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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic instability resulting in chromosome aneuploidy or mismatch repair deficiency characterizes cancer. Medullary carcinoma (MC) of the breast is a specific form of breast cancer with unique clinical, epidemiologic, and prognostic features, suggesting distinctive tumorigenic pathways. To investigate the nature of the genetic changes associated with MC we analyzed a series of 22 tumors. Chromosomal imbalances were assessed by comparative genomic hybridization (CGH) and mismatch repair (MMR) deficiency tested for through assessment of microsatellite instability (MSI) and expression of MLH1 and MSH2 genes. MMR deficiency was detected in only a small proportion of cases. The chromosomal copy number changes showed some similarities to BRCA1-associated tumors. A high level of BRCA1 promoter hypermethylation was detected, suggesting a possible role of this gene in MC development.
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PMID:Distinct genetic and epigenetic changes in medullary breast cancer. 1289 46

A prospective study of psychosocial consequences following predictive testing for inherited mutations in breast/ovarian and colon cancer susceptibility genes BRCA1, BRCA2, MLH1, and MSH2 was performed. Eighty-seven healthy women were tested for known family mutations and self-assessment scales were used to evaluate anxiety, depression and quality of life. Extensive pre- and post-test information was given. Questionnaires were responded before testing and four times after during the following year. A statistically significant decrease in anxiety mean scores over time was observed among the studied participants. The levels of depression in cancer genes carriers decreased over time while, surprisingly the levels in non-carriers increased. Compared to a normative Swedish sample all women tested showed similar levels of anxiety but women tested for breast cancer genes showed statistically lower levels of depression. Vitality dropped initially after disclosure of the testing of colon cancer genes carriers, followed by increasing levels. No change in vitality or in other quality of life parameters was seen in the other groups and the levels were similar to Swedish norm data. Most tested individuals were satisfied with the testing procedure including genetic counselling and testing and all of them but one would redo the testing. Healthy self-referred women going through predictive breast/ovarian or colon cancer gene testing, including extensive pre- and post-test information and support, in general, will not experience adverse psychological consequences.
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PMID:Evaluation of psychosocial effects of pre-symptomatic testing for breast/ovarian and colon cancer pre-disposing genes: a 12-month follow-up. 1534 Feb 61

The molecular background of sporadic endometrial cancer coexisting with colorectal or breast cancer is not clear. We investigated microsatellite instability (MSI) and status of mismatch repair (MMR) gene product, MLH1, MSH2 and MSH6, in 63 sporadic endometrial cancers coexisting with colorectal or breast cancer. Sixteen sporadic endometrial cancers with colorectal cancers (EC), 26 sporadic endometrial cancers with breast cancer (EB) and 21 endometrial cancers without a coexisting cancer (control) were analyzed. EC had the highest frequency of MSI among the 3 groups (EC, 69%; EB, 23%; and control, 43%). Incidence of low-frequency MSI was significantly higher in EC (38%). Among endometrial cancer cases diagnosed before age 50, all high-frequency MSI (MSI-H) cases belonged to EC. Interestingly, incidence of MSI-H was significantly higher in tamoxifen-non-treated cases (75%) than that of treated cases (14%). These results suggest that alterations in MMR genes appear to be involved in carcinogenesis of EC but seem to be uncommon in those of EB. Presence of MSI in sporadic endometrial cancer may be a useful marker to predict the risk of colorectal cancer.
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PMID:Microsatellite instability and expression of mismatch repair genes in sporadic endometrial cancer coexisting with colorectal or breast cancer. 1558 95

Mutational analysis of large multiexon genes without prevalent mutations is a laborious undertaking that requires the use of a high-throughput scanning technique. The Human Genome Project has enabled the development of powerful techniques for mutation detection in large multiexon genes. We have transferred heteroduplex analysis (HA) by conformation-sensitive gel electrophoresis of the two major breast cancer (BC) predisposing genes, BRCA1 and BRCA2, to a multicapillary DNA sequencer in order to increase the throughput of this technique. This new method that we have called heteroduplex analysis by capillary array electrophoresis (HA-CAE) is based on the use of multiplex-polymerase chain reaction (PCR), different fluorescent labels and HA in a 16-capillary DNA sequencer. To date, a total of 114 different DNA sequence variants (19 insertions/deletions and 95 single-nucleotide substitutions - SNS) of BRCA1 and BRCA2 from 431 unrelated BC families have been successfully detected by HA-CAE. In addition, we have optimized the multiplex-PCR conditions for the colorectal cancer genes MLH1 and MSH2 in order to analyze them by HA-CAE. Both genes have been amplified in 13 multiplex groups, which contain the 35 exons, and their corresponding flanking intronic sequences. MLH1 and MSH2 have been analyzed in nine hereditary nonpolyposis colorectal cancer patients, and we have found six different DNA changes: one complex deletion/insertion mutation in MLH1 exon 19 and another five SNS. Only the complex mutation and one SNS may be classified as cancer-prone mutations. Our experience has revealed that HA-CAE is a simple, fast, reproducible and sensitive method to scan the sequences of complex genes.
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PMID:Rapid mutation detection in complex genes by heteroduplex analysis with capillary array electrophoresis. 1593 82

Breast cancer is the most common malignancy which affects women. In 5-10% of all cases, breast cancer presents as a hereditary cancer syndrome. Since 1996, 68 families with suspicion of familial breast cancer have been referred to our department. In 5 of the 68 families (7.4%), the clinical diagnosis was hereditary breast ovarian cancer syndrome. In 17 families (25%), two or more breast cancer cases were present. Mutation screening of BRCA1 and BRCA2 in these families revealed a BRCA1 mutation (185delAG) in one family. Three families (4.4%) had a diagnosis of Li-Fraumeni syndrome and germline mutations in TP53 (Lys292Ile, Pro278Ser and Pro278Thr). Breast cancer occurred in a family with hereditary nonpolyposis colon carcinoma (HNPCC; Lynch syndrome) carrying an MLH1 mutation (IVS17-3G>C). Most of our families (41 families; 60.2%) had only one case with breast cancer or cystic adenoma (or both) and did not need counseling and DNA testing. In summary, in 10 of the 68 families in our series (14.7%), a germline mutation in a breast cancer predisposing gene was detected. Our data show the importance of detailed examination of clinical data, pedigree analyses, and molecular germline diagnostics for the counseling of breast cancer cases.
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PMID:Hereditary breast cancer syndromes in a Turkish population. Results of molecular germline analysis. 1599 73

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.
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PMID:Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents. 1622 97

Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.
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PMID:Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome. 1628 84

A 49-year-old woman presented with breast cancer. She is a member of a family with the hereditary nonpolyposis colorectal cancer syndrome for which a 2-base pair deletion in exon 11 of the mismatch repair gene MSH2 (c1705_1706 delGA) had been identified. Breast cancer is rare in the hereditary nonpolyposis colorectal cancer syndrome. Microsatellite analysis of the tumor showed a microsatellite instable pattern for markers Bat25, Bat26, and Bat40, and no changes for markers D2S123 and D5S346, a so-called microsatellite instability-high pattern. Immunohistochemical staining for the mismatch repair enzymes MSH2 and MSH6 was negative, whereas the tumor cells were positive for MLH1, a pattern suggestive for biallelic MSH2 gene inactivation. We tested the tumor for loss of heterozygosity of the MSH2 gene and found loss of the wild-type MSH2 allele. These data strongly suggest that the MSH2 gene was involved in the development of this breast tumor.
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PMID:Breast cancer in an MSH2 gene mutation carrier. 1631 Nov 27

We assessed the association between breast cancer (BC) and colorectal cancer (CRC) from referral pattern to the Regional Genetics Service including molecular analysis. Hospital computer records and/or department referral books were used to identify cases referred to the Regional Genetic Service during a 16-year period (1990-2005 inclusive). All files were reviewed along with associated demographic data, risk assessments, referral details and results from mutation testing. Families were assessed for hereditary breast and colorectal cancer (HBCC) criteria, and all families with eligible individuals were tested for the 1100delC mutation in CHEK2. A total of 8,612 families were identified. One hundred and sixteen of 1,631 (7.5%) families with a primary referral for CRC fulfilled the criteria for HBCC, whereas only 68/6981 (1%) BC referrals fulfilled these criteria. Blood samples were obtained from 113 individuals from 83/184 families. Only 1/113 (1%) has screened positive for the CHEK2 mutation, whereas 14 (17%) families segregate BRCA1/2 mutations and at least 7 (8.5%) carry MLH1/MSH2 mutations. HBCC syndrome, if it exists as a separate entity, is not likely to be due to CHEK2 mutations. Many families are explicable by existing high-penetrance genes, and further work is necessary to elucidate whether the remainder is due to chance or as yet undiscovered genes.
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PMID:Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high-penetrance genes. 1702 20

The objective is to determine the relationship between obesity and defects in DNA mismatch repair (MMR) in women with endometrial cancer and to establish whether our previous finding of a higher rate of previous malignancy in thinner women with endometrial cancer is related to these factors. Specimens from 109 patients with primary uterine cancer were used to create a tissue microarray, which was stained with antibodies against MMR genes MLH1, MSH2, MSH6, and PMS2. Genotyping of normal and tumor tissues for microsatellite instability (MSI) was performed. Patients were stratified by body mass index (BMI) and correlated with a history of previous malignancy and defects in MMR. The average BMI of the overall population was 33 kg/m(2). Defective MMR was seen in 22% of tumors. The mean BMI in patients with tumors with MSI was 30.5, compared with 33.8 in microsatellite stable (MSS) tumors (P= 0.06); MSS tumors were more commonly seen in patients with a BMI more than 40 (25% vs 5% in patients with tumors with MSI, P= 0.07). Prior to their diagnosis of endometrial cancer, 16/109 (15%) patients reported having a prior malignancy, 11 (69%) had breast cancer, and 1 had colorectal cancer. Patients with tumors with MSI had previous cancer in 17% of cases, compared with 14% of patients with MSS tumors (P= 0.75). Our previous finding of an increased rate of prior malignancy in thinner patients with endometrial cancer does not appear to be due to alterations in MMR, and hereditary nonpolyposis colorectal cancer-associated cancers are rarely the prior malignancy.
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PMID:Correlation between patient weight and defects in DNA mismatch repair: is this the link between an increased risk of previous cancer in thinner women with endometrial cancer? 1746 51


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