Revisiting breast cancer patients who previously tested negative for BRCA mutations using a 12-gene panel (original) (raw)
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Journal of Medical Genetics, 2003
S tudies using multicase breast cancer families led to the mapping and eventual cloning of the two susceptibility genes for breast or ovarian cancer or both, BRCA1 (MIM 113705) and BRCA2 (MIM 600185). 1 2 In early studies attempting to characterise the clinical impact of mutations in these genes, investigators continued to analyse large multicase families. More recently, groups have focused on patients with breast cancer unselected for strong family cancer history to make their findings more generally applicable. 4-7 With the broadening of study participant ascertainment, there has been a drop in the estimates of lifetime breast cancer penetrance attributable to BRCA1 and BRCA2 from greater than 80% initially to values as low as 40%. 3 8 Attempts to characterise the range and frequency of BRCA1 and BRCA2 mutations in breast cancer families have also been complicated by the different molecular techniques used to identify them. Owing to the large size, multiexonic nature, and lack of any universally identified mutational hot spots in the genes, few studies have conducted a thorough investigation of the presence of mutations in both genes. Also, there have been some missense mutations of unknown clinical significance identified (Breast Cancer Information Core). There is also some evidence that the position of the mutation in the BRCA2 gene may influence the clinical manifestation of cancer risk, which would further complicate the interpretation of findings from studies that use targeted molecular analysis. Molecular studies of cases ascertained through a population based design more accurately reflect the range and frequency of BRCA1 and BRCA2 mutations in a specific population. The Ontario Familial Breast Cancer Registry (OFBCR) 10 11 is one of six sites participating in the international Cooperative Family Registry for Breast Cancer Studies (CFRBCS). The OFBCR is a population based breast cancer registry, the purpose of which is to collect pedigree information, epidemiological data, and biological specimens from patients with incident breast cancer and their families for studies considering familial breast cancer. The OFBCR includes families with a wide range of family history of cancer and provides a large and unique resource for studies of familial cancer.
Familial cancer, 2017
Increasing evidence supports the benefit of identifying BRCA1 and BRCA2 germline mutations in early breast cancer. Selection of patients for genetic testing is based on defined criteria taking individual and family history related factors into account. It is important to make a distinction between efficacy and effectiveness of BRCA testing criteria. Efficacy can be defined as the performance under ideal circumstances, whereas effectiveness refers to its real life performance. To allow for an unbiased and detailed evaluation of efficacy and effectiveness of the Swedish BRCA testing criteria, we retrospectively analyzed a prospectively collected cohort of 273 breast cancer patients from the well-characterized, population-based, single-site All Breast Cancer in Malmö (ABiM) study. The patients were diagnosed with breast cancer during the years 2007 through 2009. Out of 20 mutation carriers identified, 13 fulfilled Swedish criteria at time of diagnosis. Thus, the efficacy of these crite...
Molecular profile and clinical variables in BRCA1-positive breast cancers. A population-based study
Tumori
To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutation...
Breast cancer susceptibility genes: Options for those carrying BRCA1 mutations
Archive of oncology, 2002
The discovery of the association between breast and ovarian cancer and the BRCA genes and the development of methods for genetic testing made it possible to screen women for genetic predisposition to develop hereditary breast cancer (HBC). Parallelly, prevention strategies, including clinical, surgical and medical interventions become available in order to reduce cancer risk. In a meantime, we became aware of limitations of genetic testing from the aspect of BRCA gene penetrance, negative result interpretation etc. All of these, together with data that invasive prevention strategies such as prophylactic surgery demonstrate better results in risk reduction than regimens including self and clinical-examination, face BRCA mutation carriers with difficult choice for risk reduction options. Therefore, the patients at high risk of HBC can best make informed decisions when guided by a multidisciplinary genetic counseling team.
Breast Cancer Research, 2011
Introduction: Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1. Methods: We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via populationbased sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligationdependent Probe Amplification.
BMC Cancer
Background: Identification of BRCA mutations in breast cancer (BC) patients influences treatment and survival and may be of importance for their relatives. Testing is often restricted to women fulfilling high-risk criteria. However, there is limited knowledge of the sensitivity of such a strategy, and of the clinical aspects of BC caused by BRCA mutations in less selected BC cohorts. The aim of this report was to address these issues by evaluating the results of BRCA testing of BC patients in SouthEastern Norway. Methods: 1371 newly diagnosed BC patients were tested with sequencing and Multi Ligation Probe Amplification (MLPA). Prevalence of mutations was calculated, and BC characteristics among carriers and non-carriers compared. Sensitivity and specificity of common guidelines for BRCA testing to identify carriers was analyzed. Number of identified female mutation positive relatives was evaluated. Results: A pathogenic BRCA mutation was identified in 3.1%. Carriers differed from non-carriers in terms of age at diagnosis, family history, grade, ER/PR-status, triple negativity (TNBC) and Ki67, but not in HER2 and TNM status. One mutation positive female relative was identified per mutation positive BC patient. Using age of onset below 40 or TNBC as criteria for testing identified 32-34% of carriers. Common guidelines for testing identified 45-90%, and testing all below 60 years identified 90%. Thirty-seven percent of carriers had a family history of cancer that would have qualified for predictive BRCA testing. A Variant of Uncertain Significance (VUS) was identified in 4.9%. Conclusions: Mutation positive BC patients differed as a group from mutation negative. However, the commonly used guidelines for testing were insufficient to detect all mutation carriers in the BC cohort. Thirty-seven percent had a family history of cancer that would have qualified for predictive testing before they were diagnosed with BC. Based on our combined observations, we suggest it is time to discuss whether all BC patients should be offered BRCA testing, both to optimize treatment and improve survival for these women, but also to enable identification of healthy mutation carriers within their families. Health services need to be aware of referral possibility for healthy women with cancer in their family.
European Journal of Breast Health, 2021
Objective: This study aimed to determine the differences in clinicopathological features of Turkish patients with high-risk breast cancer based on the mutation status of two breast cancer susceptibility genes (BRCA1/2). Materials and Methods: This study enrolled patients with invasive breast cancer who have been evaluated for BRCA1/2 mutations due to the presence of high-risk factors admitted to two tertiary referral centers in Turkey. Clinical and histopathological features were analyzed in BRCA1 mutation carriers, BRCA2 mutation carriers, and non-carriers. Results: A total of 302 patients with a mean age of 44.2±9.9 (22-82) years were included. BRCA1/2 mutation was found in 75 (24%) patients, of whom 41 (13.6%) were BRCA1 mutation carriers and 37 (12.3%) were BRCA2 mutation carriers. Moreover, 104 (34.4%) and 4 (1.3%) patients had family history of breast and ovarian carcinoma, respectively. The rates of triple negativity (56.1%), histologic grade 3 (65.9%), and lymphovascular invasion (78%) were significantly higher in BRCA1 mutation carriers than in non-carriers and BRCA2 mutation carriers. Furthermore, 87% of triple-negative BRCA1 mutation carriers had histologic grade 3 tumors compared with 38.9% in non-triple-negative BRCA1 mutation carriers, and the difference was significant. Conclusion: Findings of this study showed that BRCA1-related breast cancers represent a distinct group with unique pathological features, which are usually associated with a poor prognosis.
Diyala Journal of Medicine, 2018
Background:Both BRCA1 and BRCA2 are tumor suppressor gene and are inherited as an autosomal dominant. The cumulative lifetime risk of developing invasive breast cancer for those with BRCA1 or BRCA2 mutations ranges from 53% to 89%. Familial breast cancer represent less than 10% of all cancers of the breast, and cancers related to BRCA1 and BRCA2 familial disease account only for three-fourths to two-thirds of these cases. In women younger than 35 year old with CA breast, 10% to 15% have a BRCA1 mutation. Females with mutations involving BRCA 1/2 who are already affected by breast cancer have an increased risk of breast cancer involving the other breast of 52% and 66%. Objective: To identify the frequency and the type of mutation in exon 11 in the genes BRCA1 and BRCA2 in breast cancer women with positive family history. Patients and Methods: This is a prospective study of fourteen females having breast cancer with positive family history of breast cancer. The study done in Baquba Teaching Hospital over a period of eight months (October 2016-July 2017). The age range of the patients was 40-70 years. Genomic DNA was extracted from lymphocytes yielded from the peripheral blood using the salting out procedure. Primers were used to amplify exon 11 region of the genes BRCA1 and BRCA2 by using polymerase chain reaction (PCR) cycling. Results: A total of eight variants in the BRCA1 gene and four variants in the BRCA2 gene were seen. Only one deleterious germline mutation in BRCA1 was detected in 1/14 (7.14%). The patient with deleterious mutation was 31 year-old and was having strong family history of the disease (two relatives, first and second degree). The sequence variant of the mutation was c.795_789delTT with an effect as p.Val256-Ser261ValLys. The remaining 11 identified variants belonging to BRCA1 and BRCA2) are classified as polymorphisms or unknown variants. Conclusion:BRCA1 and BRCA2 mutations in females with breast cancer with positive family history of the disease is never low and cannot be neglected. Therefore screening for these mutations is important for strict follow up of those with positive results.