Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

No more than approximately 30% of hereditary breast cancer has been accounted for by mutations in known genes. Most of these genes, such as BRCA1, BRCA2, TP53, CHEK2, ATM, and FANCJ/BRIP1, function in DNA repair, raising the possibility that germ line mutations in other genes that contribute to this process also predispose to breast cancer. Given its close relationship with BRCA2, PALB2 was sequenced in affected probands from 68 BRCA1/BRCA2-negative breast cancer families of Ashkenazi Jewish, French Canadian, or mixed ethnic descent. The average BRCAPRO score was 0.58. A truncating mutation (229delT) was identified in one family with a strong history of breast cancer (seven breast cancers in three female mutation carriers). This mutation and its associated breast cancers were characterized with another recently reported but unstudied mutation (2521delA) that is also associated with a strong family history of breast cancer. There was no loss of heterozygosity in tumors with either mutation. Moreover, comparative genomic hybridization analysis showed major similarities to that of BRCA2 tumors but with some notable differences, especially loss of 18q, a change that was previously unknown in BRCA2 tumors and less common in sporadic breast cancer. This study supports recent observations that PALB2 mutations are present, albeit not frequently, in breast cancer families. The apparently high penetrance noted in this study suggests that at least some PALB2 mutations are associated with a substantially increased risk for the disease.
 ...
PMID:Analysis of PALB2/FANCN-associated breast cancer families. 1742 Apr 51

Breast cancer is one of the most frequent cancers in the world. The majority of cases are sporadic but around 15% show some type of familial aggregation and about 5% exhibit a clear hereditary pattern. Common and rare low- moderate-penetrance genes, and high-penetrance genes are thought to explain the genetic susceptibility to the disease. Only around 20% of the inherited risk to breast cancer is explained by germline mutations in the known high-penetrance susceptibility genes BRCA1 and BRCA2. Mutations in genes such as TP53 and PTEN have also been linked with high risk for breast cancer within specific cancer syndromes and rare germline variants in genes such as CHEK2 and ATM have been found to confer modest risk to breast cancer. However, we can say that less than 30% of familial risk of breast cancer is due to known genes. Identification in 2002 of the Fanconi anaemia (FA) gene FANCD1 as BRCA2 and recent studies indicating that heterozygous mutations in FANCN/PALB2 and FANCJ/ BRIP1 predispose to breast cancer have emphasised an important connection between the FA and BRCA pathway. Here we review the emerging DNA-damage response network consisting of FA and BRCA proteins, summarise what is currently known about the direct involvement of these molecules in breast cancer susceptibility and discuss the prospect offered by this pathway in order to identify more breast cancer related genes. We finally present the current stage of therapeutic options specifically targeting the FA/BRCA pathway and summarise the challenges this field encounters.
 ...
PMID:The Fanconi anaemia/BRCA pathway and cancer susceptibility. Searching for new therapeutic targets. 1825 6

Breast cancer (BC) is a heterogeneous disease. The majority of breast cancer cases (about 70 percent) are considered sporadic. Familial breast cancer (about 30 percent of patients), often seen in families with a high incidence of BC, has been associated with a number of high-, moderate-, and low-penetrance susceptibility genes. Family linkage studies have identified high-penetrance genes, BRCA1, BRCA2, PTEN and TP53, that are responsible for inherited syndromes. Moreover, a combination of family-based and population-based approaches indicated that genes involved in DNA repair, such as CHEK2, ATM, BRIP1 (FANCJ), PALB2 (FANCN) and RAD51C (FANCO), are associated with moderate BC risk. Genome wide association studies (GWAS) in BC revealed a number of common low penetrance alleles associated with a slightly increased or decreased risk of BC. Currently, only high penetrance genes are used in clinical practice on a wide scale. Due to the development of next generation sequencing technologies, it is envisaged that all familial breast cancer genes will be included in the genetic test. However, additional research in clinical management of moderate and low-risk variants is needed before full implementation of multi-gene panel testing into clinical work-flows. In this review, we focus on the different components of familial breast cancer risk.
 ...
PMID:Breast cancer genes: beyond BRCA1 and BRCA2. 2374 89

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.
 ...
PMID:Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion. 3285 19