Germ-line BRCA1 mutations in women with sporadic breast cancer: clinical correlations.

PURPOSE Sporadic nonhereditary breast cancer is recognized as the most common form of this malignancy. Presence of germ-line mutations in the BRCA1 gene of these tumors is an infrequent event. We undertook the present study to evaluate the prevalence of germ-line mutations in patients diagnosed with sporadic breast cancer, and to delimit the clinical spectrum of this subgroup of patients with germ-line mutations and their differences with respect to patients with no evidence of BRCA1 gene mutations. METHODS We studied 105 patients diagnosed with breast cancer, selected from among our living patients; those with carcinoma-in-situ and those with a definite family history of breast or ovarian cancer were excluded. Genomic DNA, obtained from peripheral-blood lymphocytes, was studied for BRCA1 mutations by polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) and direct DNA sequencing. Fourteen clinicopathologic parameters were analyzed in each patient. RESULTS Six (5.7%) frameshift mutations that corresponded to truncating proteins and three missense mutations, the functional meaning of which remains speculative, were identified. The patients with germ-line mutations were found to have a more advanced age at diagnosis, as well as a longer median survival (51 months). CONCLUSION Women with sporadic breast cancer of late onset may display a significant incidence of germline BRCA1 mutations, which occur at a rate not previously determined in this group of patients. The presence of variations in the sequence of the BRCA1 gene could influence the longer survival observed in these patients.

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Germline Mutation Analysis in Sporadic Breast Cancer Cases with Clinical Correlations

10.1101/2021.03.29.21254525 ◽

2021 ◽

Author(s):

Sadia Ajaz ◽

Sani-e-Zehra Zaidi ◽

Saleema Mehboob Ali ◽

Aisha Siddiqa ◽

Mohammad Ali Memon

Keyword(s):

Breast Cancer ◽

Sporadic Breast Cancer ◽

Ductal Carcinoma ◽

Germ Line ◽

Copy Number Variations ◽

P Value ◽

Breast Cancers ◽

Pakistani Population ◽

Germ Line Mutations ◽

Clinical Correlations

Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately in Pakistani population. In the present study, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy controls. The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The analyses were stratified on the basis of age (<40 years vs >40 years) and ethnicity. The breast cancer gene panel assay was carried out by a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 assay with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (<40 years) was higher in Sindhis (n=12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grades II and III (46.4%), tumor size 2-5cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of preventive and treatment strategies against breast cancers in Pakistani population.

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Prevalence of BRCA1 and BRCA2 Mutations Among High-Risk Saudi Patients With Breast Cancer

Journal of Global Oncology ◽

10.1200/jgo.18.00066 ◽

2018 ◽

pp. JGO.18.00066 ◽

Cited By ~ 1

Author(s):

Omalkhair Abulkhair ◽

Mohammed Al Balwi ◽

Ola Makram ◽

Lamia Alsubaie ◽

Medhat Faris ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Novel Mutation ◽

Brca Mutation ◽

Brca1 Gene ◽

Brca1 And Brca2 ◽

Brca1 Mutations ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations ◽

Saudi Patients

Purpose Over the past three decades, the incidence rate of breast cancer (BC) among Arab women has continually increased. However, data on the prevalence of BRCA1/2 mutations are scarce. Although the population in Saudi Arabia is at large homogeneous and consanguinity is common, especially in the central, eastern, and southern regions of the country, the prevalence of BRCA1 and BRCA2 mutations and the characteristics of BC are not well studied in the country. Methods This prospective observational study intended to determine the prevalence of BRCA1 and BRCA2 mutations and sought to examine the clinicopathologic features of BC associated with these mutations. Results Of 310 patients, 270 (87%) had no mutation. BRCA mutations were identified in 40 patients; BRCA1 mutations were found in 11% of patients, and BRCA2 mutations were found in 2% of patients. Variants of unknown significance were found in 15% of patients (45 patients). Triple-negative BC (TNBC) accounted for 86% of all patients with BC and mutations. The following three recurrent deleterious founder BRCA1 mutations were observed: c.4136_4137delCT was observed in five unrelated patients, c.5530delC was observed in three unrelated patients, and c.4524G>A mutations were observed in five unrelated patients. One novel mutation was identified in the BRCA1 gene (c.5512 dup [p.Glu1838Glyfs*42]). Conclusion Among high-risk Saudi patients with BC, BRCA1 mutations are prevalent (11%). TNBC is the most common BC subtype. Furthermore, age alone does not have a significant association with mutation, but a combination of risk factors such as age, familial history, and TNBC has a significant association with BRCA mutation.

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Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations

Breast Cancer Research and Treatment ◽

10.1007/s10549-007-9846-7 ◽

2007 ◽

Vol 112 (2) ◽

pp. 343-349 ◽

Cited By ~ 4

Author(s):

Ian J. Seymour ◽

Silvia Casadei ◽

Valentina Zampiga ◽

Simonetta Rosato ◽

Rita Danesi ◽

...

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Germ Line ◽

Central Italy ◽

Population Based ◽

North Central ◽

Germ Line Mutations

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Breast cancer phenotype in women with TP53 germ-line mutations: An LFS consortium effort.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.1519 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 1519-1519 ◽

Cited By ~ 2

Author(s):

S. Masciari ◽

D. Dillon ◽

M. G. Dick ◽

M. E. Robson ◽

J. N. Weitzel ◽

...

Keyword(s):

Breast Cancer ◽

Germ Line ◽

Germ Line Mutations ◽

Cancer Phenotype

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Bilateral breast cancer in a patient with a strong family history of cancer: Analysis of p53 germ line mutations

Breast Cancer ◽

10.1007/bf02967046 ◽

1994 ◽

Vol 1 (2) ◽

pp. 151-155 ◽

Cited By ~ 1

Author(s):

Takashi Fukutomi ◽

Rie Inoue ◽

Toshikazu Ushijima ◽

Hitoshi Tsuda ◽

Isamu Adachi

Keyword(s):

Breast Cancer ◽

Family History ◽

Germ Line ◽

Bilateral Breast Cancer ◽

Strong Family History ◽

Family History Of Cancer ◽

Germ Line Mutations ◽

History Of ◽

History Of Cancer

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Familial Invasive Breast Cancers: Worse Outcome Related to BRCA1 Mutations

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.24.4053 ◽

2000 ◽

Vol 18 (24) ◽

pp. 4053-4059 ◽

Cited By ~ 126

Author(s):

Dominique Stoppa-Lyonnet ◽

Yan Ansquer ◽

Hélène Dreyfus ◽

Chantal Gautier ◽

Marion Gauthier-Villars ◽

...

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Germ Line ◽

Brca1 Mutation ◽

Progesterone Receptors ◽

Time Interval ◽

Breast Cancers ◽

Brca1 Mutations ◽

Long Time ◽

Grade 3

PURPOSE: Although all studies confirm that BRCA1 tumors are highly proliferative and poorly differentiated, their outcomes remain controversial. We propose to examine, through a cohort study, the pathologic characteristics, overall survival, local recurrence, and metastasis-free intervals of 40 patients with BRCA1 breast cancer. PATIENTS AND METHODS: A cohort of 183 patients with invasive breast cancer, treated at the Institut Curie and presenting with a familial history of breast and/or ovarian cancer, were tested for BRCA1 germ-line mutation. Tumor characteristics and clinical events were extracted from our prospectively registered database. RESULTS: Forty BRCA1 mutations were found among the 183 patients (22%). Median follow-up was 58 months. BRCA1 tumors were larger in size (P = .03), had a higher rate of grade 3 histoprognostic factors (P = .002), and had a higher frequency of negative estrogen (P = .003) and progesterone receptors (P = .002) compared with non-BRCA1 tumors. Overall survival was poorer for carriers than for noncarriers (5-year rate, 80% v 91%, P = .002). Because a long time interval between cancer diagnosis and genetic counseling artificially increases survival time due to unrecorded deaths, the analysis was limited to the 110 patients whose diagnosis-to-counseling interval was less than 36 months (19 BRCA1 patients and 91 non-BRCA1 patients). The differences between the BRCA1 and non-BRCA1 groups regarding overall survival and metastasis-free interval were dramatically increased (49% v 85% and 18% v 84%, respectively). Multivariate analysis showed that BRCA1 mutation was an independent prognostic factor. CONCLUSION: Our results strongly support that among patients with familial breast cancer, those who have a BRCA1 mutation have a worse outcome than those who do not.

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Mutation screening of the BRCA1 gene in sporadic breast cancer in southern Chinese populations

The Breast ◽

10.1016/j.breast.2008.08.003 ◽

2008 ◽

Vol 17 (6) ◽

pp. 563-567 ◽

Cited By ~ 4

Author(s):

Zhang Haitian ◽

Lu Yunfei ◽

Zeng Jian ◽

Lin Jian ◽

Liao Qinghua ◽

...

Keyword(s):

Breast Cancer ◽

Sporadic Breast Cancer ◽

Mutation Screening ◽

Brca1 Gene ◽

Chinese Populations ◽

Southern Chinese

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SEARCHING FOR MISSING HERITABILITY FOR BREAST CANCER BY WHOLE EXOME SEQUENCING: EVALUATION OF VARIANT PATHOGENICITY AND SELECTION OF CANDIDATE MUTATIONS

Problems in oncology ◽

10.37469/0507-3758-2018-64-3-310-318 ◽

2018 ◽

Vol 64 (3) ◽

pp. 310-318

Author(s):

Yekaterina Kuligina ◽

Anna Sokolenko ◽

Ilya Bizin ◽

Aleksandr Ivantsov ◽

Yevgeniy Imyanitov ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Protein Interactions ◽

Germ Line ◽

Great Promise ◽

Cancer Genes ◽

Whole Exome ◽

Increased Risk ◽

Germ Line Mutations

Approximately 10 % of breast cancer (BC) incidence is attributed to inherited germ-line mutations in tumor suppressor genes, and about a half of all hereditary BC cases remain unexplained by known genetic determinants. Whole exome sequencing (WES) offers great promise for the identification of novel hereditary cancer genes, however the interpretation of disease-causing significance for newly identified variants presents a challenge. Here we present the results of WES analysis of 32 hereditary BC patients with unknown causative mutations. In total, 52070 germ-line genetic variants were identified. We designed a special selection algorithm, which uses a sequence of filtering steps for highlighting probably pathogenic mutations. The pipeline is capable to compute minor allele frequencies (MAF) based on public databases; to estimate the potential pathogenicity of mutation according to CADD-database; to summarize the data regarding the gene functions, its pattern of expression and protein interactions networks. As a result we assembled the list of 245 potentially deleterious germ-line mutations probably associated with increased risk of BC. Some of these variants were validated in a case-control study. For example, homozygous missense substitution BRCA1 p.Gln356Arg was detected in 0.9 % of consecutive BC cases; it was associated with 7-fold increased BC risk (95 % CI: 0.83 - 54.83). This finding supports the existence of recessive inheritance of breast cancer predisposition.

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