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PubMed2006

Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriers.

Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1-3, 4-5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72-1.12), 0.75 (95% CI 0.47-1.19) and 0.31 (95% CI 0.13-0.71; p-trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk.

Adult↗
PubMed2006

BRCA1 and BRCA2 mutations in a South American population.

A sample of 64 high-risk breast and/or ovarian cancer families from Chile were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIN no. 113705) and BRCA2 (MIN no. 600185) genes using conformation-sensitive gel electrophoresis, and the mutations found were confirmed with direct sequencing. Seven families (10.9%) were found to carry BRCA1 mutations and three families (4.7%) had BRCA2 mutations. Six different pathogenic mutations were detected in BRCA1, four that had been reported previously (c.187_188delAG; c.300T-->G, c.3450_3453delCAAG and IVS17-1G-->A) and two novel mutations (c.2605_2606delTT and c.4185_4188delCAAG). In BRCA2, we found three different pathogenic mutations, two previously described (c.6174delT and c.6503_6504delTT) and one novel mutation (c.5667delT). We also identified nine variants of unknown significance (five in BRCA1 and four in BRCA2). These findings indicate that the Chilean population has a heterogeneous spectrum of prevalent BRCA mutations. Given the results obtained in our study, the screening of the entire BRCA1 and BRCA2 coding regions is necessary for the molecular genetic testing of Chilean high-risk breast/ovarian cancer patients. To our knowledge, this is the first genetic study of BRCA gene mutations conducted in Chile. The Chilean population has a well-known admixed Amerindian-Caucasian ratio and, therefore, our findings are not only important per se, but they constitute the basis for improved and more specific genetic counselling, as well as to support for preventive campaigns geared toward the Chilean population.

Adult↗
PubMed2001

Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis.

OBJECTIVE: BRCA-1 and BRCA-2 germline mutations increase the risk of ovarian and breast cancer. Primary cancer of the fallopian tube is rare; however, recent evidence suggests that patients harboring a germline mutation conferring an increased risk of ovarian cancer may be at risk for fallopian tube cancer as well. We discuss the finding of occult fallopian tube cancer diagnosed at surgical prophylaxis in women harboring BRCA-1 mutations. METHODS/RESULTS: Two patients undergoing surgical prophylaxis to address an increase in ovarian cancer risk were discovered to harbor occult primary fallopian tube carcinoma on final pathology review. Mutational analysis confirmed the presence of a deleterious mutation in BRCA-1 in both patients. CONCLUSION: Currently, consensus opinions regarding ovarian cancer surgical prophylaxis in gene mutation carriers do not include hysterectomy as part of the preventative procedure. This report as well as a growing number of cases of fallopian tube cancer reported in known BRCA-1 and BRCA-2 mutation carriers has important implications for recommendations regarding surgical prophylaxis in these women.

BRCA2 Protein↗
PubMed2005

Coinheritance of BRCA1 and BRCA2 mutations with Fanconi anemia and Bloom syndrome mutations in Ashkenazi Jewish population: possible role in risk modification for cancer development.

Fanconi anemia (FA) and Bloom syndrome (BS) are rare autosomal recessive genetic disorders manifesting in childhood, with a predisposition to cancer development in adolescence and adulthood. Both syndromes are relatively prevalent among the Ashkenazi Jewish population, and, in both syndromes, mutations specific to this population have been identified. Similarly, unique Ashkenazi mutations were found in the genes BRCA1 and BRCA2. These two genes, when mutated, play important roles in familial breast and ovarian carcinogenesis. The genes involved in the pathogenesis of the FA and BS belong to the general class of instability genes. Heterozygosity for the FA gene has no known promalignant potential, while the BS mutation carrier state was associated with an increased frequency of colorectal cancer. The especially frequent carrier state among the Ashkenazi Jewish population coupled with the high prevalence of BRCA1 and BRCA2 in the same population has led us to search for coinheritance affecting the potential for cancer development. One hundred Ashkenazi women with known BRCA1 and BRCA2 mutations were screened for the FA mutation IVS4+4 A-->T and the BS mutation blm(Ash). Our results indicate that there is an increased prevalence of both FA and BS mutation carriers among the population studied compared with the general Ashkenazi population (prevalence of FA mutation 4/100 women [4%] as compared to 35/3104 previously published controls [1.1%], P=0.031, and for BS mutation 3/100 [3.2%] as compared to 36/4001 [0.9%], P=0.058). There was no statistically significant effect of the coinheritance on cancer prevalence, type of cancer, or age of cancer onset. Coinheritance of FA and/or BS mutations seems to be more prevalent among BRCA mutation carriers, but a larger study encompassing more women may help in clarifying this issue.

Bloom Syndrome↗
PubMed2003

Effect of genetic cancer risk assessment on surgical decisions at breast cancer diagnosis.

HYPOTHESIS: Breast cancer gene (BRCA) mutation status affects patients' surgical decisions when genetic cancer risk assessment is offered at the time of breast cancer diagnosis, prior to definitive treatment. PATIENTS AND INTERVENTIONS: Outcomes following genetic cancer risk assessment were studied for women newly diagnosed as having breast cancer who were prospectively enrolled in an institutional review board-approved hereditary cancer registry during a 1-year sampling frame. BRCA gene analysis was offered to subjects with a calculated mutation probability of 10% or higher. Review of medical records and telephone survey were used to document surgical treatment decisions following genetic cancer risk assessment. RESULTS: Thirty-seven of 233 women in the registry were enrolled at the time of a breast cancer diagnosis. The interval from diagnosis to genetic cancer risk assessment ranged from 3 to 60 days. The mean calculated probability of a BRCA gene mutation was 21% across the cohort. Two women were not tested because of low prior probabilities of mutation detection, and 3 declined owing to intercurrent psychological stressors. Of the remaining 32 patients, no BRCA gene mutation was detected in 22 (69%), 3 (9%) were found to carry a variant of uncertain significance, and 7 (22%) had a deleterious mutation. All 7 subjects with a deleterious mutation opted for bilateral mastectomy, whereas 20 of 22 patients with negative test results chose stage-appropriate treatment (P<.001). CONCLUSIONS: Genetic cancer risk assessment at the time of breast cancer diagnosis significantly affected women's treatment decisions. Although need and feasibility are demonstrated, the logistics of genetic cancer risk assessment during breast cancer diagnosis prove challenging.

Adult↗
PubMed2017

Predictors of BRCA1/2 genetic testing among Black women with breast cancer: a population-based study.

Evidence shows that Black women diagnosed with breast cancer are substantially less likely to undergo BRCA testing and other multipanel genetic testing compared to White women, despite having a higher incidence of early-age onset breast cancer and triple-negative breast cancer (TNBC). Our study identifies predictors of BRCA testing among Black women treated for breast cancer and examines differences between BRCA testers and nontesters. We conducted an analysis of 945 Black women ages 18-64 diagnosed with localized or regional-stage invasive breast cancer in Pennsylvania and Florida between 2007 and 2009. Logistic regression was used to identify predictors of BRCA 1/2 testing. Few (27%) (n&#xa0;=&#xa0;252) of the participants reported having BRCA testing. In the multivariate analysis, we found that perceived benefits of BRCA testing (predisposing factor) ([OR], 1.16; 95% CI: 1.11-1.21; P&#xa0;<&#xa0;0.001), income (enabling factor) ([OR], 2.10; 95% CI: 1.16-3.80; p&#xa0;=&#xa0;0.014), and BRCA mutation risk category (need factor) ([OR], 3.78; 95% CI: 2.31-6.19; P&#xa0;<&#xa0;0.001) predicted BRCA testing. These results suggest that interventions to reduce disparities in BRCA testing should focus on identifying patients with high risk of mutation, increasing patient understanding of the benefits of BRCA testing, and removing financial and other administrative barriers to genetic testing.

Adolescent↗
PubMed2026

Prognostic and predictive value of HRD in early triple negative breast cancer (TNBC).

This review explores the emerging role of homologous recombination deficiency (HRD) as both a prognostic and predictive biomarker in early-stage triple-negative breast cancer (TNBC). HRD arises from the defective repair of DNA double-strand breaks through homologous recombination, resulting in genomic instability and increased sensitivity to DNA-damaging agents such as platinum compounds. The review outlines the biological basis of HRD, including genomic signatures such as loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, and highlights its prevalence in TNBC compared with other breast cancer subtypes. Clinical trials have shown that HRD-positive patients often achieve higher pathological complete response rates and improved disease-free survival when treated with chemotherapy. However, conflicting evidence across trials underscores the need for more reliable and standardized methods for HRD assessment. The review also explores the therapeutic potential of poly(ADP-ribose) polymerase inhibitors in TNBC, particularly in BRCA-mutated or HRD-positive tumors. Agents such as olaparib, talazoparib, and niraparib have demonstrated promising efficacy in both neoadjuvant and adjuvant settings with some trials suggesting that selected patients may avoid chemotherapy. Furthermore, HRD-positive tumors are characterized by increased genomic instability and a higher neoantigen burden, promoting immune cell infiltration, particularly of tumor-infiltrating lymphocytes, which may enhance responsiveness to immune checkpoint inhibitors. Overall, current evidence supports the role of HRD as a promising biomarker in TNBC. However, further research is required to refine its clinical utility and to integrate HRD testing into personalized treatment strategies, especially in combination with emerging therapies such as immunotherapy.

Humans↗
PubMed2002

Recurrent BRCA1 and BRCA2 germline mutations in ovarian cancer: a founder mutation of BRCA1 identified in the Chinese population.

Previous mutational analysis for BRCA gene mutations in sporadic ovarian cancer occurring in Chinese patients in Hong Kong identified six germline BRCA1 mutations and one germline BRCA2 mutation, six of which were novel (Khoo et al., 2000). Knowledge of BRCA gene mutations in the Chinese population is relatively scant. In this study, we focussed on whether any of these mutations could be recurrent in our Chinese population, making use of archival paraffin embedded tissue. A consecutive series of 214 ovarian cancer cases, half of Southern Chinese origin from Hong Kong whilst the other half of Northern Chinese origin from Beijing were used for the study. We identified one further novel mutation, 1081delG, in BRCA1. This was found to occur in two unrelated individuals with shared haplotype as revealed by allelotype analysis, thus demonstrating founder effect. Two other recurrent mutations were also identified, the 2371-2372delTG mutation in BRCA1 and the 3337C>T mutation in BRCA2 recurring in two and three unrelated individuals respectively, giving an overall prevalence 4.7% of recurrent BRCA mutations in ovarian cancer in the Southern Chinese population. Most importantly, all our recurrent mutation carriers were identified from Southern Chinese patients from Hong Kong whilst such mutations were absent in samples from the Northern Chinese. Our findings indicate possible heterogeneity in the BRCA genotype between Northern and Southern Chinese. The identification of a founder mutation and two recurrent mutations moreover, has important implications towards screening strategies for breast and ovarian cancer among Chinese of southern ancestral origin who are now dispersed throughout the world.

Adult↗
PubMed2003

Hereditary ovarian cancer in Poland.

There is increasing evidence that hereditary factors play a greater role in ovarian cancer than in any of the other common cancers of adulthood. This is attributable, to a large extent, to a high frequency of mutations in the BRCA1 or BRCA2 genes. In Poland, 3 common founder mutations in BRCA1 account for the majority of families with identified BRCA mutations. Our study was conducted in order to estimate the prevalence of any of 3 founder BRCA1 mutations (5382insC, C61G and 4153delA) in 364 unselected women with ovarian cancer, and among 177 women with ovarian cancer and a family history of breast or ovarian cancer. A mutation was identified in 49 out of 364 unselected women with ovarian cancer (13.5%) and in 58 of 177 women with familial ovarian cancer (32.8%). The majority of women with ovarian cancer and a BRCA1 mutation have no family history of breast or ovarian cancer. The high frequency of BRCA1 mutations in Polish women with ovarian cancer supports the recommendation that all Polish women with ovarian cancer should be offered testing for genetic susceptibility, and that counseling services be made available to them and to their relatives. It is important that mutation surveys be conducted in other countries prior to the introduction of national genetic screening programs.

BRCA2 Protein↗
PubMed2003

[Detection and occurrence of BRCA 1 gene mutation in patients with carcinoma of the breast and ovary].

OBJECTIVE: The article presents a review of basic information on incidence and detection of BRCA 1 and BRCA 2 genes mutations. Results of investigation in a group of women with ovarian and breast cancer are presented. DESIGN: Retrospective clinical-laboratory study and review. SETTING: Department of Gynaecology and Obstetrics, 1st Medical Faculty of Charles University, Prague, Apolinárská 18, Czech Republic. MATERIAL AND METHODS: Investigated group consisted of 16 persons--12 patients with ovarian or breast cancer and 4 healthy relatives of a woman--breast cancer patient and a carrier of BRCA 1 gene mutation. Protein truncation test (PTT) was performed in order to detect BRCA 1 gene mutation. This test detects mutations leading to premature termination of protein synthesis. Truncated proteins are easily discriminated from full size. RESULTS: Three BRCA 1 gene alterations were identified in the investigated group of women suffering from ovarian or breast cancer. One asymptomatic person--carrier of BRCA 1 gene mutation--was identified in this study. She was daughter of a woman, a carrier of BRCA 1 gene mutation, with early onset of breast cancer and positive family history. CONCLUSIONS: BRCA 1 and BRCA 2 gene mutations are of particular importance in the increasing risk of ovarian cancer and early onset of breast cancer as well as some other malignancies. Genetic testing and counselling including investigation of some other genetic and environmental factors, related to cancer risk, may be of clinical significance in patients with increased risk of certain malignancies.

Adult↗
PubMed2002

Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain.

BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families.

Adult↗
PubMed2002

BRCA1 and BRCA2 heterozygosity and repair of X-ray-induced DNA damage.

PURPOSE: Up to 90% of hereditary breast cancer cases are linked to germ-line mutations in one of the two copies of the BRCA1 or BRCA2 genes. Brca1 and Brca2 proteins are both involved in the cellular defence against DNA damage, although the precise function of the proteins is still not known. Some studies on a small number of samples as well as the present pilot study also suggested that BRCA1 heterozygosity may lead to impaired repair of ionizing-radiation-induced DNA double-strand breaks. The purpose of the study was to test in a larger family-matched study whether carriers of BRCA1 or BRCA2 mutations have an increased sensitivity to ionizing radiation. MATERIALS AND METHODS: In a blind study, the effect of different germ-line mutations in one allele of the BRCA1 or BRCA2 gene on the ability to repair X-ray-induced DNA breaks was investigated. Fibroblasts and lymphocytes were taken from heterozygotic individuals (BRCA1+ /- and BRCA2+ /-) with different mutations and from relatives proven to be non-carriers of the BRCA mutations. Rejoining of DNA breaks was analysed by pulsed-field gel electrophoresis (for fibroblasts) or the comet assay (for lymphocytes). RESULTS: Significant interindividual differences were found in the capacities of the fibroblasts and lymphocytes to rejoin DNA breaks induced by X-radiation. However, these differences were not related to heterozygosity in BRCA1 or BRCA2. CONCLUSIONS: Cells from carriers of mutations in one allele of the BRCA1 or BRCA2 genes have no gross defects in their ability to rejoin radiation-induced DNA breaks. Hence, these carriers may not be at risk of developing excess normal tissue reactions after radiotherapy consistent with data from recent clinical studies.

Breast Neoplasms↗
PubMed2006

Breast cancer susceptibility testing: past, present and future.

Breast cancer is a genetic disease. The cancer phenotype is defined by a complex interplay between oncogenes, tumor-suppressor genes and epigenetic factors. Only 5-10% of all breast cancers can be attributed to one of several breast cancer familial syndromes, the most common of which is the hereditary breast and ovarian syndrome caused by deleterious mutations of the BRCA1 or BRCA2 tumor-suppressor genes. The functions of the BRCA proteins are not fully understood, although it is clear that they play a role in the control of transcription, regulation of the cell cycle and management of DNA damage. The inheritance of a deleterious BRCA mutation is accompanied by a 50-80% risk of developing breast cancer, 60% risk of developing a contralateral breast cancer and 15-25% risk of developing ovarian cancer. The clinical management of BRCA heterozygotes involves several strategies of primary, secondary and tertiary prevention. These include risk-reducing surgery, chemoprevention, lifestyle changes and increased surveillance. As we move beyond the 10-year anniversary of the discovery of the BRCA genes, we are inevitably led to thoughtful reflection on the impact of these genes in regards to the greater problem of sporadic breast cancer.

BRCA1 Protein↗
PubMed1997

High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history.

To better understand the role of germline BRCA mutations in ovarian cancer in Ashkenazi Jews, we tested 29 consecutive patients admitted to our service for the three mutations common in this ethnic group. These mutations are 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2. Six patients had both breast and ovarian cancer, and 23 had ovarian cancer only. In the first group, all women had germline mutations, 2 with each mutation. Of 23 ovarian cancer patients, 11 were carriers (48%): 6 of 185delAG, 2 of 5382insC, and 3 of 6174delT. Regarding family history, of 13 women with no family history, 3 (23%) were carriers. Of 10 women with any family history of breast or ovarian cancer, 8 (80%) were carriers. We discuss possible explanations for this surprisingly high carrier rate, including a high proportion of familial disease coupled with lack of adequate family history, lower penetrance than previously expected, or increasing penetrance in recent generations due to nongenetic factors. Our data suggest that genetic testing is merited in all Ashkenazi women with ovarian cancer, regardless of family history.

Adult↗
PubMed2001

A founder mutation of the BRCA1 gene in Western Sweden associated with a high incidence of breast and ovarian cancer.

The aim of this study was to describe and characterise a founder mutation of the BRCA1 gene in western Sweden. Of 62 families screened for BRCA mutations, 24 had BRCA1 mutations and two had BRCA2 mutations. Tumours that occurred in family members were histologically reviewed and mutational status was analysed using archival paraffin-embedded tissues. The same BRCA1 mutation, 3171ins5, was found in 16 families who were clustered along the western coast of Sweden. Mutation analysis revealed a maternal linkage in 13 families and a paternal linkage in 3. There was complete agreement between mutation analysis results obtained from blood and archival tissues. The penetrance of breast or ovarian cancer by age 70 years was estimated to be between 59 and 93%. There were no differences in survivals between breast or ovarian cancer patients with the mutation and age-matched controls. Thus, a predominant BRCA1 gene founder mutation associated with a high risk of breast and ovarian cancer has been identified and found to occur in a restricted geographical area, thereby allowing timely and cost-effective mutation screening using blood samples or archival histological material.

Adult↗
PubMed2002

BRCA2 founder mutation in Slovenian breast cancer families.

Linkage analysis has identified BRCA1 and BRCA2 germline mutations as the major cause for cancer predisposition in breast and/or ovarian cancer families. In previous screening efforts on Belgian families we had a BRCA1/2 gene mutation detection rate of 25%.(1) Here we report the results of a BRCA mutation screening in seven high-risk breast/ovarian cancer families from Slovenia. We found a single but highly recurrent BRCA2 splice site mutation (IVS16-2A>G) in three breast cancer-only families. This cancer-linked mutation could not be identified in three families with ovarian cancer, suggesting that the mutation predisposes at least predominantly to breast cancer. All mutation carriers shared a common disease associated haplotype indicating a founder effect. This mutation most probably occurred in a single ancestor and seems essentially confined to the Slovene population.

Aged↗
PubMed2005

Mammography, breast ultrasound, and magnetic resonance imaging for surveillance of women at high familial risk for breast cancer.

PURPOSE: To compare the effectiveness of mammography, breast ultrasound, and magnetic resonance imaging (MRI) for surveillance of women at increased familial risk for breast cancer (lifetime risk of 20% or more). PATIENTS AND METHODS: We conducted a surveillance cohort study of 529 asymptomatic women who, based on their family history and/or mutational analysis, were suspected or proven to carry a breast cancer susceptibility gene (BRCA). A total of 1,542 annual surveillance rounds were completed with a mean follow-up of 5.3 years. Diagnostic accuracies of the three imaging modalities used alone or in different combinations were compared. RESULTS: Forty-three breast cancers were identified in the total cohort (34 invasive, nine ductal carcinoma-in-situ). Overall sensitivity of diagnostic imaging was 93% (40 of 43 breast cancers); overall node-positive rate was 16%, and one interval cancer occurred (one of 43 cancers, or 2%). In the analysis by modality, sensitivity was low for mammography (33%) and ultrasound (40%) or the combination of both (49%). MRI offered a significantly higher sensitivity (91%). The sensitivity of mammography in the higher risk groups was 25%, compared with 100% for MRI. Specificity of MRI (97.2%) was equivalent to that of mammography (96.8%). CONCLUSION: Mammography alone, and also mammography combined with breast ultrasound, seems insufficient for early diagnosis of breast cancer in women who are at increased familial risk with or without documented BRCA mutation. If MRI is used for surveillance, diagnosis of intraductal and invasive familial or hereditary cancer is achieved with a significantly higher sensitivity and at a more favorable stage.

Adult↗