Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitogen-activated protein kinase (MAPK) kinase 4 (MKK4) is a component of a stress and cytokine-induced signal transduction pathway involving MAPK proteins. The MKK4 protein has been implicated in activation of JNK1 and p38 MAPK on phosphorylation by conserved kinase pathways. A recent report on the deletion and mutation of the MKK4 gene in human pancreatic, lung, breast, testicle, and colorectal cancer cell lines suggests an additional role for MKK4 in tumor suppression. Both the gene function and the infrequency of mutations might be considered atypical for many human tumor suppressor genes, and constitutional DNA was not previously available to determine whether the reported sequence variants had preceded tumor development. Here, we report that homozygous deletions are detected in 2 of 92 pancreatic adenocarcinomas (2%), 1 of 16 biliary adenocarcinomas (6%), and 1 of 22 breast carcinomas (when combined with reported sequence alterations, 3 of 22 or 14%). In addition, in a panel of 45 pancreatic carcinomas prescreened for loss of heterozygosity, one somatic missense mutation of MKK4 is observed and confirmed in the primary tumor (2%). Mapping of the homozygous deletions further indicated MKK4 to lie at the target of deletion. The finding of a somatic missense mutation in the absence of any other nucleotide polymorphisms or silent nucleotide changes continues to favor MKK4 as a mutationally targeted tumor suppressor gene. Coexistent mutations of other tumor suppressor genes in MKK4-deficient tumors suggest that MKK4 may participate in a tumor suppressive signaling pathway distinct from DPC4, p16, p53, and BRCA2.
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PMID:Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. 962 70

The breast cancer susceptibility gene BRCA2 is expressed in a wide range of tissues as an 11-kb mRNA transcript encoding a 3418-amino acid protein, which is involved in the response to DNA damage. To obtain a better molecular characterization of BRCA2 expression in breast tissue, we analyzed full-length BRCA2 mRNA by means of reverse transcriptase-PCR with a panel of primer pairs encompassing the entire cDNA sequence. We report the identification of an exon 12 alternatively spliced BRCA2 transcript (delta12-BRCA2) in normal human breast tissue, in a wide variety of other normal human tissues, and in several mouse tissues. The deletion observed in this transcript (96 bp) preserves the open reading frame, and translation of the transcript would result in a BRCA2 isoform lacking 32 amino acids between codons 2280 and 2311. The analysis of matched normal and primary tumor breast tissues from 12 patients showed that the expression level of the delta12-BRCA2 transcript was higher in 4 of 12 (33%) tumor tissues compared with their normal breast tissues. Overproduction of the delta12-BRCA2 variant was associated with steroid receptor-negative tumors (P = 0.0005). These data suggest that the mechanisms generating the BRCA2 mRNA variant exist in normal breast tissue and may be dysregulated in steroid receptor-negative breast tumor tissues.
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PMID:Increased level of exon 12 alternatively spliced BRCA2 transcripts in tumor breast tissue compared with normal tissue. 1036 70

Two synchronous bilateral breast carcinomas and their matched lymph node metastases from a 70-year-old man were cytogenetically analyzed. All four tumors were near-diploid, and except for the primary tumor from the right breast, had a 45,X,-Y clone in common. The loss of the Y chromosome was, however, common to all four tumors, whereas metaphase cells from peripheral blood lymphocytes showed a normal 46, XY chromosome complement. The primary tumor from the right breast was monoclonal, with loss of the Y chromosome and gain of 1q, whereas its metastasis had two related clones: the 45,X,-Y clone, and the other a more complex version of the clone in the primary tumor, with inv(3), -14, and del(16)(q13) as additional changes. The primary tumor from the left breast was polyclonal with three unrelated clones: 45,X,-Y/45,XY,-18/47,XY,+20, two of which were present in its metastasis. DNA flow cytometric studies showed diploidy for both primary tumors. No mutation in the BRCA2 gene was found on analysis of DNA from peripheral blood lymphocytes. The present findings show that del(16)(q13) is a recurrent finding among male breast carcinomas and that some of the primary cytogenetic abnormalities, as well as the pattern of chromosomal changes during the progression of sporadic breast carcinoma in the male, are similar to those in the female. In addition, the loss of the Y chromosome in the tumors but not in peripheral blood lymphocytes, suggests a possible role for this abnormality in the pathogenesis of male breast carcinoma.
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PMID:Cytogenetic heterogeneity and clonal evolution in synchronous bilateral breast carcinomas and their lymph node metastases from a male patient without any detectable BRCA2 germline mutation. 1073 89

Up to 10% of the breast cancers detected in the United States are related to an inherited germline mutation, usually in the BRCA1 or BRCA2 genes, and the majority of these patients will at some point require surgical evaluation and/or treatment. Women who harbor a genetic predisposition for breast cancer face an increased risk for early onset disease, bilateral tumors, and other non-breast malignancies, such as ovarian cancer. These issues raise questions regarding the appropriate surveillance regimen, and the potential efficacy of risk reduction strategies that should be considered. Once a breast cancer diagnosis has been established, the prognosis appears to be similar to stage-controlled sporadic breast cancer, despite an increased prevalence of adverse primary tumor features. However, the role of breast conservation therapy for these patients and the optimal means of addressing the substantially increased risk for contralateral tumors is not yet defined. The reported literature in this area, including a discussion of the value of genetic counseling and genetic testing, is reviewed.
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PMID:Educational review: role of the surgeon in hereditary breast cancer. 1135 12

Inactivation of the FANC-BRCA pathway via promoter methylation of the FANCF gene renders cells sensitive to DNA crosslinking agents, and has been identified in ovarian cancer cell lines and sporadic primary tumor tissues. We investigated epigenetic alterations in the FANC-BRCA pathway in head and neck squamous cell carcinomas (HNSCC) and non-small-cell lung cancers (NSCLC) using methylation-specific PCR. Promoter methylation of FANCF occurred in 15% (13/89) of HNSCCs and 14% (22/158) of NSCLCs. Methylation of BRCA1 occurred only in 6/158 NSCLC, and was limited to adenocarcinomas and large-cell carcinomas of the lung. No methylation of BRCA2 was detected. FANCF methylation was associated with a shorter duration of tobacco use (P=0.03) and a younger age of starting smoking (P=0.06) in NSCLC, and with a greater number of years of alcohol drinking (P=0.02) in HNSCC. In adenocarcinomas of the lung, FANCF promoter methylation was a significant predictor of poor survival with a hazard ratio of 3.1 (95% CI 1.2-7.9). This study demonstrates that inactivation of the FANC-BRCA pathway is relatively common in solid tumors and may be related to tobacco and alcohol exposure and survival of these patients.
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PMID:Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival. 1464 19

Germline mutations in the BRCA1 and BRCA2 genes confer a high lifetime risk of developing breast and other cancers; however, remarkable differences exist regarding disease manifestation in mutation carriers. It has been suggested that other genetic and/or environmental factors modify not only the appearance but also the age of onset and type of tumor in BRCA1/2-associated cases. The aim of the present study was to investigate the role of two p53 polymorphisms (c.97-147ins16bp and c.215c>g, p.Arg72Pro) as potential modifiers. For this purpose we investigated the possible association between the two polymorphisms and disease status in 447 BRCA1/2 mutation carriers belonging to 170 Spanish breast and/or ovarian cancer families. Genotype and haplotype analyses revealed that the presence of a specific haplotype carrying the allele without the 16-bp insertion and the variant allele for the Arg72Pro (No Ins-72Pro haplotype) was associated with an earlier age of onset in BRCA2 mutation carriers. We found an increased risk of developing a first primary tumor (breast or ovarian) before 35 years of age for individuals who carried at least one No Ins-72Pro haplotype (OR: 2.69; 95% CI: 1.15-6.29; P=0.022). We confirmed these data by a functional study in which we compared different p53 genotypes in relation to their apoptotic response after cell treatment with a cytotoxic drug (AraC). Our results revealed a decrease in p53 apoptotic rate associated with the No Ins-72Pro haplotype.
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PMID:A haplotype containing the p53 polymorphisms Ins16bp and Arg72Pro modifies cancer risk in BRCA2 mutation carriers. 1641 81

Although ovarian carcinomas with mutated BRCA1 or BRCA2 are sensitive to platinum compounds, such carcinomas eventually develop platinum resistance. Previously, we showed that acquired resistance to cisplatin in BRCA2-mutated tumors can be mediated by secondary intragenic mutations in BRCA2 that restore the wild-type BRCA2 reading frame. Here, we show that secondary mutations of BRCA1 also occur in BRCA1-mutated ovarian cancer with platinum resistance. We evaluated nine recurrent BRCA1-mutated ovarian cancers previously treated with platinum compounds, including five with acquired platinum resistance, one with primary platinum resistance, and three with platinum sensitivity. Four of the six recurrent platinum-resistant tumors had developed secondary genetic changes in BRCA1 that restored the reading frame of the BRCA1 protein, whereas none of the three platinum-sensitive recurrent tumors developed BRCA1 sequence alterations. We immunohistochemically confirmed restored expression of BRCA1 protein in two cases with secondary mutations. Intriguingly, the case with primary platinum resistance showed back mutation of BRCA1 in the primary tumor and showed another secondary mutation in the recurrent tumor. Our results suggest that secondary mutations in BRCA1 can mediate resistance to platinum in BRCA1-mutated ovarian tumors.
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PMID:Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. 1841 25

Women with BRCA1 and BRCA2 mutations have an elevated risk of breast cancer and ovarian cancer, but also of developing second primary breast cancer. BRCA1/2 mutation carriers with breast cancer must choose between breast conservation (BCT) and mastectomy (M) yet data on outcomes are limited. The purpose of this study is to compare long-term outcome following BCT and M in BRCA1/2 carriers. 655 women with BRCA1/2 mutations diagnosed with breast cancer and treated with BCT (n = 302) or M (n = 353) were identified and underwent follow-up to assess local, regional, and systemic recurrence. Local failure as first failure was significantly more likely in those treated with BCT compared to M, with a cumulative estimated risk of 23.5 vs. 5.5%, respectively, at 15 years (P < 0.0001); 15-year estimates in carriers treated with BCT and chemotherapy was 11.9% (P = 0.08 when compared to M). Most events appeared to be second primary cancers rather than failure to control the primary tumor. The risk of contralateral breast cancer was high in all groups, exceeding 40%, but was not statistically significantly different by use of adjuvant radiotherapy (RT) or not, suggesting no added risk from scatter RT at 10 and 15 years. There were no differences seen in regional or systemic recurrences between the BCT and M groups, and no difference in overall survival. In conclusion, BRCA1/2 mutation carriers with breast cancer have similar survival whether treated with M or BCT. However, women undergoing BCT have an elevated risk of a second in-breast event that is significantly reduced in the presence of chemotherapy. Contralateral breast cancer events are very common.
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PMID:Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy. 2041 23

The aim of this study was to verify whether histopathological features of extratumoral and of primary tumor breast tissue could play a role in identifying patients with familial characteristics. We examined the clinicopathological features of 504 patients with sporadic or familial breast cancer stratified for risk of BRCA mutation. Patients with a higher risk of being carrier of BRCA gene mutations were significantly associated with tumor poor differentiation (p=0.003), positive lymph node invasion (p=0.02) and presence of vascular peritumoral invasion (p=0.008). Among the extra-tumoral lesions, only the epithelial proliferative lesions were related to higher mutation risk both in the overall series and familial patients (p<0.0001 and p=0.003, respectively). Interestingly, a significant difference in terms of high mutation risk was observed in usual ductal hyperplasia lesions (UDH), (p=0.002). We suggest that vascular peritumoral invasion and UDH lesions could predict a higher mutation risk of BRCA1 and BRCA2 genes and help in individuating patient candidates to further molecular analysis.
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PMID:Histological features of extratumoral breast lesions as a predictive factor of familial breast cancer. 2042 20

Somatic mosaicism for DNA copy-number alterations (SMC-CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC-CNAs can undergo clonal expansion, it has been proposed that SMC-CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array-based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC-CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC-CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC-CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co-occurrence of gross SMC-CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.
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PMID:Concurrent DNA Copy-Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients. 2621 65


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