BRCA mutation characteristics in a series of index cases of breast cancer selected independent of family history

Certain genetic predisposition factors, such as BRCA1 and BRCA2 mutations play a pivotal role in familial breast cancer development in both males and females. Due to this, the importance and necessity of genetic screening to identify mutations affecting the population is paramount. Undergoing genetic screenings allows for a more knowledgeable risk assessment for the patients and their care providers. The aim of this study was to evaluate the prevalence of BRCA1/BRCA2 mutated genes in the Turkish population among unselected patients. To identify the molecular markers, we utilized a gene panel analysis consisting of BRCA1 and BRCA2 genes, with a next generation sequencing platform (MiSeq System, Illumina). Sequencing was performed using leukocyte DNA from breast cancer patients. In‐silico analysis for novel mutations was carried out using SIFT, PolyPhen2 and MutationTaster. BRCA1 and BRCA2 pathogenic variants were identified in 18 of 129 (14%) patients among the study population; of those 18 patients, seven (39%) were found in the BRCA1 gene and 11 (61%) in the BRCA2 gene. Ten of the eleven BRCA2 variants (90%) were novel mutations. Four of ten (40%) of the novel mutations were determined to be deleterious and six out of ten (60%) were identified as single nucleotide variations. Clinically significant mutations of the BRCA1/BRCA2 genes are related to an increased susceptibility for breast cancer. There is however, little known about BRCA mutations amongst the general population. Thus, it is important that patients are able to undergo genetic screenings and counseling. This also allows for greater care from health care providers and can only facilitate disease prevention which in turn can lead to a decreased cancer morbidity rate.     

Prostate Cancer Risks for Male BRCA1 and BRCA2 Mutation Carriers: A Prospective Cohort Study

BackgroundBRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies.ObjectiveTo estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location.Design, setting, and participantsThis was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3 yr, respectively).Outcome measurements and statistical analysisStandardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods.Results and limitationsSixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99–6.61) and absolute PCa risk of 27% (95% CI 17–41%) and 60% (95% CI 43–78%) by ages 75 and 85 yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43–3.88); the corresponding SIR at age <65 yr was 3.57 (95% CI 1.68–7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99–2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07–5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14–0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ≥7 (SIR 5.07, 95% CI 3.20–8.02) than Gleason score ≤6 PCa (SIR 3.03, 95% CI 1.24–7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44–10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses.ConclusionsThe results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers.Patient summaryIn this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.     

Analysis of the gene coding for the BRCA2-interacting protein PALB2 in hereditary prostate cancer

BACKGROUND: The genetic basis of susceptibility to prostate cancer (PRCA) remains elusive. Mutations in BRCA2 have been associated with increased prostate cancer risk and account for around 2% of young onset (<56 years) prostate cancer cases. PALB2 is a recently identified breast cancer susceptibility gene whose protein is closely associated with BRCA2 and is essential for BRCA2 anchorage to nuclear structures. This functional relationship made PALB2 a candidate PRCA susceptibility gene. METHODS: We sequenced PALB2 in probands from 95 PRCA families, 77 of which had two or more cases of early onset PRCA (age at diagnosis <55 years), and the remaining 18 had one case of early onset PRCA and five or more total cases of PRCA. RESULTS: Two previously unreported variants, K18R and V925L were identified, neither of which is in a known PALB2 functional domain and both of which are unlikely to be pathogenic. No truncating mutations were identified. CONCLUSIONS: These results indicate that deleterious PALB2 mutations are unlikely to play a significant role in hereditary prostate cancer.     

BRCA2 mutation screening is clinically relevant in breast and early prostate cancer families

It is known that in some families an association exists between breast and prostate cancer. Several reports have suggested that BRCA2 mutations may be associated with an increased risk of these cancers. Herein, we report three cases of early onset of prostate cancer in families with female and male breast cancers. In each case, the familial phenotype is associated with a mutation of the BRCA2 gene. More generally, genetic counseling, including screening for BRCA2 mutations, should become standard practice in kindred with prostate and breast cancers.     

Management of breast cancer risk in BRCA1/2 mutation carriers who are unaffected with cancer

Pathogenic mutations in BRCA1 and BRCA2 genes markedly increase the risk of breast cancer and other cancers such as ovarian/fallopian tube, pancreatic, prostate, and melanoma. Patients with BRCA1 mutations have a slightly higher lifetime risk of breast cancer than BRCA2 mutation carriers, and both BRCA1 and BRCA2 carriers tend to develop breast cancer at an earlier age than the general population. In this review, we will discuss management recommendations to reduce breast cancer risk for BRCA1/2 mutation carriers including special populations of carriers such as pregnant or lactating patients and men. Breast cancer screening, including clinical breast examination, mammogram, and breast MRI, is important for detecting breast cancer at an early and likely curable stage. In addition to screening, counseling on risk‐reducing surgeries is strongly recommended for BRCA1/2 carriers. Risk‐reducing mastectomy decreases the risk of breast cancer development, and risk‐reducing salpingo‐oophorectomy decreases ovarian cancer‐specific as well as overall mortality, but controversy exists regarding its impact on breast cancer‐specific mortality. Given the effectiveness of screening for breast cancer, further management should be carried out on an individual basis taking into account quality of life and psychosocial factors, and recommendations should be readdressed periodically as science progresses and patients’ goals may change.     

Emergence of BRCA Reversion Mutations in Patients with Metastatic Castration-resistant Prostate Cancer After Treatment with Rucaparib

BackgroundPoly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors are approved in the USA for the treatment of patients with BRCA1 or BRCA2 (BRCA) mutated (BRCA+) metastatic castration-resistant prostate cancer (mCRPC). BRCA reversion mutations are a known mechanism of acquired resistance to PARP inhibitors in multiple cancer types, although their impact and prevalence in mCRPC remain unknown.ObjectiveTo examine the prevalence of BRCA reversion mutations in the plasma of patients with BRCA+ mCRPC after progression on rucaparib.Design, setting, and participantsMen with BRCA+ mCRPC enrolled in Trial of Rucaparib in Prostate Indications 2 (TRITON2) were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected at the end of treatment after confirmed progression before May 5, 2020, was queried for BRCA reversion mutations using next-generation sequencing (NGS).Outcome measurements and statistical analysisThe association of clinical efficacy and postprogression genomics was measured in 100 patients with BRCA+ mCRPC treated with rucaparib.Results and limitationsNo baseline BRCA reversion mutations were observed in 100 BRCA+ patients. NGS identified somatic BRCA reversion mutations in 39% (39/100) of patients after progression. Reversion rates were similar for BRCA2 and BRCA1, irrespective of germline or somatic status, but higher in samples with a high tumor DNA fraction. Most patients with reversions (74%, 29/39) had two or more reversion mutations occurring subclonally at lower allele frequencies than the original BRCA mutations. The incidence of BRCA reversion mutations increased with the duration of rucaparib treatment. The frequency of reversion mutations was higher in patients with an objective (58%) or a prostate-specific antigen (69%) response compared with those without either (39% and 29%, respectively).ConclusionsThese findings suggest that BRCA reversion mutations are a significant mechanism of acquired resistance to rucaparib in patients with BRCA+ mCRPC, with evidence of subclonal convergence promoting systemic resistance.Patient summaryMen with BRCA mutated metastatic castration-resistant prostate cancer enrolled in TRITON2 were treated with rucaparib after progressing on one to two lines of androgen receptor–directed and one taxane-based therapy. Cell-free DNA from the plasma of 100 patients, collected after radiographic or prostate-specific antigen progression before May 5, 2020, was analyzed by next-generation sequencing and queried for BRCA reversion mutations.     

From BRCA1 to Polygenic Risk Scores: Mutation-Associated Risks in Breast Cancer-Related Genes

BackgroundThere has been huge progress over the last 30 years in identifying the familial component of breast cancer.SummaryCurrently around 20% is explained by the high-risk genes BRCA1 and BRCA2, a further 2% by other high-penetrance genes, and around 5% by the moderate risk genes ATM and CHEK2. In contrast, the more than 300 low-penetrance single-nucleotide polymorphisms (SNP) now account for around 28% and they are predicted to account for most of the remaining 45% yet to be found. Even for high-risk genes which confer a 40–90% risk of breast cancer, these SNP can substantially affect the level of breast cancer risk. Indeed, the strength of family history and hormonal and reproductive factors is very important in assessing risk even for a BRCA carrier. The risks of contralateral breast cancer are also affected by SNP as well as by the presence of high or moderate risk genes. Genetic testing using gene panels is now commonplace.Key-MessagesThere is a need for a more parsimonious approach to panels only testing those genes with a definite 2-fold increased risk and only testing those genes with challenging management implications, such as CDH1 and TP53, when there is strong clinical indication to do so. Testing of SNP alongside genes is likely to provide a more accurate risk assessment.     

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers.Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression.ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively).ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.     

Screening and Clinical Implications for BRCA1 and BRCA2 Mutation Carriers

In this article, we review the history oftesting for mutations in breast cancer susceptibilitygenes and discuss the current state of testing formutations in BRCA1 and BRCA2 in different clinicalsettings including at-risk individuals and cancerpatients. The risk of breast cancer, other associatedmalignancies and prognosis in carriers of thesemutations are reviewed. A final section includesdiscussion of current recommendations for surveillance andthe need for further research to identify environmentaland genetic factors which modify the risk of developingcancer in mutation carriers.     

The prevalence of germline BRCA1 and BRCA2 mutations in young women with breast cancer undergoing breast-conservation therapy

BACKGROUND: Germline mutations of BRCA1 and BRCA2 increase the risk for breast cancer. Mutation carriers selecting breast-conservation therapy (BCT) for treatment of operable breast cancer experience a higher rate of new primary breast cancers. We sought to determine the frequency of BRCA1/BRCA2 mutations in women who underwent BCT. Genetic testing results were compared with the prior probability of mutations in either gene. METHODS: Eighty-nine patients age 39 or younger entered the study. Genetic testing was performed for BRCA1 and BRCA2 and the BRCAPRO model determined the probability of carrying a mutation. RESULTS: Eight mutations were discovered (prevalence, 9.0%). Twenty (22%) uncharacterized sequence variants were found. The prior probability of carrying a mutation was 14%. Mutation carriers had a higher prior probability (.49) compared with women with uncharacterized variants (.09) or with normal genes (.11). CONCLUSIONS: BRCA1 and BRCA2 mutations are common (9%) among unselected young breast cancer patients undergoing BCT.     

Germline landscape of BRCAs by 7-site collaborations as a BRCA consortium in Turkey

BRCA1/2 mutations play a significant role in cancer pathogenesis and predisposition particularly in breast, ovarian and prostate cancers. Thus, germline analysis of BRCA1 and BRCA2 is essential for clinical management strategies aiming at the identification of recurrent and novel mutations that could be used as a first screening approach. We analyzed germline variants of BRCA1/2 genes for 2168 individuals who had cancer diagnosis or high risk assessment due to BRCAs related cancers, referred to 10 health care centers distributed across 7 regions covering the Turkish landscape. Overall, 68 and 157 distinct mutations were identified in BRCA1 and BRCA2, respectively. Twenty-two novel variants were reported from both genes while BRCA2 showed higher mutational heterogeneity. We herein report the collective data as BRCA Turkish consortium that confirm the molecular heterogeneity in BRCAs among Turkish population, and also as the first study presenting the both geographical, demographical and gene based landscape of all recurrent and novel mutations which some might be a founder effect in comparison to global databases. This wider perspective leads to the most accurate variant interpretations which pave the way for the more precise and efficient management affecting the clinical and molecular aspects.     

Breast cancer risk in relation to alcohol consumption and BRCA gene mutations--a case-only study of gene-environment interaction

The variable penetrance of the BRCA1 and BRCA2 genes suggests that other genetic or environmental factors may interact with these mutations to modify breast cancer risk. The objective of this study was to measure departures from multiplicative effects of alcohol consumption and BRCA gene mutations. A cohort of French-Canadian breast cancer patients was tested for BRCA gene mutations and completed a food frequency questionnaire. The case-only odds ratio (COR) was calculated. A total of 857 women, including 10 BRCA1 and 33 BRCA2 mutation carriers, participated in the study. No significant interaction between alcohol consumption and BRCA1 mutations was detected, although the interaction with wine consumption suggested a sub-multiplicative effect (COR = 0.38, 95% CI: 0.08-1.81). Consumption of alcohol other than wine interacted significantly with BRCA2 mutations (COR = 2.15, 95% CI: 1.03-4.49). Consumption of wine may protect against BRCA1-associated tumors, while women with BRCA2 mutations may be at greater risk of alcohol-induced breast cancer.     

Germline BRCA mutation does not prevent response to taxane-based therapy for the treatment of castration-resistant prostate cancer

Study Type – Prognosis (case series) Level of Evidence 4 What’s known on the subject? and What does the study add? In the preclinical setting BRCA mutations appear to modulate response to chemotherapy, increasing sensitivity to platinums and increasing resistance to taxanes. Clinical data supports a greater platinum sensitivity among BRCA mutation carriers. This study suggests that BRCA mutation carriers may also respond to taxanes.

OBJECTIVE

? To investigate the relationship between BRCA mutation status and response to taxane‐based chemotherapy, since BRCA mutation carriers with prostate cancer appear to have worse survival than non‐carriers and docetaxel improves survival in patients with castration‐resistant prostate cancer.

PATIENTS AND METHODS

? We determined BRCA mutation prevalence in 158 Ashkenazi Jewish (AJ) men with castration‐resistant prostate cancer. Clinical data were collected as part of an institutional prostate cancer research database and through additional medical record review. ? Clinical records and DNA samples were linked through a unique identifier, anonymizing the samples before genetic testing for the AJ BRCA1/2 founder mutations. ? Response to taxane‐based therapy was defined by the prostate‐specific antigen nadir within 12 weeks of therapy.

RESULTS

? In all, 88 men received taxane‐based treatment, seven of whom were BRCA carriers (three BRCA1, four BRCA2; 8%). Initial response to taxane was available for all seven BRCA carriers and for 69 non‐carriers. ? Overall, 71% (54/76) of patients responded to treatment, with no significant difference between carriers (57%) and non‐carriers (72%) (absolute difference 15%; 95% confidence interval –23% to 53%; P= 0.4). ? Among patients with an initial response, the median change in prostate‐specific antigen was similar for BRCA carriers (?63%, interquartile range ?71% to ?57%) and non‐carriers (?60%, interquartile range ?78% to ?35%) (P= 0.6). ? At last follow‐up, all seven BRCA carriers and 49 non‐carriers had died from prostate cancer. One BRCA2 carrier treated with docetaxel plus platinum survived 37 months.

CONCLUSION

? In this small, hypothesis‐generating study approximately half of BRCA carriers had a prostate‐specific antigen response to taxane‐based chemotherapy, suggesting that it is an active therapy in these individuals.     

Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men.

BACKGROUND: Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives. We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer. METHODS: We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population. RESULTS: Our study should have been able to detect a 4-5-fold increase in the risk of prostate cancer due to mutation of BRCA1 or BRCA2. However, only one (1.15%; 95% confidence interval, 0-3.6%) of the patients was heterozygous for the BRCA1 mutant allele, and only two were heterozygous for the BRCA2 mutation (2.4%; 95% confidence interval, 0-6.2%). CONCLUSIONS: The incidence of each of the germline mutations in these prostate cancer patients closely matched their incidence (about 1%) in the general Ashkenazi Jewish population. This suggests that unlike cases of breast and ovarian cancers, mutations in BRCA1 or BRCA2 do not significantly predispose men to prostate cancer.     

No evidence for a role of BRCA1 or BRCA2 mutations in Ashkenazi Jewish families with hereditary prostate cancer.

BACKGROUND: Two genes responsible for hereditary breast cancer (BRCA1 and BRCA2) have been identified, and predisposing mutations identified. Several studies have provided evidence that germline mutations in BRCA1 and BRCA2 confer an increased risk of prostate cancer. Based on these findings, one might expect to find an increased frequency of mutations in these genes in family clusters of prostate cancer. The Ashkenazi Jewish population is unique in that it has an approximate 2% incidence of specific founder BRCA1 and BRCA2 mutations (i.e., 185delAG and 5382insC in BRCA1, and 6174delT in BRCA2). METHODS: To address the question of whether or not mutations in either of these genes were overrepresented in prostate cancer families, we searched for these mutations in germline DNA samples collected from affected and unaffected members of 18 Ashkenazi Jewish families, each having at least 3 first-degree relatives affected with prostate cancer. RESULTS: No mutations were found in the BRCA1 gene in any of the 47 individuals tested. One individual possessed a BRCA2 mutation (6174delT). This individual was unaffected at the time of analysis, but had an affected paternal uncle, and an affected first cousin, neither of whom harbored the mutant gene. CONCLUSIONS: In this sample of Ashkenazi prostate cancer families, the frequency of founder BRCA1 and BRCA2 mutations was not elevated, suggesting that such mutations will account for only a small, perhaps minimal, fraction of familial prostate cancer.     

Male BRCA1 and BRCA2 mutation carriers: a pilot study investigating medical characteristics of patients participating in a prostate cancer prevention clinic

BACKGROUND: Male BRCA1 and BRCA2 mutation carriers are at an increased risk to develop prostate cancer and are subject to screening protocols for high-risk men. The utility of targeted screening, and the clinical and pathological features associated with prostate cancer, have received little attention in this population. METHODS: We report on the clinical screening and pathological characteristics of a group of 19 men with BRCA1 or BRCA2 mutation, as compared to an age-matched group of men with a family history of prostate cancer. RESULTS: Mutation carriers were significantly more likely to have an elevated PSA at first visit (P = 0.03). Prostate cancer was twice as likely to be diagnosed in mutation carriers although this difference was not statistically significant (P = 0.55). CONCLUSIONS: Prostate cancer surveillance of BRCA1 and BRCA2 mutation carriers is warranted. Further research on larger cohorts is needed to evaluate whether unique pathological prostate cancer characteristics exist in these men.     

Nonsurgical Prevention Strategies in BRCA1 and BRCA2 Mutation Carriers

BackgroundFemale carriers of a BRCA1 or 2 germline mutation face a high lifetime risk to develop breast and ovarian cancer. Risk-reducing surgery, such as prophylactic bilateral mastectomy and prophylactic bilateral salpingo-oophorectomy, are proven strategies to prevent breast and ovarian cancer. These procedures are, however, associated with considerable side effects, and the uptake of these highly effective interventions is therefore low in many countries. This highlights the need for alternative and noninvasive strategies for risk reduction in mutation carriers.SummaryWhile endocrine treatments with tamoxifen and aromatase inhibitors (AI) have been shown to be effective in secondary prevention, their benefit in primary prevention has never been prospectively evaluated. Moreover, their side effect profile makes them inappropriate candidates for chemoprevention in healthy premenopausal women. Recently, denosumab, a well-tolerated osteoprotective drug, has been shown to have an antitumoral effect on RANK+, BRCA1-deficient luminal progenitor cells in vitro, and has been demonstrated to abrogate tumors in BRCA1-deficient mouse models.Key MessageThe prospectively randomized, double-blind BRCA-P trial is currently investigating the preventative effect of denosumab in healthy BRCA1 germline mutation carriers.     

Disparities in BRCA testing: when insurance coverage is not a barrier

Background

Strategies to reduce the risk of developing breast and ovarian cancer in carriers of deleterious BRCA 1 and 2 mutations are readily available. However, many people who are at high risk of having these genetic mutations are reluctant to obtain the test. We sought to identify factors associated with choice of testing.

Methods

We performed a retrospective cohort review of high-risk patients referred to a multidisciplinary breast health center for BRCA testing between January 2001 and March 2008. Demographic variables were compared by using logistic regression between those who completed genetic testing and those who did not.

Results

A total of 213 patients were referred for BRCA testing. The mean age was 49.2 years (range, 16-84 y). Five patients were male. The majority of individuals (63.4%) were white, 15% were Hispanic, 6.6% were black, and 4.7% were Asian. Insurance coverage for testing was available in 91.1% of patients, of whom 49.2% had private insurance, 26.7% had managed care insurance, and 24.1% had government-sponsored insurance. A total of 111 patients (52.1%) underwent testing. On multivariate analysis, patients were significantly more likely to complete testing if they had a personal history of breast cancer (73.0% of tested patients) (P = .005) and had at least some college education (61.3%) (P = .03). There were no statistically significant differences in tested versus untested groups by age, race, language, family history, parity, marital status, religion, socioeconomic status, or insurance status. Of patients whose insurance plans offered coverage for genetic testing, 51.4% underwent testing and 48.6% did not (P = not significant [NS]). Of those who had no insurance coverage for testing, 41.2% underwent testing and 58.9% did not (P = NS).

Conclusions

Our data show that half of those patients at risk for carrying a BRCA mutation do not undergo testing. Insurance coverage for genetic testing does not influence the decision to test. Developing counseling instruments that explain the benefits of testing to unaffected high-risk individuals or targeted to those with a high school level education may be a strategy to improve testing rates.     

Heterogenic Loss of the Wild-Type BRCA Allele in Human Breast Tumorigenesis

Background For individuals genetically predisposed to breast and ovarian cancer through inheritance of a mutant BRCA allele, somatic loss of heterozygosity affecting the wild-type allele is considered obligatory for cancer initiation and/or progression. However, several lines of evidence suggest that phenotypic effects may result from BRCA haploinsufficiency. Methods Archival fixed and embedded tissue specimens from women with germ line deleterious mutations in BRCA1 or BRCA2 were identified. After pathologic review, focal areas of normal breast epithelium, atypical ductal hyperplasia, ductal carcinoma-in-situ, and invasive ductal carcinoma were identified from 14 BRCA1-linked and 9 BRCA2-linked breast cancers. Ten BRCA-linked prophylactic mastectomy specimens and 12 BRCA-linked invasive ovarian carcinomas were also studied. Laser catapult microdissection was used to isolate cells from the various pathologic lesions and corresponding normal tissues. After DNA isolation, real-time polymerase chain reaction assays were used to quantitate the proportion of wild-type to mutant BRCA alleles in each tissue sample. Results Quantitative allelotyping of microdissected cells revealed a high level of heterogeneity in loss of heterozygosity within and between preinvasive lesions and invasive cancers from BRCA1 and BRCA2 heterozygotes with breast cancer. In contrast, all BRCA-associated ovarian cancers displayed complete loss of the wild-type BRCA allele. Conclusions These data suggest that loss of the wild-type BRCA allele is not required for BRCA-linked breast tumorigenesis, which would have important implications for the genetic mechanism of BRCA tumor suppression and for the clinical management of this patient population.     

Genotype–Phenotype Correlations by Ethnicity and Mutation Location in BRCA Mutation Carriers

The genotype–phenotype correlations of the specific BRCA1 and BRCA2 mutations in multi‐ethnic populations in USA have not yet been fully investigated. This study was designed to evaluate the effects of ethnicity at specific mutation locations and breast/ovarian cancer phenotypes. Our cohort included 445 women with different ethnic backgrounds who underwent BRCA genetic testing between 1997 and 2010. Known clinical and pathologic characteristics were compared with Chi‐Square Analysis or Fisher's Exact test as appropriate. The three most common mutation locations in BRCA1 (exons 2, 11, and 20) and BRCA2 (exons 10, 11, and 25) genes were chosen. Prevalence of BRCA1 exon 2 mutations were significantly higher in Ashkenazi Jewish (AJ) women compared to Caucasians (41% versus 15%; p = 0.001). Similarly, AJ women with breast cancer were more likely to have BRCA1 exon 2 mutation (47% positivity in AJ women versus 0–12.5% positivity in other ethnicities; p = 0.004). Women carrying the exon 20 BRCA1 mutation had the highest probability of having combined breast and ovarian cancers compared to women carrying other exon mutations (p = 0.05). The median age at initial cancer diagnosis, phenotypic features of breast cancer tumors, and overall survival did not vary significantly by ethnicity or mutation location. Our data suggest that ethnicity does not affect age of onset, overall survival or confer different risks of breast and ovarian cancer development in BRCA carriers. These results also suggest that women carrying the exon 20 BRCA1 mutation may warrant mutation‐specific counseling and be more aggressively managed for risk reduction.