Abstract LB-159: Methylation of BRCA1 gene in blood is not inherited via maternal germ line and may predispose to triple-negative or medullary breast cancer

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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STUDY ON THE GENETIC PREDISPOSITION TO BREAST CANCER AND THE DNA DAMAGE RESPONSE AT TELOMERES AND IN CELLULAR SENESCENCE

Istituto Lombardo - Accademia di Scienze e Lettere - Rendiconti di Scienze ◽

10.4081/scie.2016.548 ◽

2020 ◽

Author(s):

Francesca Rossiello, et al. (#)

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Germ Line ◽

Brca1 Gene ◽

Coding Region ◽

Brca1 And Brca2 ◽

Proliferating Cells ◽

Breast Cancer Predisposition ◽

Damage Response

Germ line mutations in the coding sequence of some genes, mainly BRCA1 and BRCA2, confer a high risk of developing breast cancer. However, about 70% of tumors cases are not associated with any known mutation. By screening by sequencing peripheral blood of patients and healthy controls, we identified some previously unknown germline mutations in the 3 'UTR non-coding region of the BRCA1 gene. These mutations can modify gene expression, and can therefore be useful to predict, with greater accuracy, familiar breast cancer predisposition. Subsequently, to understand the mechanisms of aging in non-proliferating cells we studied the persistent DNA damage response (DDR) signal in senescent cells, both in cell cultures and in animal tissues, and we found that these signals mainly localize to telomeres, independently from their length. The accumulation of damage at the telomeric DNA, due to the inhibition of the repair mechanisms, causes cellular and individual aging, but it is also an important anti-tumor mechanism, as it prevents the uncontrolled cell growth during the early stages of neoplastic transformation.

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Evaluation of Complete Pathological Regression after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer Patients with BRCA1 Founder Mutation Aided Bayesian A/B Testing Approach

Diagnostics ◽

10.3390/diagnostics11071144 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1144

Author(s):

Piotr Kedzierawski ◽

Pawel Macek ◽

Izabela Ciepiela ◽

Artur Kowalik ◽

Stanislaw Gozdz

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Brca1 Mutation ◽

Brca1 Gene ◽

Complete Regression ◽

Breast Cancer Patients ◽

Brca1 Gene Mutation ◽

Brca1 Status

The aim of this study was to evaluate the probability of pathologic complete regression (pCR) by the BRCA1 gene mutation status in patients with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy. The study involved 143 women (mean age 55.4 ± 13.1 years) with TNBC. The BRCA1 mutation was observed in 17% of the subjects. The most commonly used (85.3%) chemotherapy regimen was four cycles of adriamycine and cyclophosphamide followed by 12 cycles of paclitaxel (4AC + 12T). The differences between clinico-pathological factors by BRCA1 status were estimated. Odds ratios and 95% confidence intervals for pCR vs. non-pCR were calculated using logistic regression. The probability distribution of pCR based on BRCA1 status was estimated using beta distributions. The presence of T3–T4 tumours, cancer in stages II and III, lymphovascular invasion, and the use of chemotherapy schedules other than 4AC + 12T significantly decreased the odds of pCR. It was established that there was a 20% chance that pCR in patients with the BRCA1 mutation was 50% or more times as frequent than in patients without the mutation. Thus, the BRCA1 mutation can be a predictive factor for pCR in patients with TNBC.

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Final results of a phase II trial of trabectedin (T) in triple-negative, HER2-positive, and BRCA1/2 germ-line-mutated metastatic breast cancer (MBC) patients (pts).

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.1125 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 1125-1125 ◽

Cited By ~ 5

Author(s):

K. L. Tedesco ◽

J. L. Blum ◽

A. Goncalves ◽

J. Lubinski ◽

C. R. C. Osborne ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Phase Ii ◽

Triple Negative ◽

Germ Line ◽

Phase Ii Trial ◽

Metastatic Breast ◽

Her2 Positive

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184. Methylation of the BRCA1 gene promoter in triple negative breast cancer

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2014.08.179 ◽

2014 ◽

Vol 40 (11) ◽

pp. S79

Author(s):

S. Daniels ◽

O. Dotsenko ◽

S.S. Cross ◽

L. Wyld ◽

M.W.R. Reed ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Gene Promoter ◽

Brca1 Gene

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Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms21103670 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3670 ◽

Cited By ~ 1

Author(s):

Janusz Blasiak ◽

Elzbieta Pawlowska ◽

Jan Chojnacki ◽

Joanna Szczepanska ◽

Michal Fila ◽

...

Keyword(s):

Breast Cancer ◽

Vitamin D ◽

Triple Negative ◽

Therapeutic Potential ◽

Brca1 Gene ◽

Molecular Characteristics ◽

Cancer Type ◽

Protective Effects ◽

Loss Of Function

Several studies show that triple-negative breast cancer (TNBC) patients have the lowest vitamin D concentration among all breast cancer types, suggesting that this vitamin may induce a protective effect against TNBC. This effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), can be attributed to its potential to modulate proliferation, differentiation, apoptosis, inflammation, angiogenesis, invasion and metastasis and is supported by many in vitro and animal studies, but its exact mechanism is poorly known. In a fraction of TNBCs that harbor mutations that cause the loss of function of the DNA repair-associated breast cancer type 1 susceptibility (BRCA1) gene, 1,25(OH)2D may induce protective effects by activating its receptor and inactivating cathepsin L-mediated degradation of tumor protein P53 binding protein 1 (TP53BP1), preventing deficiency in DNA double-strand break repair and contributing to genome stability. Similar effects can be induced by the interaction of 1,25(OH)2D with proteins of the growth arrest and DNA damage-inducible 45 (GADD45) family. Further studies on TNBC cell lines with exact molecular characteristics and clinical trials with well-defined cases are needed to determine the mechanism of action of vitamin D in TNBC to assess its preventive and therapeutic potential.

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