuals not selected for family history or other risk factors is uncertain. We determined the frequency of the common BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) mutations in a series of 268 anonymous Ashkenazi Jewish women with breast cancer, regardless of family history or age at onset. DNA was analyzed for the three mutations by allele-specific oligonucleotide hybridization. Eight patients (3.0%, 95% confidence interval [CI] 1.5%-5.8%) were heterozygous for the 185delAG mutation, two (0.75%, 95% CI 0.20-2.7) for the 5382insC mutation, and eight (3.0%, 95% CI 1.5-5.8) for the 6174delT mutation. The lifetime risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be 36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5-5.8). For the 5382insC mutation, because of the low number of carriers found, further studies are necessary. The results differ markedly from previous estimates based on high-risk breast cancer families and are consistent with lower estimates derived from a recent population-based study in the Baltimore area. Thus, presymptomatic screening and counseling for these common mutations in Ashkenazi Jewish women not selected for family history of breast cancer should be reconsidered until the risk associated with these mutations is firmly established, especially since early diagnostic and preventive-treatment modalities are limited.     

Referral and experience with genetic testing among women with early onset breast cancer

The purpose of this study was to determine whether physicians refer women with early onset breast cancer for genetic testing for BRCA1 and BRCA2, and how women respond to being offered testing and use the results. A web-based survey was distributed to 1221 women with early onset breast cancer. The survey included 158 questions divided into the following sections: demographics, family history of cancer, medical history, treatment history, and experience with genetic testing. Of 551 women diagnosed since 1993 who responded to the survey (45.1%), less than half (45%, n = 246) had ever discussed genetic testing with their physician and/or been referred to see a genetic counselor. Women with a family history of cancer (53%) and Ashkenazi Jewish women (81%) were more likely to have been referred. Of those who had discussed testing, 60% had undergone or were interested in testing. Overall 92 women were tested and 19 (20.6%) of these tested positive for a deleterious BRCA1 or BRCA2 mutation. Fourteen (74%) who tested positive subsequently underwent prophylactic surgery. Satisfaction with counseling and the decision to be tested was high. Among women who were not offered testing, the fact that the test had not been offered by their physician (89%), and fear of discrimination (83%) were the two most frequently cited factors for lack of interest in testing. A substantial number of women are not being referred to genetic counseling and/or testing after a diagnosis of early onset breast cancer. Among those who were tested, there was high interest in prophylactic surgery after confirmation of a BRCA1/2 mutation.     

Progress of a Comprehensive Familial Cancer Genetic Counseling Program in the Era of BRCA1 and BRCA2

BRCA1 and BRCA2 mutation carriers have an increased risk of developing breast and/or ovarian cancer. Technical advances in genetic testing have increased the need for genetic counseling services; therefore, we have developed a counseling program for these individuals. The purpose of this study is to characterize this population, assess level of interest in genetic testing, and evaluate our program over a 5-year period. Our Familial Cancer Genetic Counseling Program was established in November, 1994. Information was collected prospectively, with comprehensive evaluation including complete pedigree, risk assessment, and counseling by a genetic counselor, geneticist, and oncologist. Data were collected on risk level, and subsequent recommendations for screening and/or genetic testing. There were 824 contacts recorded from November, 1994, through August, 1999. To date, 162 families have undergone comprehensive genetic evaluation and counseling. 90 (56%) were seen for a concerning family history and 72 (44%) were seen due to a personal history of malignancy. The majority of families had a significant level of risk with 126 (78%) families having two and 70 (43%) families having three affected first-degree relatives. Of the 162 families who received full counseling, 125 (77%) met criteria to recommend BRCA1/BRCA2 genetic testing. At this time, 30 of the 162 (18%) have had genetic testing. A brief phone contact or clinic visit is useful to screen individuals so that counseling can be directed toward truly high-risk families. In our program, the majority of families counseled were eligible for BRCA1/BRCA2 testing, but only 18% have elected to proceed at this time.     

Impact of genetic testing for breast-ovarian cancer susceptibility

Previously, we have reported a clinical trial in which any woman in a defined geographic region who had a qualifying family history and who was referred by her physician or who was identified through a regional cancer registry was offered free genetic counseling, BRCA testing, and recommendations based on test results. Each family was represented by one affected and one unaffected person. Of the 87 families actually tested, 13 were found to have deleterious mutations. To assess the impact of the counseling and testing process, we contacted the tested individuals 1 month and 1 year after receiving the test result and those with an abnormal test result after 4 years. Index subjects, we found, differed significantly from relatives. Before coming for counseling, index subjects perceived both their general health and emotional health as worse than did their relatives. After counseling and testing, index subjects continue to worry more about breast cancer than do relatives. Affected subjects, we found, differed significantly from unaffected subjects. Before counseling, affected subjects knew more about breast cancer, perceived their general health as poorer, and reported greater adherence to recommended breast cancer surveillance than did unaffected subjects. After counseling and testing, affected subjects were less satisfied than unaffected subjects with having been tested. This study indicates that the group most prone to distress by cancer risk genetic counseling and testing is not the recruited relatives, nor even those affected with cancer, but rather the index patients themselves. The index patients, i.e., the ones who want the risk information most, appear to undergo the most stress in obtaining it.     

Motivations and concerns of women considering genetic testing for breast cancer: a comparison between affected and at-risk probands

Since the discovery of the BRCA1 and BRCA2 genes, there has been an increasing demand for breast cancer risk assessment programs. In an effort to understand and serve the population such programs target better, several studies have identified factors influencing high-risk women to pursue breast cancer risk assessment and genetic testing services; none, however, has focused on how the motivations and concerns of at-risk women may differ from their previously affected counterparts, who are typically the initial members of their families to undergo genetic testing. The majority of both previously affected and unaffected women felt that preventative surgery decisions, surveillance practices, the assessment of children's risks, and increased breast cancer anxiety were "more important" or "very important" issues regarding their thoughts about genetic testing. Significantly more affected women deemed family members' opinions "more" or "very important" (p < 0.01). Opinions concerning insurance and employment discrimination did not vary significantly between groups; however, a larger percentage of affected women felt this issue was of importance. Although all issues above should be addressed with women seeking cancer risk assessment and genetic testing, this research may help health care providers to gain a greater understanding of how the motivators and concerns of high-risk women can differ with personal cancer status so that referral, counseling, and education can be executed optimally.     

Simultaneous interdisciplinary counseling in German breast/ovarian cancer families: first experiences with patient perceptions, surveillance behavior and acceptance of genetic testing

As part of a multicenter study supported by the German Mildred Scheel foundation we have established an interdisciplinary counseling setting for members of breast and/or ovarian cancer families. We offer simultaneous counseling by a team consisting of a geneticist, a gynecologist and a psycho-oncologist. Here we describe our counseling protocol and our first short-term experience with this interdisciplinary approach. Preliminary data on patient perceptions and behaviors in the context of DNA testing are reported. Overall, our counseling approach was perceived as beneficial both by the counselors and the consultants. A marked overestimation of the risk to develop breast and/or ovarian cancer was noted in the group of unaffected individuals from medium to low risk breast cancer families in contrast to an appropriate risk perception in members from high risk families. All participants shared many of the same expectations about genetic testing and counseling and appeared to base their decision-making about testing on the risk classification given by the genetic counselor. The reported participation in gynecological cancer prevention programs was high in all families at risk, but was less sufficient in unaffected as compared to affected persons. Although current data on BRCA1/BRCA2 mutation analyses render testing in medium to low risk individuals questionable, our findings emphasize the importance of genetic counseling and education in all risk categories of breast and/or ovarian cancer families.     

The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews

Three founder mutations in the cancer-associated genes BRCA1 and BRCA2 occur frequently enough among Ashkenazi Jews to warrant consideration of genetic testing outside the setting of high-risk families with multiple cases of breast or ovarian cancer. We estimated the prevalence of these founder mutations in BRCA1 and BRCA2 in the general population of Ashkenazi Jews according to age at testing, personal cancer history, and family cancer history. We compared the results of anonymous genetic testing of blood samples obtained in a survey of >5,000 Jewish participants from the Washington, DC, area with personal and family cancer histories obtained from questionnaires completed by the participants. In all subgroups defined by age and cancer history, fewer mutations were found in this community sample than in clinical series studied to date. For example, 11 (10%) of 109 Jewish women who had been given a diagnosis of breast cancer in their forties carried one of the mutations. The most important predictor of mutation status was a previous diagnosis of breast or ovarian cancer. In men and in women never given a diagnosis of cancer, family history of breast cancer before age 50 years was the strongest predictor. As interest in genetic testing for BRCA1 and BRCA2 in the Jewish community broadens, community-based estimates such as these help guide those seeking and those offering such testing. Even with accurate estimates of the likelihood of carrying a mutation and the likelihood of developing cancer if a mutation is detected, the most vexing clinical problems remain.     

Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2.

Breast cancer-susceptibility genes BRCA1 and BRCA2 have recently been identified on the human genome. Women who carry a mutation of one of these genes have a greatly increased chance of developing breast and ovarian cancer, and they usually develop the disease at a much younger age, compared with normal individuals. Women can be tested to see whether they are carriers. A woman who undergoes genetic counseling before testing can be told the probabilities that she is a carrier, given her family history. In this paper we develop a model for evaluating the probabilities that a woman is a carrier of a mutation of BRCA1 and BRCA2, on the basis of her family history of breast and ovarian cancer in first- and second-degree relatives. Of special importance are the relationships of the family members with cancer, the ages at onset of the diseases, and the ages of family members who do not have the diseases. This information can be elicited during genetic counseling and prior to genetic testing. The carrier probabilities are obtained from Bayes's rule, by use of family history as the evidence and by use of the mutation prevalences as the prior distribution. In addressing an individual's carrier probabilities, we incorporate uncertainty about some of the key inputs of the model, such as the age-specific incidence of diseases and the overall prevalence of mutations. There is some evidence that other, undiscovered genes may be important in explaining familial breast cancer. Users of the current version of the model should be aware of this limitation. The methodology that we describe can be extended to more than two genes, should data become available about other genes.     

BRCA2 gene mutations in Slovenian male breast cancer patients

Male breast cancer (MBC) is a rare disease, comprising less than 1% of breast cancer patients in Slovenia. Some inherited cases are due to the mutations of BRCA1 or BRCA2 genes. There is no information available about the frequency of BRCA gene mutations in Slovenian MBC population. The purpose of this study was to characterize BRCA germline mutations in Slovenian MBC patients. Forty-one patients who were diagnosed with breast cancer at the Institute of Oncology Ljubljana between 1970 and 2006 were proposed to take part in this study. Of them, 27 agreed to follow a genetic counseling session and 25 patients agreed to provide a blood sample for genetic testing. The BRCA1 and BRCA2 genes from the MBC patients were screened for four highly recurrent mutations in the Slovenian population. When an additional breast cancer case or an ovarian cancer was present in the family, a more extended analysis was performed. No BRCA1 mutations were found. A BRCA2 gene mutation was identified in four MBC patients. Three of them carried the Slovenian founder mutation IVS16-2A>G. All four mutations were confined to the patients with a family history of breast cancer. Among the MBC patients with a family history of breast cancer in the first- or second-degree relatives, the frequency of BRCA2 gene mutation was 50%. The median age of the patients with a BRCA2 gene mutation was 60 years, not significantly different from those without a mutation. The BRCA2 mutations were diagnosed in 16% of our MBC patients.     

Management updates for women with a BRCA1 or BRCA2 mutation

In most cases of families with breast and ovarian cancer, the pattern of cancers in the family can be attributed to mutations in the BRCA1 and BRCA2 genes. Genetic testing for these cancer susceptibility genes typically takes place in the context of comprehensive genetic counseling. Strategies have been developed for the medical management of women at high risk of developing breast cancer, including options for screening and prophylactic surgery. BRCA1 and BRCA2 carriers are recommended to undergo prophylactic bilateral salpingo-oophorectomy by age 35-40 years or when childbearing is complete. This surgery significantly reduces the risk of ovarian cancer and also reduces the risk of breast cancer when performed in premenopausal mutation carriers. For breast cancer management, BRCA1 and BRCA2 carriers are offered the options of increased surveillance, with or without chemoprevention, or prophylactic surgery. Currently, BRCA carrier status is not used as an independent prognostic factor regarding systemic treatment options.     

Hereditary breast cancer; Genetic penetrance and current status with BRCA

The most important cause of developing hereditary breast cancer is germline mutations occurring in breast cancer (BCs) susceptibility genes, for example, BRCA1, BRCA2, TP53, CHEK2, PTEN, ATM, and PPM1D. Many BC susceptibility genes can be grouped into two classes, high- and low-penetrance genes, each of which interact with multiple genes and environmental factors. However, the penetrance of genes can also be represented by a spectrum, which ranges between high and low. Two of the most common susceptibility genes are BRCA1 and BRCA2, which perform vital cellular functions for repair of homologous DNA. Loss of heterozygosity accompanied by hereditary mutations in BRCA1 or BRCA2 increases chromosomal instability and the likelihood of cancer, as well as playing a key role in stimulating malignant transformation. With regard to pathological features, familial breast cancers caused by BRCA1 mutations usually differ from those caused by BRCA2 mutations and nonfamilial BCs. It is essential to acquire an understanding of these pathological features along with the genetic history of the patient to offer an individualized treatment. Germline mutations in BRCA1 and BRCA2 genes are the main genetic and inherited factors for breast and ovarian cancer. In fact, these mutations are very important in developing early onset and increasing the risk of familial breast and ovarian cancer and responsible for 90% of hereditary BC cases. Therefore, according to the conducted studies, screening of BRCA1 and BRCA2 genes is recommended as an important marker for early detection of all patients with breast or ovarian cancer risk with family history of the disease. In this review, we summarize the role of hereditary genes, mainly BRCA1 and BRCA2, in BC.     

Detection of eight BRCA1 mutations in 10 breast/ovarian cancer families, including 1 family with male breast cancer.

Genetic epidemiological evidence suggests that mutations in BRCA1 may be responsible for approximately one half of early onset familial breast cancer and the majority of familial breast/ovarian cancer. The recent cloning of BRCA1 allows for the direct detection of mutations, but the feasibility of presymptomatic screening for cancer susceptibility is unknown. We analyzed genomic DNA from one affected individual from each of 24 families with at least three cases of ovarian or breast cancer, using SSCP assays. Variant SSCP bands were subcloned and sequenced. Allele-specific oligonucleotide hybridization was used to verify sequence changes and to screen DNA from control individuals. Six frameshift and two missense mutations were detected in 10 different families. A frameshift mutation was detected in a male proband affected with both breast and prostate cancer. A 40-bp deletion was detected in a patient who developed intra-abdominal carcinomatosis 1 year after prophylactic oophorectomy. Mutations were detected throughout the gene, and only one was detected in more than a single family. These results provide further evidence that inherited breast and ovarian cancer can occur as a consequence of a wide array of BRCA1 mutations. These results suggests that development of a screening test for BRCA1 mutations will be technically challenging. The finding of a mutation in a family with male breast cancer, not previously thought to be related to BRCA1, also illustrates the potential difficulties of genetic counseling for individuals known to carry mutations.     

Study of a single BRCA2 mutation with high carrier frequency in a small population.

Germ-line changes in the cancer-predisposition gene BRCA2 are found in a small proportion of breast cancers. Mutations in the BRCA2 gene have been studied mainly in families with high risk of breast cancer in females, and male breast cancer also has been associated with BRCA2 mutations. The importance of germ-line BRCA2 mutations in individuals without a family history of breast cancer is unknown. The same BRCA2 mutation has been found in 16/21 Icelandic breast cancer families, indicating a founder effect. We determined the frequency of this mutation, 999del5, in 1,182 Icelanders, comprising 520 randomly selected individuals from the population and a series of 632 female breast cancer patients (61.4% of patients diagnosed during the study period) and all male breast cancer patients diagnosed during the past 40 years. We detected the 999del5 germ-line mutation in 0.6% of the population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast cancer at age <50 years, but its penetrance and expression are varied. A number of cancers other than breast cancer were found to be increased in relatives of mutation carriers, including those with prostate and pancreatic cancer. Furthermore, germ-line BRCA2 mutation can be present without a strong family history of breast cancer. Comparison of the age at onset for mother/daughter pairs with the 999del5 mutation and breast cancer indicates that age at onset is decreasing in the younger generation. Increase in breast cancer incidence and lower age at onset suggest a possible contributing environmental factor.     

Impact of BRCA1 testing on women with cancer: a pilot study

We sought to understand better the impact of genetic testing and counseling in a group of women who had early breast cancer (age <50) or ovarian cancer and a family history of cancer. Thirty-five women underwent genetic counseling and genetic testing for BRCA1/2 at the University of Colorado Cancer Center, Hereditary Cancer Clinic. Psychological assessment (IES and Hopkins Symptom Checklist) was made before counseling, and 1 month after genetic test results were reported to women. A statistically significant decrease in anxiety was evidenced 1 month after results were given (p = 0.024). Decreased intrusive thoughts related to genetic testing were seen only for those testing negative (p = 0.0003). Women diagnosed with cancer less than 1 year prior to genetic testing experienced the greatest cancer-specific distress (p = 0.01) and distress related to genetic testing (p = not significant). Satisfaction with the counseling and testing process was high. In conclusion, genetic testing and counseling can occur with little anxiety and stress. However, women less than 1 year from a cancer diagnosis will experience the greatest distress associated with genetic testing and counseling. Women who are considering genetic testing and counseling close to a diagnosis of cancer may require greater psychological support.     

BRCA1 and BRCA2 pathways and the risk of cancers other than breast or ovarian

OBJECTIVE: Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose women to breast and ovarian cancer. Female carriers of BRCA1 or BRCA2 gene mutations have very high lifetime risks for breast and ovarian cancers. Genetic abnormalities occur in all cancers, so BRCA-related pathways are critical because they serve to safeguard genetic content. Although protecting genetic information is a general function, BRCA-related pathways seem largely specific to preventing breast and ovarian cancer. The objective of this study was to resolve this difference between the theoretical functions of BRCA genes and their specific clinical effects. DATA SOURCES, DATA EXTRACTION, DATA SYNTHESIS: The author collected data published in > 30 epidemiologic studies on the incidence of cancers other than breast or ovarian in mutation carriers and in large populations eligible for mutation testing. Data were extracted and used directly as published whenever possible with a minimum of statistical manipulation. CONCLUSIONS: Although mutations target breast and ovary, a broader spectrum of cancers also occur with statistically significant elevated frequencies. Risks for "all cancers except breast or ovary" are elevated, with some population subgroups differing with regard to how frequently elevated risks were found at individual sites. Additional sites at risk included stomach, pancreas, prostate, and colon. The increased risk ranged from about 20% to 60%, with the greatest increases in risk in stomach and pancreas. The collected data show BRCA-pathway functions are probably required at multiple sites, not just in breast or ovary. Known interactions and relationships among BRCA-related pathways strongly support the idea that their inactivation provides growth or survival advantages for a variety of cancers. The data suggest applying an increased level of clinical alertness to those with defects in BRCA-related pathways. Identifying molecules that confer growth or survival advantages to BRCA-related cancers may provide broadly useful targets for chemotherapy or chemoprevention.     

Analysis of 5382insC (BRCA1) and 6174delT (BRCA2) mutations in 382 healthy Chilean women with a family history of breast cancer

Breast cancer is the most common malignancy among women. Chilean studies reveal that this cancer presents the third highest mortality rate. A family history of breast cancer is one of the major risk factors for the development of this disease. BRCA1 and BRCA2 are the two main hereditary breast cancer susceptibility genes, and mutations in these genes are related to inherited breast cancer. In specific populations only some mutations have been found to be associated with susceptibility. The purpose of this study was to establish the frequency of 5382insC (BRCA1) and 6174delT (BRCA2) germline mutations in 382 healthy Chilean women with at least two relatives affected with breast cancer and in probands and their relatives from 8 high risk families for breast cancer, using mismatch PCR assay. The results obtained showed that 5382insC and 6174delT mutations were not found in either of the groups studied. The ethnic origin of the contemporary Chilean population and the data reported in the literature suggest that these mutations may be absent or have a very low frequency in this population.. This genetic study is part of a breast cancer screening program that also includes annual mammography and clinical breast examination over a five-year period. Strategies to reduce morbidity and mortality associated with breast cancer lie in early detection in women with genetic risk.     

Contribution of BRCA1 germline mutation in patients with sporadic breast cancer

Hereditary artifacts in BRCA1 gene have a significant contributory role in familial cases of breast cancer. However, its germline mutational penetrance in sporadic breast cancer cases with respect to Pakistani population has not yet been very well defined. This study was designed to assess the contributory role of germline mutations of this gene in sporadic cases of breast cancer. 150 cases of unilateral breast cancer patients, with no prior family history of breast cancer and no other disorders or diseases in general with age range 35–75 yrs, were included in this study.Mutational analysis for hot spots on Exon 2, 3 and 13 of BRCA1 was done by using Single Strand Conformational Polymorphism (SSCP). Sequence analysis revealed five variants (missense) and one novel splice site mutation at exon 13. No germline mutation was observed on the remaining exons with respect sporadic breast cancer cases in Pakistani population. A vast majority of breast cancer cases are sporadic; the present study may be helpful for designing a better genetic screening tool for germline BRCA mutations in sporadic breast cancer patients of Pakistani population. Further studies involving a screening of entire coding region of BRCA1 is required to explore the merits of genetic diagnosis and counseling in breast cancer patients.     

Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.