Publications by authors named "Valentina Silvestri"

54 Publications

Face in collision: emotional looming stimuli modulate interpersonal space across development and gender.

Psychol Res 2021 Sep 29. Epub 2021 Sep 29.

Department of Psychology, University of Milan-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126, Milan, Italy.

Basic visual functions have evolved to allow for rapid detection of dynamic stimuli in our surrounding environment. In particular, looming stimuli are of relevance because they are expected to enter the individual's interpersonal space representing a potential threat. Different studies showed that emotions can modulate the perception of visual looming stimuli and the borders of interpersonal space, defined as the area around the body that individuals maintain between themselves and others during social interactions. Here, we investigated how emotions modulate the perception and the physiological correlates of interpersonal space and whether such indexes change across age and gender. Children and adults were asked to quickly react to emotional looming stimuli while measuring their skin conductance response (SCR). We found that emotional looming stimuli shrink the borders of interpersonal space of males more than females, and that this pattern does not change with age. In addition, adults reacted faster to angry than happy and neutral faces, which is in line with the notion that threatening stimuli capture attention more quickly than other types of emotional stimuli. However, this was not observed in children, suggesting that experience with negative stimuli, rather than the evolutionary meaning they possess, may influence the boundaries of interpersonal space. Overall, our study suggests that interpersonal space is modulated by emotions, but this appears to be modulated by gender and age: while behavioural responses to emotional looming stimuli refine with age, physiological responses are adult-like as early as 5 years of age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00426-021-01590-7DOI Listing
September 2021

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Cancers (Basel) 2021 Sep 8;13(18). Epub 2021 Sep 8.

Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly and . Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 6 , 2 , 1 , and 1 germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13184515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8469418PMC
September 2021

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

Pre-diagnostic DNA methylation patterns differ according to mammographic breast density amongst women who subsequently develop breast cancer: a case-only study in the EPIC-Florence cohort.

Breast Cancer Res Treat 2021 Sep 8;189(2):435-444. Epub 2021 Jun 8.

Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Via Cosimo il Vecchio 2, 50141, Florence, Italy.

Purpose: Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition.

Methods: We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III-IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a "candidate pathways" approach focusing on pre-defined inflammation-related pathways.

Results: In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The "apoptosis signalling" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women.

Conclusion: Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-021-06273-wDOI Listing
September 2021

60-S Retrogated Compressed Sensing 2D Cine of the Heart: Sharper Borders and Accurate Quantification.

J Clin Med 2021 May 29;10(11). Epub 2021 May 29.

University of Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-European Genomic Institute for Diabetes (EGID), F-59000 Lille, France.

Background And Objective: Real-time compressed sensing cine (CS) provides reliable quantification for both ventricles but may alter image quality. The aim of this study was to assess image quality and the accuracy of left (LV) and right ventricular (RV) volumes, ejection fraction and mass quantifications based on a retrogated segmented compressed sensing 2D cine sequence (CS).

Methods: Thirty patients were enrolled. Each patient underwent the reference retrogated segmented steady-state free precession cine sequence (SSFP), the real-time CS cine and the segmented retrogated prototype CS sequence providing the same slices. Functional parameters quantification and image quality rating were performed on SSFP and CS images sets. The edge sharpness, which is an estimate of the edge spread function, was assessed for the three sequences.

Results: The mean scan time was: SSFP = 485.4 ± 83.3 (SD) s (95% CI: 454.3-516.5) and CS = 58.3 ± 15.1 (SD) s (95% CI: 53.7-64.2) ( < 0.0001). CS subjective image quality score (median: 4; range: 2-4) was higher than the one provided by CS (median: 3; range: 2-4; = 0.0008) and not different from SSFP overall quality score (median: 4; range: 2-4; = 0.31). CS provided similar LV and RV functional parameters to those assessed with SSFP ( > 0.05). Edge sharpness was significantly better with CS (0.083 ± 0.013 (SD) pixel; 95% CI: 0.078-0.087) than with CS (0.070 ± 0.011 (SD) pixel; 95% CI: 0.066-0.074; = 0.0004) and not different from the reference technique (0.075 ± 0.016 (SD) pixel; 95% CI: 0.069-0.081; = 0.0516).

Conclusions: CS cine provides in one minute an accurate quantification of LV and RV functional parameters without compromising subjective and objective image quality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10112417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199407PMC
May 2021

Right Ventricular Volume and Function Assessment in Congenital Heart Disease Using CMR Compressed-Sensing Real-Time Cine Imaging.

J Clin Med 2021 Apr 29;10(9). Epub 2021 Apr 29.

University of Lille, Inserm, CHU Lille, Institut Pasteur Lille, U1011-European Genomic Institute for Diabetes (EGID), F-59000 Lille, France.

Background And Objective: To evaluate the reliability of compressed-sensing (CS) real-time single-breath-hold cine imaging for quantification of right ventricular (RV) function and volumes in congenital heart disease (CHD) patients in comparison with the standard multi-breath-hold technique.

Methods: Sixty-one consecutive CHD patients (mean age = 22.2 ± 9.0 (SD) years) were prospectively evaluated during either the initial work-up or after repair. For each patient, two series of cine images were acquired: first, the reference segmented multi-breath-hold steady-state free-precession sequence (SSFP), including a short-axis stack, one four-chamber slice, and one long-axis slice; then, an additional real-time compressed-sensing single-breath-hold sequence (CS) providing the same slices. Two radiologists independently assessed the image quality and RV volumes for both techniques, which were compared using the Wilcoxon test and paired Student's test, Bland-Altman, and linear regression analyses. The visualization of wall-motion disorders and tricuspid-regurgitation-related signal voids were also analyzed.

Results: The mean acquisition time for CS was 22.4 ± 6.2 (SD) s (95% CI: 20.8-23.9 s) versus 442.2 ± 89.9 (SD) s (95% CI: 419.2-465.2 s) for SSFP ( < 0.001). The image quality of CS was diagnostic in all examinations and was mostly rated as good ( = 49/61; 80.3%). There was a high correlation between SSFP and CS images regarding RV ejection fraction (49.8 ± 7.8 (SD)% (95% CI: 47.8-51.8%) versus 48.7 ± 8.6 (SD)% (95% CI: 46.5-50.9%), respectively; = 0.94) and RV end-diastolic volume (192.9 ± 60.1 (SD) mL (95% CI: 177.5-208.3 mL) versus 194.9 ± 62.1 (SD) mL (95% CI: 179.0-210.8 mL), respectively; = 0.98). In CS images, tricuspid-regurgitation and wall-motion disorder visualization was good (area under receiver operating characteristic curve (AUC) = 0.87) and excellent (AUC = 1), respectively.

Conclusions: Compressed-sensing real-time cine imaging enables, in one breath hold, an accurate assessment of RV function and volumes in CHD patients in comparison with standard SSFP, allowing a substantial improvement in time efficiency.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm10091930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125206PMC
April 2021

Gut microbiome profile in psoriatic patients treated and untreated with biologic therapy.

J Dermatol 2021 Jun 28;48(6):786-793. Epub 2021 Jan 28.

Unit of Dermatology, Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy.

There are increasing data about the role of the gut microbiome in various autoimmune diseases, including psoriasis, a chronic inflammatory and immune-mediated disease. Current treatment strategies in psoriasis include immunomodulating biologic agents. A variable response to this type of therapy has been reported in psoriatic patients. A possible effect of biologic therapy on the gut microbiome composition has been suggested, but data are still limited. The aim of this study was to compare the gut microbiome composition between psoriatic patients treated and untreated with biologic drugs in order to identify differences which may highlight the potential impact of the treatment on the gut microbiome. 16S rRNA sequencing and bioinformatic analyses were performed on the fecal samples of 30 psoriatic patients with similar clinicopathological features, 10 of whom were undergoing biologic therapy and 20 not receiving systemic therapy. Alpha and beta diversity significantly differed between the two groups of patients. A reduced bacterial biodiversity in the group of treated patients compared with the group of untreated patients was observed. Differential relative abundances of key gut microbial communities, including Akkermansia muciniphila and Bacteroides plebeius, were identified between the two groups of patients. This study showed that biologic therapy may have an impact on the composition of the gut microbiome of psoriatic patients. Gut microbiome composition could be used as an indicator of response to therapy and the modulation of the microbial composition could help to restore the intestinal symbiosis in psoriatic patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1346-8138.15680DOI Listing
June 2021

Single breath-hold compressed sensing real-time cine imaging to assess left ventricular motion in myocardial infarction.

Diagn Interv Imaging 2021 May 8;102(5):297-303. Epub 2020 Dec 8.

Department of Cardiovascular Radiology, Institut Cœur-Poumon, CHU de Lille, Boulevard du Pr Jules Leclercq, 59037 Lille Cedex, France; INSERM UMR 1011, Institut Pasteur de Lille, EGID (European Genomic Institute for Diabetes), FR3508, Univ. Lille, 59000 Lille, France. Electronic address:

Purpose: To evaluate the reliability of a real-time compressed sensing (CS) cine sequence for the detection of left ventricular wall motion disorders after myocardial infarction in comparison with the reference steady-state free precession cine sequence.

Materials And Methods: One hundred consecutive adult patients referred for either initial work-up or follow-up by cardiac magnetic resonance (CMR) in the context of myocardial infarction were prospectively included. There were 77 men and 23 women with a mean age of 63.12±11.3 (SD) years (range: 29-89 years). Each patient underwent the reference segmented multi-breath-hold steady-state free precession cine sequence including one short-axis stack and both vertical and horizontal long-axis slices (SSFP) and the CS real-time single-breath-hold evaluated sequence (CS) providing the same slices. Wall motion disorders were independently and blindly assessed with both sequences by two radiologists, using the American Heart Association left ventricle segmentation. Paired Wilcoxon signed-rank test was used to search for differences in wall motion disorders conspicuity between both sequences and receiver operating characteristic curve (ROC) analysis was performed to assess the diagnosis performance of CS sequence using SSFP as the reference method.

Results: Each patient had at least one cardiac segment with wall motion abnormality on SSFP and CS images. The 1700 segments analyzed with SSFP were classified as normokinetic (360/1700; 21.2%), hypokinetic (783/1700; 46.1%), akinetic (526/1700; 30.9%) or dyskinetic (31/1700; 1.8%). Sensitivity and specificity of the CS sequence were 99.6% (95% CI: 99.1-99.9%) and 99.7% (95% CI: 98.5-100%), respectively. Area under ROC of CS diagnosis performance was 0.997 (95% CI: 0.993-0.999).

Conclusion: CS real-time cine imaging significantly reduces acquisition time without compromising the conspicuity of left ventricular -wall motion disorders in the context of myocardial infarction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.diii.2020.11.012DOI Listing
May 2021

Targeting SMYD3 to Sensitize Homologous Recombination-Proficient Tumors to PARP-Mediated Synthetic Lethality.

iScience 2020 Oct 7;23(10):101604. Epub 2020 Oct 7.

Medical Genetics, National Institute of Gastroenterology "S. de Bellis" Research Hospital, Castellana Grotte, Bari 70013, Italy.

is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical animal models. However, extensive characterization failed to clarify function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a mutant variant identified in a high-risk breast cancer family, here we show that SMYD3 phosphorylation by ATM enables the formation of a multiprotein complex including ATM, SMYD3, CHK2, and BRCA2, which is required for the final loading of RAD51 at DNA double-strand break sites and completion of homologous recombination (HR). Remarkably, SMYD3 pharmacological inhibition sensitizes HR-proficient cancer cells to PARP inhibitors, thereby extending the potential of the synthetic lethality approach in human tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.isci.2020.101604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648160PMC
October 2020

Paradoxical Psoriasis Induced by Anti-TNFα Treatment: Evaluation of Disease-Specific Clinical and Genetic Markers.

Int J Mol Sci 2020 Oct 23;21(21). Epub 2020 Oct 23.

Clinic of Dermatology Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy.

Paradoxical psoriasis (PP) may occur during treatment with anti-tumor necrosis factor-alpha (TNF-α) drugs in various chronic immune-mediated diseases, mainly inflammatory bowel diseases (IBD) and psoriasis. In this study, clinical and genetic characteristics of PP arising in IBD and psoriatic patients were investigated to identify disease-specific markers of the paradoxical effect. A total of 161 IBD and psoriatic patients treated with anti-TNF-α drugs were included in the study. Of these patients, 39 developed PP. All patients were characterized for the main clinical-pathologic characteristics and genotyped for six candidate single nucleotide polymorphisms (SNPs) selected for their possible role in PP susceptibility. In IBD patients, the onset of PP was associated with female sex, presence of comorbidities, and use of adalimumab. IBD patients with PP had a higher frequency of the rs1799964 rare allele ( = 0.006) compared with cases without the paradoxical effect, and a lower frequency of the human leucocyte antigen ()- rs10484554 rare allele ( = 0.03) compared with psoriatic patients with PP. Overall, these findings point to specific clinical and genetic characteristics of IBD patients with PP and provide data showing that genetic variability may be related to the paradoxical effect of anti-TNF-α drugs with possible implications into clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21217873DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660646PMC
October 2020

Common Susceptibility Loci for Male Breast Cancer.

J Natl Cancer Inst 2021 04;113(4):453-461

Division of Oncology, Department of Clinical Sciences, Lund, Lund University and Skåne University Hospital, Lund, Sweden.

Background: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC.

Methods: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided.

Results: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30).

Conclusions: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jnci/djaa101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023850PMC
April 2021

Utility of Three-Dimensional Transesophageal Echocardiography for Mitral Annular Sizing in Transcatheter Mitral Valve Replacement Procedures: A Cardiac Computed Tomographic Comparative Study.

J Am Soc Echocardiogr 2020 10 25;33(10):1245-1252.e2. Epub 2020 Jul 25.

Department of Clinical Physiology and Echocardiography - Heart Valve Center, CHU Lille, Lille, France; Université de Lille, U1011 - EGID, Lille, France; Inserm, U1011, Lille, France; Institut Pasteur de Lille, Lille, France.

Background: Three-dimensional (3D) transesophageal echocardiographic (TEE) imaging is frequently used as an initial screening tool in the evaluation of patients who are candidates for transcatheter mitral valve replacement (TMVR). However, little is known about the imaging correlation with the gold standard, computed tomographic (CT) imaging. The aims of this study were to test the quantitative differences between these two modalities and to determine the best 3D TEE parameters for TMVR screening.

Methods: Fifty-seven patients referred to the heart valve clinic for TMVR with prostheses specifically designed for the mitral valve were included. Mitral annular (MA) analyses were performed using commercially available software on 3D TEE and CT imaging.

Results: Three-dimensional TEE imaging was feasible in 52 patients (91%). Although 3D TEE measurements were slightly lower than those obtained on CT imaging, measurements of both projected MA area and perimeter showed excellent correlations, with small differences between the two modalities (r = 0.88 and r = 0.92, respectively, P < .0001). Correlations were significant but lower for MA diameters (r = 0.68-0.72, P < .0001) and mitroaortic angle (r = 0.53, P = .0001). Receiver operating characteristic curve analyses showed that 3D TEE imaging had a good ability to predict TMVR screening success, defined by constructors on the basis of CT measurements, with ranges of 12.9 to 15 cm for MA area (area under the curve [AUC] = 0.88-0.91, P < .0001), 128 to 139 mm for MA perimeter (AUC = 0.85-0.91, P < .0001), 35 to 39 mm for anteroposterior diameter (AUC = 0.79-0.84, P < .0001), and 37 to 42 mm for posteromedial-anterolateral diameter (AUC = 0.81-0.89, P < .0001).

Conclusions: Three-dimensional TEE measurements of MA dimensions display strong correlations with CT measurements in patients undergoing TMVR screening. Three-dimensional TEE imaging should be proposed as a reasonable alternative to CT imaging in this vulnerable population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.echo.2020.04.030DOI Listing
October 2020

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

JAMA Oncol 2020 08;6(8):1218-1230

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, And Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes And Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions And Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaoncol.2020.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333177PMC
August 2020

An unusual left anterior descending artery myocardial bridging.

J Cardiovasc Comput Tomogr 2020 Sep - Oct;14(5):e78-e79. Epub 2019 May 10.

Centre Hémodynamique et Service des soins intensifs de cardiologie, Institut Cœur Poumon, Centre Hospitalier Universitaire de Lille, Lille, France; Faculté de médecine de Lille, université de Lille, Lille, France; Institut Pasteur de Lille, Inserm U1011, Lille, France; FACT (French Alliance for Cardiovascular Trials), Paris, France. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcct.2019.05.008DOI Listing
October 2020

Cancer Risks Associated With Germline Pathogenic Variants: An International Study of 524 Families.

J Clin Oncol 2020 03 16;38(7):674-685. Epub 2019 Dec 16.

Biopathologie, Centre Léon Bérard, Lyon, France.

Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline pathogenic variants (PVs) because these risks have not been extensively characterized.

Methods: We analyzed data from 524 families with PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

Results: We found associations between PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; = 6.5 × 10), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; = 4.1 × 10), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; = 8.7 × 10), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; = 2.6 × 10). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( for trend = 2.0 × 10). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

Conclusion: These results confirm as a major breast cancer susceptibility gene and establish substantial associations between germline PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of into risk prediction models and optimize the clinical cancer risk management of PV carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.19.01907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049229PMC
March 2020

Identification of novel large genomic rearrangements by a computational algorithm of amplicon-based Next-Generation Sequencing data.

PeerJ 2019 15;7:e7972. Epub 2019 Nov 15.

Department of Molecular Medicine, University of Roma "La Sapienza", Roma, Italy.

Background: Genetic testing for germline mutations in hereditary breast/ovarian cancer patients requires screening for single nucleotide variants, small insertions/deletions and large genomic rearrangements (LGRs). These studies have long been run by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The recent introduction of next-generation sequencing (NGS) platforms dramatically improved the speed and the efficiency of DNA testing for nucleotide variants, while the possibility to correctly detect LGRs by this mean is still debated. The purpose of this study was to establish whether and to which extent the development of an analytical algorithm could help us translating NGS sequencing via an Ion Torrent PGM platform into a tool suitable to identify LGRs in hereditary breast-ovarian cancer patients.

Methods: We first used NGS data of a group of three patients (training set), previously screened in our laboratory by conventional methods, to develop an algorithm for the calculation of the dosage quotient (DQ) to be compared with the Ion Reporter (IR) analysis. Then, we tested the optimized pipeline with a consecutive cohort of 85 uncharacterized probands (validation set) also subjected to MLPA analysis. Characterization of the breakpoints of three novel LGRs was obtained via long-range PCR and direct sequencing of the DNA products.

Results: In our cohort, the newly defined DQ-based algorithm detected 3/3 LGRs, demonstrating 100% sensitivity and 100% negative predictive value (NPV) (95% CI [87.6-99.9]) compared to 2/3 cases detected by IR (66.7% sensitivity and 98.2% NPV (95% CI [85.6-99.9])). Interestingly, DQ and IR shared 12 positive results, but exons deletion calls matched only in five cases, two of which confirmed by MLPA. The breakpoints of the 3 novel deletions, involving exons 16-17, 21-22 and 20, have been characterized.

Conclusions: Our study defined a DQ-based algorithm to identify LGRs using NGS data. Whether confirmed on larger data sets, this tool could guide the selection of samples to be subjected to MLPA analysis, leading to significant savings in time and money.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7717/peerj.7972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859874PMC
November 2019

Association of Genomic Domains in and with Prostate Cancer Risk and Aggressiveness.

Cancer Res 2020 02 13;80(3):624-638. Epub 2019 Nov 13.

Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France.

Pathogenic sequence variants (PSV) in or () are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 and 171 male PSV carriers with prostate cancer, and 3,388 and 2,880 male PSV carriers without prostate cancer. PSVs in the 3' region of (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25-2.52; = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; = 0.0002). No genotype-phenotype associations were detected for PSVs in . These results demonstrate that specific PSVs may be associated with elevated risk of developing aggressive prostate cancer. SIGNIFICANCE: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-1840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553241PMC
February 2020

Compressed sensing real-time cine imaging for assessment of ventricular function, volumes and mass in clinical practice.

Eur Radiol 2020 Jan 1;30(1):609-619. Epub 2019 Aug 1.

Department of Cardiovascular Radiology, Institut Cœur-Poumon, CHU Lille, Boulevard du Pr Jules Leclercq, 59037, Lille Cedex, France.

Objectives: This study was conducted in order to evaluate the accuracy of a compressed sensing (CS) real-time single-breath-hold cine sequence for the assessment of left and right ventricular functional parameters in daily practice.

Methods: Cardiac magnetic resonance (CMR) cine images were acquired from 100 consecutive patients using both the reference segmented multi-breath-hold steady-state free precession (SSFP) acquisition and a prototype single-breath-hold real-time CS sequence, providing the same slice number, position, and thickness. For both sequences, the left (LV) and right ventricular (RV) ejection fractions (EF) and end-diastolic volumes (EDV) were assessed as well as LV mass (LVM). The visualization of wall-motion disorders (WMD) and signal void related to mitral or tricuspid regurgitation was also analyzed.

Results: The CS sequence mean scan time was 23 ± 6 versus 510 ± 109 s for the multi-breath-hold SSFP sequence (p < 0.001). There was an excellent correlation between the two sequences regarding mean LVEF (r = 0.995), LVEDV (r = 0.997), LVM (r = 0.981), RVEF (r = 0.979), and RVEDV (r = 0.983). Moreover, inter- and intraobserver agreements were very strong with intraclass correlations of 0.96 and 0.99, respectively. On CS images, mitral or tricuspid regurgitation visualization was good (AUC = 0.85 and 0.81, respectively; ROC curve analysis) and wall-motion disorder visualization was excellent (AUC ≥ 0.97).

Conclusion: CS real-time single-breath-hold cine imaging reduces CMR scan duration by almost 20 times in daily practice while providing reliable measurements of both left and right ventricles. There was no clinically relevant information loss regarding valve regurgitation and wall-motion disorder depiction.

Key Points: • Compressed sensing single-breath-hold real-time cine imaging is a reliable sequence in daily practice. • Fast CS real-time imaging reduces CMR scan time and improves patient workflow. • There is no clinically relevant information loss with CS regarding heart valve regurgitation or wall-motion disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00330-019-06341-2DOI Listing
January 2020

MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas.

Anticancer Res 2019 Aug;39(8):4085-4093

Department of Internal Medicine and Medical Specialties, Unit of Dermatology, "Sapienza" University of Rome, Rome, Italy.

Background/aim: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors.

Materials And Methods: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR.

Results: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.13566DOI Listing
August 2019

Evaluation of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk.

Endocr Connect 2019 Aug;8(8):1224-1229

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/EC-19-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733362PMC
August 2019

Insight into genetic susceptibility to male breast cancer by multigene panel testing: Results from a multicenter study in Italy.

Int J Cancer 2019 07 24;145(2):390-400. Epub 2019 Jan 24.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Breast cancer (BC) in men is rare and genetic predisposition is likely to play a relevant role in its etiology. Inherited mutations in BRCA1/2 account for about 13% of all cases and additional genes that may contribute to the missing heritability need to be investigated. In our study, a well-characterized series of 523 male BC (MBC) patients from the Italian multicenter study on MBC, enriched for non-BRCA1/2 MBC cases, was screened by a multigene custom panel of 50 cancer-associated genes. The main clinical-pathologic characteristics of MBC in pathogenic variant carriers and non-carriers were also compared. BRCA1/2 pathogenic variants were detected in twenty patients, thus, a total of 503 non-BRCA1/2 MBC patients were examined in our study. Twenty-seven of the non-BRCA1/2 MBC patients were carriers of germline pathogenic variants in other genes, including two APC p.Ile1307Lys variant carriers and one MUTYH biallelic variant carrier. PALB2 was the most frequently altered gene (1.2%) and PALB2 pathogenic variants were significantly associated with high risk of MBC. Non-BRCA1/2 pathogenic variant carriers were more likely to have personal (p = 0.0005) and family (p = 0.007) history of cancer. Results of our study support a central role of PALB2 in MBC susceptibility and show a low impact of CHEK2 on MBC predisposition in the Italian population. Overall, our data indicate that a multigene testing approach may benefit from appropriately selected patients with implications for clinical management and counseling of MBC patients and their family members.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32106DOI Listing
July 2019

Contribution of Variants to Male Breast Cancer Risk: Results From a Multicenter Study in Italy.

Front Oncol 2018 4;8:583. Epub 2018 Dec 4.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Inherited mutations in , and, mainly, genes are associated with increased risk of male breast cancer (MBC). Mutations in and genes may also increase MBC risk. Overall, these genes are functionally linked to DNA repair pathways, highlighting the central role of genome maintenance in MBC genetic predisposition. is a DNA repair gene whose biallelic germline variants cause MUTYH-associated polyposis (MAP) syndrome. Monoallelic variants have been reported in families with both colorectal and breast cancer and there is some evidence on increased breast cancer risk in women with monoallelic variants. In this study, we aimed to investigate whether germline variants may contribute to MBC susceptibility. To this aim, we screened the entire coding region of in 503 mutation negative MBC cases by multigene panel analysis. Moreover, we genotyped selected variants, including p.Tyr179Cys, p.Gly396Asp, p.Arg245His, p.Gly264Trpfs7, and p.Gln338His, in a total of 560 MBC cases and 1,540 male controls. Biallelic pathogenic variants (p.Tyr179Cys/p.Arg241Trp) were identified in one MBC patient with phenotypic manifestation of adenomatous polyposis. Monoallelic pathogenic variants were identified in 14 (2.5%) MBC patients, in particular, p.Tyr179Cys was detected in seven cases, p.Gly396Asp in five cases, p.Arg245His and p.Gly264Trpfs7 in one case each. The majority of MBC cases with pathogenic variants had family history of cancer including breast, colorectal, and gastric cancers. In the case-control study, an association between the variant p.Tyr179Cys and increased MBC risk emerged by multivariate analysis [odds ratio (OR) = 4.54; 95% confidence interval (CI): 1.17-17.58; = 0.028]. Overall, our study suggests that pathogenic variants may have a role in MBC and, in particular, the p.Tyr179Cys variant may be a low/moderate penetrance risk allele for MBC. Moreover, our results suggest that MBC may be part of the tumor spectrum associated with MAP syndrome, with implication in the clinical management of patients and their relatives. Large-scale collaborative studies are needed to validate these findings.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2018.00583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288482PMC
December 2018

Metastases risk in thin cutaneous melanoma: prognostic value of clinical-pathologic characteristics and mutation profile.

Oncotarget 2018 Aug 14;9(63):32173-32181. Epub 2018 Aug 14.

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Background: A high percentage of patients with thin melanoma (TM), defined as lesions with Breslow thickness ≤1 mm, presents excellent long-term survival, however, some patients develop metastases. Existing prognostic factors cannot reliably differentiate TM patients at risk for metastases.

Objective: We aimed at characterizing the clinical-pathologic and mutation profile of metastatic and not-metastatic TM in order to distinguish lesions at risk of metastases.

Methods: Clinical-pathologic characteristics were recorded for the TM cases analyzed. We used a Next Generation Sequencing (NGS) multi-gene panel to characterize TM for multiple somatic mutations.

Results: A statistically significant association emerged between the presence of metastases and Breslow thickness ≥0.6 mm (). None of TM with lymph-node involvement had Breslow thickness <0.6 mm. Somatic mutations were identified in 19 of 21 TM analyzed (90.5%). No mutations were observed in two not-metastatic cases with the lowest Breslow thickness (≤0.4 mm), whereas mutations in more than one gene were detected in one metastatic case with the highest Breslow thickness (1.00 mm).

Conclusion: Our study indicates Breslow thickness ≥0.6 mm as a valid prognostic factor to distinguish TM at risk for metastases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.25864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6114949PMC
August 2018

c.3140A>G mutation in a patient with suspected Proteus Syndrome: a case report.

Clin Case Rep 2018 Jul 2;6(7):1358-1363. Epub 2018 Jun 2.

Department of Molecular Medicine Sapienza University of Rome Rome Italy.

We present a patient with suspected Proteus Syndrome, an overgrowth disorder associated with mutation. NGS analysis detected mutation in the patient's affected tissue allowing for PROS (PIK3CA-related overgrowth spectrum) diagnosis. The overlapping clinical features in overgrowth disorders highlight the importance of molecular testing for a correct diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.1546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028416PMC
July 2018

Gene-specific methylation profiles in -mutation positive and -mutation negative male breast cancers.

Oncotarget 2018 Apr 13;9(28):19783-19792. Epub 2018 Apr 13.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from female breast cancer (FBC). Increasing evidence indicate that on molecular level MBC may be an heterogeneous disease different from FBC. In order to investigate whether epigenetic signatures could define molecular subgroups of MBCs, we performed promoter methylation analysis of genes involved in signal transduction and hormone signalling in mutation-positive and -negative MBCs. We examined 69 MBCs, paired blood samples, and 15 normal tissues for promoter methylation of and genes. MBCs showed higher gene promoter methylation levels compared to paired blood and normal breast samples. Significantly higher methylation levels were observed in association with mutations, HER2 expression and high tumor grade. Significantly higher methylation levels were observed in wild-type cases and higher methylation levels in PR negative cases. Overall, our results indicate that alterations in gene methylation profiles are common in MBC and that methylation pattern of tumor-associated genes may allow for the identification of MBC molecular subgroups, that could have implications in clinical management of MBC patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/oncotarget.24856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5929425PMC
April 2018

Smoking and FGFR2 rs2981582 variant independently modulate male breast cancer survival: A population-based study in Tuscany, Italy.

Breast 2018 Aug 28;40:85-91. Epub 2018 Apr 28.

Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for cancer research, prevention and clinical network (ISPRO), Via Delle Oblate 4, 50141 Florence, Italy.

Aim: Male breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population-based series of 166 MBCs enrolled in Tuscany.

Methods: We genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis.

Results: Only smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45-7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93-4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13-0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results.

Conclusions: Our results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2018.04.017DOI Listing
August 2018

A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy.

Breast 2018 Apr 4;38:92-97. Epub 2018 Jan 4.

Department of Molecular Medicine, Sapienza University of Rome, Italy. Electronic address:

Introduction: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility.

Methods: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls.

Results: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%).

Conclusion: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.breast.2017.12.013DOI Listing
April 2018

Primary Peritoneal Serous Carcinoma in Men: A Rare and Non--associated Entity.

Anticancer Res 2017 06;37(6):3069-3072

Oncogenetics Unit, Chaim Sheba Medical Center, Tel-Hashomer, Israel

Background: Primary peritoneal serous carcinoma (PPSC) is a rare neoplasm. The paucity of reported cases among men may provide insight to the cell of origin of PPSC.

Materials And Methods: A search for the ICD 0-3 code of PPSC (C48.2) in the following datasets: the Israeli National Cancer registry (INCR), the Surveillance, Epidemiology, and End Results (SEER) database in the USA, Israeli male BRCA carriers, male high-risk and BRCA carriers in a USA study, and the Italian Study on Male Breast Cancer (MBC) were performed.

Results: In the INCR dataset, 220 entries for C48.2 code were noted, with only one male (male:female ratio=0.0045). In the SEER dataset for histology codes of papillary/serous/ adenocarcinoma, 2,673 cases were recorded, with five males (male:female ratio=0.0018). None of the recorded US or Italian male BRCA carriers or MBC, or Israeli male BRCA carriers was diagnosed with PPSC.

Conclusion: PPSC is a rare neoplasm, seemingly not associated with BRCA mutations in men, and fallopian tube epithelial cell implants may contribute to its development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/anticanres.11662DOI Listing
June 2017

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

J Clin Oncol 2017 Jul 27;35(20):2240-2250. Epub 2017 Apr 27.

Julie Lecarpentier, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Goska Leslie, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Debra Frost, Steve Ellis, Douglas F. Easton, and Antonis C. Antoniou, University of Cambridge; Karoline B. Kuchenbaecker, The Wellcome Trust Sanger Institute, Hinxton; Marc Tischkowitz, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge; D. Gareth Evans, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester; Alex Henderson, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne; Carole Brewer, Royal Devon and Exeter Hospital, Exeter; Diana Eccles, Southampton University Hospitals NHS Trust, Southampton; Jackie Cook, Sheffield Children's Hospital, Sheffield; Kai-ren Ong, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham; Lisa Walker, Churchill Hospital, Oxford; Lucy E. Side, Great Ormond Street Hospital for Children NHS Trust; Shirley Hodgson, St George's, University of London; Louise Izatt, Guy's and St Thomas' NHS Foundation Trust; Ros Eeles, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Nick Orr, The Institute of Cancer Research, London; Mary E. Porteous, Western General Hospital, Edinburgh; Rosemarie Davidson, South Glasgow University Hospitals, Glasgow; Julian Adlard, Chapel Allerton Hospital, Leeds, United Kingdom; Valentina Silvestri, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, and Laura Ottini, Sapienza University of Rome, Rome; Angela Toss, Veronica Medici, and Laura Cortesi, University of Modena and Reggio Emilia, Modena; Ines Zanna and Domenico Palli, Cancer Research and Prevention Institute, Florence; Paolo Radice, Siranoush Manoukian, Bernard Peissel, and Jacopo Azzollini, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale Tumori (INT); Paolo Peterlongo, Italian Foundation for Cancer Research Institute of Molecular Oncology (IFOM), Milan; Alessandra Viel and Giulia Cini, CRO Aviano, National Cancer Institute, Aviano; Giuseppe Damante, University of Udine, Udine; Stefania Tommasi, Istituto Nazionale Tumori "Giovanni Paolo II", Bari; Elisa Alducci, Silvia Tognazzo, and Marco Montagna, Veneto Institute of Oncology IOV - IRCCS, Padua; Maria A. Caligo, University and University Hospital of Pisa, Pisa, Italy; Penny Soucy and Jacques Simard, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec; Anna Marie Mulligan and Irene L. Andrulis, University of Toronto; Gord Glendon and Irene L. Andrulis, Mount Sinai Hospital, Toronto, Ontario, Canada; Melissa Southey, Ian Campbell, Paul James, and Gillian Mitchell, University of Melbourne, Parkville, Victoria; Amanda B. Spurdle, Helene Holland, and Georgia Chenevix-Trench, QIMR Berghofer Medical Research Institute, Brisbane, Queensland; Ian Campbell, Paul James, and Gillian Mitchell, Peter MacCallum Cancer Centre, East Melbourne, New South Wales, Australia; Esther M. John, Cancer Prevention Institute of California, Fremont; Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, and Jeffrey N. Weitzel, City of Hope, Duarte, CA; Thomas A. Conner and Saundra S. Buys, Huntsman Cancer Institute; David E. Goldgar, University of Utah School of Medicine, Salt Lake City, UT; Andrew K. Godwin, University of Kansas Medical Center, Kansas City; Priyanka Sharma, University of Kansas Medical Center, Westwood, KS; Timothy R. Rebbeck, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute, Boston, MA; Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, and Kenneth Offit, Memorial Sloan Kettering Cancer Center, New York, NY; Jennifer T. Loud and Mark H. Greene, National Cancer Institute, Bethesda, MD; Amanda Ewart Toland and Leigha Senter, The Ohio State University, Columbus, OH; Dezheng Huo, Sarah M. Nielsen, and Olufunmilayo I. Olopade, University of Chicago Medical Center, Chicago, IL; Katherine L. Nathanson and Susan M. Domchek, University of Pennsylvania, Philadelphia; Christa Lorenchick and Rachel C. Jankowitz, University of Pittsburgh Medical Center, Pittsburgh, PA; Fergus J. Couch, Mayo Clinic, Rochester, MN; Ramunas Janavicius, State Research Institute Innovative Medicine Center, Vilnius, Lithuania; Thomas V.O. Hansen, Rigshospitalet, Copenhagen University Hospital, Copenhagen; Anders Bojesen and Henriette Roed Nielsen, Vejle Hospital, Vejle; Anne-Bine Skytte, Lone Sunde, and Uffe Birk Jensen, Aarhus University Hospital, Aarhus; Inge Sokilde Pedersen, Aalborg University Hospital, Aalborg; Lotte Krogh, Torben A. Kruse, and Mads Thomassen, Odense University Hospital, Odense, Denmark; Ana Osorio, National Cancer Research Centre and Spanish Network on Rare Diseases; Miguel de la Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, and Pedro Perez Segura, Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid; Judith Balmaña, University Hospital, Vall d'Hebron; Sara Gutiérrez-Enríquez and Orland Diez, Vall d'Hebron Institute of Oncology; Orland Diez, University Hospital Vall d'Hebron; Alex Teulé, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, and Conxi Lazaro, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, Barcelona; Angel Izquierdo, Esther Darder, and Joan Brunet, Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain; Florentia Fostira, National Centre for Scientific Research "Demokritos," Athens, Greece; Ute Hamann, German Cancer Research Center (DKFZ); Christian Sutter, University Hospital Heidelberg, Heidelberg; Alfons Meindl, Klinikumrechts der Isar, Technical University Munich; Nina Ditsch, Ludwig-Maximilian University, Munich; Andrea Gehrig, University Würzburg, Würzburg; Bernd Dworniczak, University of Münster, Münster; Christoph Engel, University of Leipzig; Dorothea Wand, University Hospital, Leipzig; Dieter Niederacher, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf; Doris Steinemann, Hannover Medical School, Hannover; Eric Hahnen, Jan Hauke, Kerstin Rhiem, Barbara Wappenschmidt, and Rita K. Schmutzler, University Hospital Cologne, Cologne; Karin Kast, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden; Norbert Arnold, University Hospital of Schleswig-Holstein, Christian-Albrechts University Kiel, Kiel; Shan Wang-Gohrke, University Hospital Ulm, Ulm, Germany; Christine Lasset, Francesca Damiola, and Laure Barjhoux, Centre Léon Bérard; Sylvie Mazoyer, University of Lyon, Lyon; Dominique Stoppa-Lyonnet and Muriel Belotti, Institut Curie, Paris, France; Mattias Van Heetvelde, Bruce Poppe, Kim De Leeneer, and Kathleen B.M. Claes, Ghent University, Gent, Belgium; Johanna I. Kiiski, Sofia Khan, and Heli Nevanlinna, University of Helsinki; Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, and Heli Nevanlinna, Helsinki University Hospital, Helsinki, Finland; Christi J. van Asperen, Leiden University Medical Center, Leiden, the Netherlands; Tibor Vaszko, Miklos Kasler, and Edith Olah, National Institute of Oncology, Budapest, Hungary; Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th. Johannsson, and Rosa B. Barkardottir, Landspitali University Hospital and Biomedical Centre, University of Iceland, Reykjavik, Iceland; Manuel R. Teixeira and Pedro Pinto, Portuguese Oncology Institute; Manuel R. Teixeira, Porto University, Porto, Portugal; Jong Won Lee, Ulsan College of Medicine and Asan Medical Center; Min Hyuk Lee and Jihyoun Lee, Soonchunhyang University and Hospital; Sung-Won Kim and Eunyoung Kang, Daerim St Mary's Hospital; Sue Kyung Park, Seoul National University College of Medicine, Seoul; Zisun Kim, Soonchunhyang University Bucheon Hospital, Bucheon, Korea; Yen Y. Tan, Andreas Berger, and Christian F. Singer, Medical University of Vienna, Vienna, Austria; Sook-Yee Yoon and Soo-Hwang Teo, Sime Darby Medical Centre, Subang Jaya, Malaysia; and Anna von Wachenfeldt, Karolinska University Hospital, Stockholm, Sweden.

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.69.4935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5501359PMC
July 2017

Human cardiac progenitor cells with regenerative potential can be isolated and characterized from 3D-electro-anatomic guided endomyocardial biopsies.

Int J Cardiol 2017 Aug 1;241:330-343. Epub 2017 Mar 1.

Department of Cardiovascular Medicine, Catholic University of the Sacred Heart, Rome, Italy. Electronic address:

Aims: In the present study, we aimed to develop a percutaneous approach and a reproducible methodology for the isolation and expansion of Cardiac Progenitor Cells (CPCs) from EndoMyocardial Biopsies (EMB) in vivo. Moreover, in an animal model of non-ischemic heart failure (HF), we would like to test whether CPCs obtained by this methodology may engraft the myocardium and differentiate.

Methods And Results: EMB were obtained using a preformed sheath and a disposable bioptome, advanced via right femoral vein in 12 healthy mini pigs, to the right ventricle. EMB were enzymatically dissociated, cells were expanded and sorted for c-kit. We used 3D-Electro-Anatomic Mapping (3D-EAM) to obtain CPCs from 32 patients affected by non-ischemic cardiomyopathy. The in vivo regenerative potential of CPCs was tested in a rodent model of drug-induced non-ischemic cardiomyopathy. c-kit positive CPCs replicative capacity was assessed in 30 patients. Telomere length averaged 7.4±0.4kbp and telomerase activity was present in all preparations (1.7×10 copies). The in situ hybridization experiments showed that injected human CPCs may acquire a neonatal myocyte phenotype given the expression of the alpha-sarcomeric actin together with the presence of the Alu probe, suggesting a beneficial impact on LV performance.

Conclusions: The success in obtaining CPCs characterized by high regenerative potential, in vitro and in vivo, from EMB indicates that harvesting without thoracotomy in patients affected by either ischemic or non-ischemic cardiomyopathy is feasible. These initial results may potentially expand the future application of CPCs to all patients affected by HF not undergoing surgical procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2017.02.106DOI Listing
August 2017
-->