One of the main problems in the analysis of real data is often related to the presence of anomalies. Namely, anomalous cases can both spoil the resulting analysis and contain valuable information at ...the same time. In both cases, the ability to detect these occurrences is very important. In the biomedical field, a correct identification of outliers could allow the development of new biological hypotheses that are not considered when looking at experimental biological data. In this work, we address the problem of detecting outliers in gene expression data, focusing on microarray analysis. We propose an ensemble approach for detecting anomalies in gene expression matrices based on the use of Hierarchical Clustering and Robust Principal Component Analysis, which allows us to derive a novel pseudo-mathematical classification of anomalies.
The role of macrophages (Mo) and their prognostic impact in diffuse large B‐cell lymphomas (DLBCL) remain controversial. By regulating the lipid metabolism, Liver‐X‐Receptors (LXRs) control Mo ...polarization/inflammatory response, and their pharmacological modulation is under clinical investigation to treat human cancers, including lymphomas. Herein, we surveyed the role of LXRs in DLBCL for prognostic purposes. Comparing bulk tumors with purified malignant and normal B‐cells, we found an intriguing association of NR1H3, encoding for the LXR‐α isoform, with the tumor microenvironment (TME). CIBERSORTx‐based purification on large DLBCL datasets revealed a high expression of the receptor transcript in M1‐like pro‐inflammatory Mo. By determining an expression cut‐off of NR1H3, we used digital measurement to validate its prognostic capacity on two large independent on‐trial and real‐world cohorts. Independently of classical prognosticators, NR1H3high patients displayed longer survival compared with NR1H3low cases and a high‐resolution Mo GEP dissection suggested a remarkable transcriptional divergence between subgroups. Overall, our findings indicate NR1H3 as a Mo‐related biomarker identifying patients at higher risk and prompt future preclinical studies investigating its mouldability for therapeutic purposes.
To evaluate the contribution of germline BRCA1 mutations in the incidence of hereditary and familial Breast Cancer (BC) and/or Ovarian Cancer (OC) in patients from Southern Italy (in the region of ...Sicily) and to identify a possible association between the higher frequency of BRCA1 mutations and a specific familial profile.
A consecutive series of 650 patients with BC and/or OC diagnosed between 1999 and 2005 were recruited from the Southern Italian region of Sicily, after interview at the "Regional Reference Centre for the Characterization and Genetic Screening of Hereditary Tumors" at the University of Palermo. Genetic counselling allowed us to recruit a total of 106 unrelated families affected with breast and/or ovarian cancer screened for mutations occurring in the whole BRCA1 gene by automatic direct sequencing.
Germline BRCA1 mutations were found in 17 of 106 (16%) Sicilian families. The HBOC profile had a major frequency (66%) of mutations (P < 0.01). A total of 28 sequence variants was identified. Seven of these were pathogenic, 5 unknown biological variant (UV) and 16 polymorphisms. We also identified a pathological mutation (4843delC) as a possible Sicilian founder mutation.
The present study is the first BRCA1 disease-associated mutations analysis in Southern Italian families. The early age of onset of such tumors and the association with the HBOC familial profile could be two valid screening factors for the identification of BRCA1 mutation carriers. Finally, we identified a BRCA1 mutation with a possible founder effect.
A group of 103 sicilian patients with hereditary and familiar breast and/or ovarian cancer were screened for Breast Cancer 1 gene (BRCA1) mutations by direct sequencing PCR products spanning the ...coding region and partial intronic regions of the BRCA1 gene. In this study, we report a new germline mutation in BRCA1 gene, not previously reported in the BIC database, in a woman with ovarian cancer at 46 years old. Mother's proband has been diagnosed the same histotype of ovarian cancer at 42 age. The mutational analyses that shown a 4843delC frameshift mutation in exon 16 of BRCA1 gene was extended to other family members including the proband's brother and her two sons. Direct automatic sequencing of DNA extracted from the lymphocytes showed exactly the same 4843delC frameshift mutation only in the brother. In conclusion, the characterization of this mutation could help in the identification of a founder mutation of sicilian area and this may provide significant advantages for genetic counselling.
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