PTEN (phosphatase and tensin homolog deleted on chromosome ten)

Review on PTEN (phosphatase and tensin homolog deleted on chromosome ten), with data on DNA, on the protein encoded, and where the gene is implicated

Student use of Brühl Boulevard Chemnitz

Diese Bachelor Arbeit, soll durch die genaue Betrachtung des Standortumfeldes (insbesondere des Brühl Boulevards), die Auseinandersetzung mit der Zielgruppe Studenten und der Identifikation möglicher Investoren Anregungen, den Verkauf des Gebäudes August-Bebel Str. 11 -13 betreffend, geben

Breast tumors: an overview

Review on Breast tumors: an overview, with data on clinics, and the genes involved

Identification of gene polymorphisms of human DNA topoisomerase I in the National Cancer Institute panel of human tumour cell lines

Topoisomerase 1 (Top1), a nuclear enzyme involved in DNA relaxation, is the target of several anticancer drugs. TOP1 mutations occur in camptothecin-resistant tumour cell lines. We explored, in the NCI panel of 60 human tumour cell lines, whether polymorphic variations in the TOP1 gene could explain differences in drug sensitivity. The 21 exons of the gene were fully studied as well as five intronic domains that had previously been shown to harbour single nucleotide polymorphisms (SNPs) or mutations. PCR products covering the whole exonic sequences or the relevant intronic domains were subjected to denaturing high-performance liquid chromatography. Nucleotide variations were then determined by sequencing. Discrimination between intronic common and variant homozygous samples was performed using a restriction fragment length polymorphism technique. Only one exonic mutation was detected, at the heterozygous state; it occurs in exon 19 of a colon cancer cell line (HCT-15) and consists of a G>A transition at position 75, resulting in a Met675Ile change. The intronic sequences studied harboured the SNPs expected with allelic frequencies between 20 and 40%. Three major haplotypes, generating 92% of the 10 genotypes encountered, were defined as containing none of the intronic SNPs, or three of them, or all of them. No significant relationship was evidenced between Top1 expression and the TOP1 polymorphisms studied. However, when comparing the cytotoxicity of 138 drugs as a function of the genotypes, several drug groups, namely Top1 inhibitors, antifolates and taxanes, had significantly different IC50s as a function of the distribution of the intronic SNPs of the TOP1 gene

The Isolation of Nucleic Acids from Fixed, Paraffin-Embedded Tissues–Which Methods Are Useful When?

Museums and pathology collections around the world represent an archive of genetic material to study populations and diseases. For preservation purposes, a large portion of these collections has been fixed in formalin-containing solutions, a treatment that results in cross-linking of biomolecules. Cross-linking not only complicates isolation of nucleic acid but also introduces polymerase “blocks” during PCR. A wide variety of methods exists for the recovery of DNA and RNA from archival tissues, and although a number of previous studies have qualitatively compared the relative merits of the different techniques, very few have undertaken wide scale quantitative comparisons. To help address this issue, we have undertaken a study that investigates the quality of nucleic acids recovered from a test panel of fixed specimens that have been manipulated following a number of the published protocols. These include methods of pre-treating the samples prior to extraction, extraction and nucleic acid purification methods themselves, and a post-extraction enzymatic repair technique. We find that although many of the published methods have distinct positive effects on some characteristics of the nucleic acids, the benefits often come at a cost. In addition, a number of the previously published techniques appear to have no effect at all. Our findings recommend that the extraction methodology adopted should be chosen carefully. Here we provide a quick reference table that can be used to determine appropriate protocols for particular aims

A refined molecular taxonomy of breast cancer

The current histoclinical breast cancer classification is simple but imprecise. Several molecular classifications of breast cancers based on expression profiling have been proposed as alternatives. However, their reliability and clinical utility have been repeatedly questioned, notably because most of them were derived from relatively small initial patient populations. We analyzed the transcriptomes of 537 breast tumors using three unsupervised classification methods. A core subset of 355 tumors was assigned to six clusters by all three methods. These six subgroups overlapped with previously defined molecular classes of breast cancer, but also showed important differences, notably the absence of an ERBB2 subgroup and the division of the large luminal ER+ group into four subgroups, two of them being highly proliferative. Of the six subgroups, four were ER+/PR+/AR+, one was ER−/PR−/AR+ and one was triple negative (AR−/ER−/PR−). ERBB2-amplified tumors were split between the ER−/PR−/AR+ subgroup and the highly proliferative ER+ LumC subgroup. Importantly, each of these six molecular subgroups showed specific copy-number alterations. Gene expression changes were correlated to specific signaling pathways. Each of these six subgroups showed very significant differences in tumor grade, metastatic sites, relapse-free survival or response to chemotherapy. All these findings were validated on large external datasets including more than 3000 tumors. Our data thus indicate that these six molecular subgroups represent well-defined clinico-biological entities of breast cancer. Their identification should facilitate the detection of novel prognostic factors or therapeutical targets in breast cancer

Molecular apocrine differentiation is a common feature of breast cancer in patients with germline PTEN mutations

International audienceINTRODUCTION: Breast carcinoma is the main malignant tumor occurring in patients with Cowden disease, a cancer-prone syndrome caused by germline mutation of the tumor suppressor gene PTEN characterized by the occurrence throughout life of hyperplastic, hamartomatous and malignant growths affecting various organs. The absence of known histological features for breast cancer arising in a PTEN-mutant background prompted us to explore them for potential new markers. METHODS: We first performed a microarray study of three tumors from patients with Cowden disease in the context of a transcriptomic study of 74 familial breast cancers. A subsequent histological and immunohistochemical study including 12 additional cases of Cowden disease breast carcinomas was performed to confirm the microarray data. RESULTS: Unsupervised clustering of the 74 familial tumors followed the intrinsic gene classification of breast cancer except for a group of five tumors that included the three Cowden tumors. The gene expression profile of the Cowden tumors shows considerable overlap with that of a breast cancer subgroup known as molecular apocrine breast carcinoma, which is suspected to have increased androgenic signaling and shows frequent ERBB2 amplification in sporadic tumors. The histological and immunohistochemical study showed that several cases had apocrine histological features and expressed GGT1, which is a potential new marker for apocrine breast carcinoma. CONCLUSIONS: These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers