Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some cases of pancreatic cancer (PC) are described to cluster within families. With the exception of PALLD gene mutations, which explain only a very modest fraction of familial cases, the genetic basis of familial PC is still obscure. Here the literature was reviewed in order to list the known genes, environmental factors, and health conditions associated with PC or involved in the carcinogenesis of the pancreas. Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast-ovarian familial cancer), where PC is part of the cancer spectrum of the disease. In addition, in this review I ranked known/possible risk factors extending the analysis to the hereditary pancreatitis (HP), diabetes, or to specific environmental exposures such as smoking. It appears that these factors contribute strongly to only a small proportion of PC cases. Recent work has revealed new genes somatically mutated in PC, including alterations within the pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to reveal new candidate genes for the susceptibility to this disease and to better ascertain the actual contribution of the familial forms.
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PMID:Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature. 1915 Apr 14

Mutations in BRCA1 and BRCA2 increase a woman's lifetime risk of developing breast cancer by 43% to 84%. It was originally postulated that BRCA1/2-associated breast cancers develop more rapidly than sporadic cancers and may lack preinvasive lesions. More recent studies have found preinvasive lesions in prophylactic mastectomy specimens from mutation carriers; however, there is little information on the presence of preinvasive lesions in tissue adjacent to breast cancers. Our aim is to investigate the role of preinvasive lesions in BRCA-associated breast carcinogenesis. We retrospectively compared BRCA1/2-associated breast cancers and sporadic breast cancers for the prevalence of preinvasive lesions [ductal carcinoma in situ (DCIS), lobular carcinoma in situ, and atypical lobular hyperplasia] in tissue adjacent to invasive breast cancers. Pathology was reviewed for 73 BRCA1/2-associated tumors from patients with breast cancer. We selected 146 patients with mutation-negative breast cancer as age-matched controls. Among the BRCA1/2-associated breast cancers, 59% had at least one associated preinvasive lesion compared with 75% of controls. Preinvasive lesions were more prevalent in BRCA2 mutation carriers than in BRCA1 mutation carriers (70% versus 52%, respectively). The most common preinvasive lesion in both groups was DCIS; 56% of BRCA1/2-associated breast cancers and 71% of the sporadic breast cancers had adjacent intraductal disease, respectively. Preinvasive lesions, most notably DCIS, are common in BRCA1/2-associated breast cancers. These findings suggest that BRCA1/2-associated breast cancers progress through the same intermediate steps as sporadic breast cancers, and that DCIS should be considered as a part of the BRCA1/2 tumor spectrum.
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PMID:High prevalence of preinvasive lesions adjacent to BRCA1/2-associated breast cancers. 1917 75

Cancer is a genetic disease. Breast cancer tumorigenesis can be described as a multi-step process in which each step is thought to correlate with one or more distinct mutations in major regulatory genes. The question addressed is how far a multi-step progression model for sporadic breast cancer would differ from that for hereditary breast cancer. Hereditary breast cancer is characterized by an inherited susceptibility to breast cancer on basis of an identified germline mutation in one allele of a high penetrance susceptibility gene (such as BRCA1, BRCA2, CHEK 2, TP53 or PTEN). Inactivation of the second allele of these tumour suppressor genes would be an early event in this oncogenic pathway (Knudson's "two-hit" model). Sporadic breast cancers result from a serial stepwise accumulation of acquired and uncorrected mutations in somatic genes, without any germline mutation playing a role. Mutational activation of oncogenes, often coupled with non-mutational inactivation of tumour suppressor genes, is probably an early event in sporadic tumours, followed by more, independent mutations in at least four or five other genes, the chronological order of which is likely less important. Oncogenes that have been reported to play an early role in sporadic breast cancer are MYC, CCND1 (Cyclin D1) and ERBB2 (HER2/neu). In sporadic breast cancer, mutational inactivation of BRCA1/2 is rare, as inactivation requires both gene copies to be mutated or totally deleted. However, non-mutational functional suppression could result from various mechanisms, such as hypermethylation of the BRCA1 promoter or binding of BRCA2 by EMSY. In sporadic breast tumorigenesis, at least three different pathway-specific mechanisms of tumour progression are recognizable, with breast carcinogenesis being different in ductal versus lobular carcinoma, and in well differentiated versus poorly differentiated ductal cancers. Thus, different breast cancer pathways emerge early in the process of carcinogenesis, ultimately leading to clinically different tumour types. As mutations acquired early during tumorigenesis will be present in all later stages, large-scale gene expression profiling using DNA microarray analysis techniques can help to classify breast cancers into clinically relevant subtypes.
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PMID:Oncogenic pathways in hereditary and sporadic breast cancer. 1535 Oct 94

The breast cancer susceptibility gene (BRCA2) is localized mainly in the nucleus where it plays an important role in DNA damage repair. Some BRCA2 protein is also present in the centrosome. Here, we demonstrate that BRCA2 interacts with plectin, a cytoskeletal cross-linker protein, and that this interaction controls the position of the centrosome. Phosphorylation of plectin by cyclin-dependent kinase 1/cyclin B (CDK1/CycB) kinase has been reported to abolish its cross-linking function during mitosis. Here, we induced phosphorylation of plectin in prepared fractions of HeLa cells by adding activated CDK1/CycB kinase. Consequently, there was significant dissociation of the centrosome from the nuclear membrane. Plectin has six homologous ankyrin-like repeat domains (termed PLEC M1-M6). Using a pull-down assay, we found that GST-PLEC M1 and a GST-C-terminal region fusion protein (which comprised PLEC M6, along with an adjacent vimentin site) interacted with BRCA2. Since each PLEC module exhibits high homology to the others, the possibility of all six domains participating in this interaction was indicated. Moreover, when PLEC M1 was overexpressed in HeLa cells, it competed with endogenous plectin and inhibited the BRCA2-plectin interaction. This inhibitory effect resulted in dissociation of the centrosomes from the nucleus and increased the rate of micronuclei formation which may lead to carcinogenesis. In addition, when either BRCA2 or plectin was suppressed by the appropriate siRNA, a similar change in centrosomal positioning was observed. We suggest that the BRCA2-plectin interaction plays an important role in the regulation of centrosome localization and also that displacement of the centrosome may result in genomic instability and cancer development.
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PMID:BRCA2 interacts with the cytoskeletal linker protein plectin to form a complex controlling centrosome localization. 1970 76

Fanconi Anemia (FA) is a rare recessive syndrome characterized by cellular hypersensitivity to DNA-cross-linking agents. To date, 13 FA complementation groups have been described and all 13 genes associated to each of these groups have been currently identified. Three of the known FA genes are also high-risk (FANCD1/BRCA2) or moderate-risk (FANCN/PALB2 and FANCJ/BRIP1) breast cancer susceptibility genes, which makes all members of the FA pathway particularly attractive breast cancer candidate genes. Most FA genes have been screened for mutations in breast cancer families negative for BRCA1/2 mutations but the role of FANCL, FANCM and the recently identified FANCI has not been evaluated to date. This fact and novel data sustaining greater functional relevance of the three genes within the FA pathway prompted us to scrutinize all coding sequences and splicing sites of FANCI, FANCL and FANCM in 95 BRCA1/2-negative index cases from Spanish high-risk breast cancer families. We identified 68 sequence variants of which 24 were coding and 44 non-coding. Six exonic and 26 non-coding variants had not been described previously. None of the coding changes caused clearly pathogenic changes and computational analysis of all non-described intronic variants did not revealed major impact in splicing. With the present study, all known FA genes have been evaluated within the context of breast cancer high-risk predisposition. Our results rule out a major role of FANCI, FANCL and FANCM in familial breast cancer susceptibility, suggesting that among the 13 known FA genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition.
Carcinogenesis 2009 Nov
PMID:Mutational analysis of FANCL, FANCM and the recently identified FANCI suggests that among the 13 known Fanconi Anemia genes, only FANCD1/BRCA2 plays a major role in high-risk breast cancer predisposition. 1973 59

Breast cancer is a public health problem in the Western countries. Several studies have shown that BRCA2, like BRCA1 oncosuppressors, are strongly involved in hereditary and sporadic mammary carcinogenesis. It has also been suggested that soy has a protective effect against breast cancer in Asia and, more particularly, phytoestrogens such as daidzein and genistein. Thus, phytoestrogens may have an impact on the expression of BRCA2 gene, and there is a possible link between BRCA2 and genes acting around the BRCA2. To focus on these processes, we set up the BRCA2 specific knockdown by RNA interference in two breast tumor cell lines (MCF-7 and MDA-MB-231) and also in a non-tumorigenic breast cell line (MCF-10a). After inhibition of BRCA2 expression, cells were maintained in different conditions and treated with either daidzein or genistein or left untreated. Microarray analysis of mRNAs isolated from the BRCA2 knocked down MCF-7, MDA-MB-231, and MCF-10a cell lines after being treated with phytoestrogens showed 35 differentially expressed genes between positive-ERbeta cells and negative-ERbeta cells. After genistein or daidzein treatments, BRCA1 was found to be up-regulated when knocked down with BRCA2-siRNA MCF-7 and BRCA2 was found to be up-regulated when knocked down with BRCA2-siRNA MDA-MB 231 cells. In MCF-10a, we observed a significant decrease in BAX and BCL2 expressions with a greater effect of daidzein. We also found an increase in BRIP expression between genistein and daidzein treatment knocked down with BRCA2-siRNA MCF-7 and MDA-MB-231 cell lines.
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PMID:Phytoestrogens regulate the expression of genes involved in different biological processes in BRCA2 knocked down MCF-7, MDA-MB-231 and MCF-10a cell lines. 2012 2

It is now understood that epigenetic alterations occur frequently in sporadic breast carcinogenesis, but little is known about the epigenetic alterations associated with familial breast tumors. We performed genome-wide DNA-methylation profiling on familial breast cancers (n = 33) to identify patterns of methylation specific to the different mutation groups (BRCA1, BRCA2, and BRCAx) or intrinsic subtypes of breast cancer (basal, luminal A, luminal B, HER2-amplified, and normal-like). We used methylated DNA immunoprecipitation (MeDIP) on Affymetrix promoter chips to interrogate methylation profiles across 25,500 distinct transcripts. Using a support vector machine classification algorithm, we demonstrated that genome-wide methylation profiles predicted tumor mutation status with estimated error rates of 19% (BRCA1), 31% (BRCA2), and 36% (BRCAx) but did not accurately predict the intrinsic subtypes defined by gene expression. Furthermore, using unsupervised hierarchical clustering, we identified a distinct subgroup of BRCAx tumors defined by methylation profiles. We validated these findings in the 33 tumors in the test set, as well as in an independent validation set of 47 formalin-fixed, paraffin-embedded familial breast tumors, by pyrosequencing and Epityper. Finally, gene-expression profiling and SNP CGH array previously performed on the same samples allowed full integration of methylation, gene-expression, and copy-number data sets, revealing frequent hypermethylation of genes that also displayed loss of heterozygosity, as well as of genes that show copy-number gains, providing a potential mechanism for expression dosage compensation. Together, these data show that methylation profiles for familial breast cancers are defined by the mutation status and are distinct from the intrinsic subtypes.
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PMID:DNA methylome of familial breast cancer identifies distinct profiles defined by mutation status. 2020 35

Although DNA double-strand breaks (DSBs) are substrates for homologous recombination (HR) repair, it is becoming apparent that DNA lesions produced at replication forks, for instance by many anticancer drugs, are more significant substrates for HR repair. Cells defective in HR are hypersensitive to a wide variety of anticancer drugs, including those that do not produce DSBs. Several cancers have mutations in or epigenetically silenced HR genes, which explain the genetic instability that drives cancer development. There are an increasing number of reports suggesting that mutation or epigenetic silencing of HR genes explains the sensitivity of cancers to current chemotherapy treatments. Furthermore, there are also many examples of re-expression of HR genes in tumours to explain drug resistance. Emerging data suggest that there are several different subpathways of HR, which can compensate for each other. Unravelling the overlapping pathways in HR showed that BRCA1- and BRCA2-defective cells rely on the PARP protein for survival. This synthetic lethal interaction is now being exploited for selective treatment of BRCA1- and BRCA2-defective cancers with PARP inhibitors. Here, I discuss the diversity of HR and how it impacts on cancer with a particular focus on how HR can be exploited in future anticancer strategies.
Carcinogenesis 2010 Jun
PMID:Homologous recombination in cancer development, treatment and development of drug resistance. 2035 Oct 92

Double heterozygosity (DH) for BRCA1 and BRCA2 mutations is a very rare finding, particularly in non-Ashkenazi individuals, and only a few cases have been reported to date. In addition, little is known on the pathological features of the tumors that occur in DH cases and on their family history of cancer. Four carriers of pathogenic mutations in both BRCA1 and BRCA2 were identified among women who underwent genetic counseling for hereditary susceptibility to breast and ovarian carcinoma at three different Italian institutions. Clinical, pathological, and family history data were collected from medical records and during genetic counseling sessions. All identified DH cases developed breast carcinoma and three of them were also diagnosed with ovarian carcinoma. Mean ages of breast and ovarian cancer diagnosis were 42.7 and 48.6 years, respectively. The majority of breast cancers showed a BRCA1-related phenotype, being negative for hormone receptors and HER2. Two cases reported different gastrointestinal tumors among relatives. Although the individuals described in this study show more severe clinical features in comparison to previously reported BRCA1 and BRCA2 DH cases, our observations support the hypothesis of a non specific phenotype of DH cases in terms of age of disease onset. In addition, our observations indicate that in DH patients breast carcinogenesis appears to be driven mainly by the mutations in BRCA1. The possible association of DH for BRCA gene mutations with gastrointestinal tumors is in keeping with previous reports, but needs to be confirmed by further analyses.
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PMID:Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. 2037 18

BRCA1 and BRCA2 are tumor suppressor genes, familial mutations in which account for approximately 5% of breast cancer cases in the USA annually. Germ line mutations in BRCA1 that truncate or inactivate the protein lead to a cumulative risk of breast cancer, by age 70, of up to 80%, whereas the risk of ovarian cancer is 30-40%. For germ line BRCA2 mutations, the breast cancer cumulative risk approaches 50%, whereas for ovarian cancers, it is between 10 and 15%. Both BRCA1 and BRCA2 are involved in maintaining genome integrity at least in part by engaging in DNA repair, cell cycle checkpoint control and even the regulation of key mitotic or cell division steps. Unsurprisingly, the complete loss of function of either protein leads to a dramatic increase in genomic instability. How they function in maintaining genome integrity after the onset of DNA damage will be the focus of this review.
Carcinogenesis 2010 Jun
PMID:BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. 2040 Apr 77


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