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result(s) for
"Genes, BRCA1"
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Germline BRCA1 mutations increase prostate cancer risk
Background:
Prostate cancer (PrCa) is one of the most common cancers affecting men but its aetiology is poorly understood. Family history of PrCa, particularly at a young age, is a strong risk factor. There have been previous reports of increased PrCa risk in male
BRCA1
mutation carriers in female breast cancer families, but there is a controversy as to whether this risk is substantiated. We sought to evaluate the role of germline
BRCA1
mutations in PrCa predisposition by performing a candidate gene study in a large UK population sample set.
Methods:
We screened 913 cases aged 36–86 years for germline
BRCA1
mutation, with the study enriched for cases with an early age of onset. We analysed the entire coding region of the
BRCA1
gene using Sanger sequencing. Multiplex ligation-dependent probe amplification was also used to assess the frequency of large rearrangements in 460 cases.
Results:
We identified 4 deleterious mutations and 45 unclassified variants (UV). The frequency of deleterious
BRCA1
mutation in this study is 0.45%; three of the mutation carriers were affected at age ⩽65 years and one developed PrCa at 69 years. Using previously estimated population carrier frequencies, deleterious
BRCA1
mutations confer a relative risk of PrCa of ∼3.75-fold, (95% confidence interval 1.02–9.6) translating to a 8.6% cumulative risk by age 65.
Conclusion
This study shows evidence for an increased risk of PrCa in men who harbour germline mutations in
BRCA1
. This could have a significant impact on possible screening strategies and targeted treatments.
Journal Article
Benign polymorphisms in the BRCA genes with linkage disequilibrium is associated with cancer characteristics
Germline pathogenic mutation of the BRCA gene increases the prevalence of breast cancer. Reports on the benign variants of BRCA genes are limited. However, the definition of these variants might be altered with the accumulation of clinical evidence. Therefore, in the present study, we focused on benign single nucleotide polymorphisms (SNPs) of BRCA genes. Linkage disequilibrium was calculated from whole genome sequencing of the BRCA genes obtained from 500 healthy controls and 49 breast cancer patients. Sanger sequencing was used to confirm the mutation. The linkage disequilibrium was noted for seven and three SNPs in the BRCA1 and BRCA2 genes, respectively. Breast cancer with BRCA1/2 linkage disequilibrium was not correlated with a personal history of benign diseases or family history of cancer. Nevertheless, breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor‐infiltrating lymphocytes and positive extensive intraductal components. The patients with BRCA1 linkage disequilibrium tended to have worse disease‐specific survival. Cancers with BRCA2 linkage disequilibrium are associated with a lower ratio of grade III cancer. Moreover, patients with BRCA2 linkage disequilibrium tended to have better overall survival. In conclusion, linkage disequilibrium from benign SNPs of the BRCA genes potentially affects cancer characteristics. Linkage disequilibrium from benign single nucleotide polymorphisms of the BRCA genes potentially affects the cancer characteristics. Breast cancer with BRCA1 linkage disequilibrium was correlated with high tumor‐infiltrating lymphocytes and positive extensive intraductal components.
Journal Article
Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage
BRCA1 (BReast‐CAncer susceptibility gene 1) and BRCA2 are tumor suppressor genes, the mutant phenotypes of which predispose to breast and ovarian cancers. Intensive research has shown that BRCA proteins are involved in a multitude of pivotal cellular processes. In particular, both genes contribute to DNA repair and transcriptional regulation in response to DNA damage. Recent studies suggest that BRCA proteins are required for maintenance of chromosomal stability, thereby protecting the genome from damage. New data also show that BRCAs transcriptionally regulate some genes involved in DNA repair, the cell cycle, and apo ptosis. Many of these functions are mediated by a large number of cellular proteins that interact with BRCAs. The functions of BRCA proteins are also linked to distinct and specific phosphory‐lation events; however, the extent to which phosphorylation‐acti‐vated molecular pathways contribute to tumor suppressor activity remains unclear. Finally, the reasons why mutations in BRCA genes lead to the development of breast and ovarian cancers are not clearly understood. Elucidation of the precise molecular functions of BRCAs is expected to improve our understanding of hereditary as well as sporadic mammary carcinogenesis.
Journal Article
BRCA mutations: Implications of genetic testing in ovarian cancer
Ovarian cancer (OC) is one of the most lethal gynecological cancers with a 5-year survival rate that ranges from 30% to 40%. Breast cancer genes (BRCA1 and BRCA2) play a key role in maintaining genomic stability. Mutations in BRCA1/2 genes lead to the accumulation of double-strand breaks, resulting in tumorigenesis. The risk of developing OC in women with BRCA1 and BRCA2 mutations is 39% and 11%, respectively, by 70 years of age. BRCA1/2 mutation testing is thus important to identify women at greatest risk of developing OC in addition to its impact on diagnosis, prognosis, and targeted therapy. Genetic testing is required to identify the BRCA mutations and thus select patients who can benefit from polyadenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitor therapy. Tumor BRCA mutation testing can detect both germline and somatic mutations allowing implementation of preventive strategies on a broader population. Various international guidelines recommend BRCA1/2 mutation genetic testing in all OC patients irrespective of age and family history. This review focuses on the role of BRCA mutation testing in OC.
Journal Article
Gene-Expression Profiles in Hereditary Breast Cancer
Inheritance of a mutant
BRCA1
or
BRCA2
gene (numbers 113705 and 600185, respectively, in Online Mendelian Inheritance in Man, a catalogue of inherited diseases) confers a lifetime risk of breast cancer of 50 to 85 percent and a lifetime risk of ovarian cancer of 15 to 45 percent.
1
–
6
These germ-line mutations account for a substantial proportion of inherited breast and ovarian cancers,
7
but it is likely that additional susceptibility genes will be discovered.
8
,
9
Certain pathological features can help to distinguish breast tumors with
BRCA1
mutations from those with
BRCA2
mutations. Tumors with
BRCA1
mutations are high-grade cancers with . . .
Journal Article
Breast Cancer after Prophylactic Bilateral Mastectomy in Women with a BRCA1 or BRCA2 Mutation
This investigation strengthens the case for mastectomy in women with a mutation of the
BRCA1
or
BRCA2
gene.
The identification of the breast-cancer–susceptibility genes
BRCA1
1
and
BRCA2
2
evoked widespread interest in genetic testing among women at risk for a mutation in these genes.
3
,
4
We found that 57 percent of women without breast cancer who had a 50 percent chance of carrying a
BRCA1
or
BRCA2
mutation requested genetic testing.
4
This result indicates the need to determine the efficacy of the various options for reducing the risk of breast cancer and for early detection in women with a
BRCA1
or
BRCA2
mutation.
Women with a
BRCA1
or
BRCA2
mutation have a cumulative lifetime risk of invasive breast cancer . . .
Journal Article
Role of direct interaction in BRCA1 inhibition of estrogen receptor activity
The BRCA1 gene was previously found to inhibit the transcriptional activity of the estrogen receptor [ER-alpha] in human breast and prostate cancer cell lines. In this study, we found that breast cancer-associated mutations of BRCA1 abolish or reduce its ability to inhibit ER-alpha activity and that domains within the amino- and carboxyl-termini of the BRCA1 protein are required for the inhibition. BRCA1 inhibition of ER-alpha activity was demonstrated under conditions in which a BRCA1 transgene was transiently or stably over-expressed in cell lines with endogenous wild-type BRCA1 and in a breast cancer cell line that lacks endogenous functional BRCA1 (HCC1937). In addition, BRCA1 blocked the expression of two endogenous estrogen-regulated gene products in human breast cancer cells: pS2 and cathepsin D. The BRCA1 protein was found to associate with ER-alpha in vivo and to bind to ER-alpha in vitro, by an estrogen-independent interaction that mapped to the amino-terminal region of BRCA1 (ca. amino acid 1-300) and the conserved carboxyl-terminal activation function [AF-2] domain of ER-alpha. Furthermore, several truncated BRCA1 proteins containing the amino-terminal ER-alpha binding region blocked the ability of the full-length BRCA1 protein to inhibit ER-alpha activity. Our findings suggest that the amino-terminus of BRCA1 interacts with ER-alpha, while the carboxyl-terminus of BRCA1 may function as a transcriptional repression domain. Oncogene (2001) 20, 77 - 87.
Journal Article
A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes
Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage caused by nonsense mutations
1
,
2
,
3
,
4
. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons (PTCs), targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS), and its underlying mechanism is unclear
1
,
2
,
5
,
6
. By analyzing NAS in
BRCA1
, we show here that inappropriate exon skipping can be reproduced
in vitro
, and results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by single nonsense, missense and translationally silent point mutations, without recognition of an open reading frame as such. These results argue against a nuclear reading-frame scanning mechanism for NAS. Coding-region single-nucleotide polymorphisms
7
(cSNPs) within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene.
Journal Article
Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer
The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability and germ-line loss-of-function mutations in either
BRCA1
or
BRCA2
strongly predispose carriers to cancers of the breast and other organs. It has been demonstrated previously that inhibiting elements of the cellular DNA maintenance pathways represents a novel therapeutic approach to treating tumors in these individuals. Here, we show that inhibition of the telomere-associated protein, Tankyrase 1, is also selectively lethal with BRCA deficiency. We also demonstrate that the selectivity caused by inhibition of Tankyrase 1 is associated with an exacerbation of the centrosome amplification phenotype associated with BRCA deficiency. We propose that inhibition of Tankyrase 1 could be therapeutically exploited in BRCA-associated cancers.
Journal Article