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

Author

Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez de Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, Consortium of Investigators of Modifiers of BRCA1 and BRCA2, Barnes, Daniel R [0000-0002-3781-7570], Silvestri, Valentina [0000-0003-0712-9379], Leslie, Goska [0000-0001-5756-6222], Dennis, Joe [0000-0003-4591-1214], Yang, Xin [0000-0003-0037-3790], Adlard, Julian [0000-0002-1693-0435], Agnarsson, Bjarni A [0000-0001-7721-9965], Andrulis, Irene L [0000-0002-4226-6435], Arason, Adalgeir [0000-0003-0480-886X], Arnold, Norbert [0000-0003-4523-8808], Auber, Bernd [0000-0003-1880-291X], Azzollini, Jacopo [0000-0002-9364-9778], Barkardottir, Rosa B [0000-0003-0629-2772], Barrowdale, Daniel [0000-0003-1661-3939], Benitez, Javier [0000-0002-0923-7202], Boonen, Susanne E [0000-0002-7824-2080], Bozsik, Aniko [0000-0001-5410-9173], Brennan, Paul [0000-0003-1128-6254], Brunet, Joan [0000-0003-1945-3512], Bucalo, Agostino [0000-0003-3475-1067], Caligo, Maria A [0000-0003-0589-1829], Campbell, Ian [0000-0002-7773-4155], Cassingham, Hayley [0000-0001-9922-2321], Cini, Giulia [0000-0002-8696-8922], Claes, Kathleen BM [0000-0003-0841-7372], Coppa, Anna [0000-0001-9758-5444], Cortesi, Laura [0000-0001-8950-8561], Darder, Esther [0000-0002-7764-1397], de la Hoya, Miguel [0000-0002-8113-1410], de Putter, Robin [0000-0001-9410-8941], Del Valle, Jesús [0000-0003-3607-7045], Domchek, Susan M [0000-0002-5914-7272], Donaldson, Alan [0000-0001-9193-4172], Eason, Jacqueline [0000-0002-8711-8671], Engel, Christoph [0000-0002-7247-282X], Fostira, Florentia [0000-0003-2751-2332], Frone, Megan [0000-0001-8273-8866], Glendon, Gord [0000-0001-8630-6673], Godwin, Andrew K [0000-0002-3987-9580], Greene, Mark H [0000-0003-1852-9239], Hahnen, Eric [0000-0003-2448-7872], Hanson, Helen [0000-0002-3303-8713], Izatt, Louise [0000-0003-1258-4843], Izquierdo, Angel [0000-0003-2004-3246], James, Paul A [0000-0002-4361-4657], John, Esther M [0000-0003-3259-8003], Kroeldrup, Lone [0000-0003-3623-6536], Kruse, Torben A [0000-0002-2460-6483], Lazaro, Conxi [0000-0002-7198-5906], Lesueur, Fabienne [0000-0001-7404-4549], Matrai, Zoltan [0000-0001-8160-7100], Montagna, Marco [0000-0002-4929-2150], Monteiro, Alvaro N [0000-0002-8448-4801], Morrison, Patrick J [0000-0002-2823-1762], Muranen, Taru A [0000-0002-5895-1808], Nathanson, Katherine L [0000-0002-6740-0901], Neuhausen, Susan L [0000-0001-5053-0390], Nevanlinna, Heli [0000-0002-0916-2976], Nguyen-Dumont, Tu [0000-0002-6217-0182], Niederacher, Dieter [0000-0001-6231-9226], Palli, Domenico [0000-0002-5558-2437], Parsons, Michael T [0000-0003-3242-8477], Perez-Segura, Pedro [0000-0001-5049-7199], Peterlongo, Paolo [0000-0001-6951-6855], Pinto, Pedro [0000-0001-6289-5792], Pottinger, Caroline [0000-0003-4233-882X], Radice, Paolo [0000-0001-6298-4111], Robson, Mark [0000-0002-3109-1692], Rump, Andreas [0000-0001-7116-6364], Sharif, Saba [0000-0002-9564-4890], Steele, Linda [0000-0003-3628-2022], Stoppa-Lyonnet, Dominique [0000-0002-5438-8309], Teixeira, Manuel R [0000-0002-4896-5982], Thull, Darcy L [0000-0001-7999-2804], Tischkowitz, Marc [0000-0002-7880-0628], Toland, Amanda E [0000-0002-0271-1792], Tommasi, Stefania [0000-0002-2157-2978], Toss, Angela [0000-0002-1854-6701], Tripathi, Vishakha [0000-0001-8118-8364], Valentini, Virginia [0000-0003-3393-7185], van Asperen, Christi J [0000-0002-1436-7650], Venturelli, Marta [0000-0003-0658-8004], Viel, Alessandra [0000-0003-2804-0840], Vijai, Joseph [0000-0002-7933-151X], Whaite, Anna [0000-0003-4485-0341], Simard, Jacques [0000-0001-6906-3390], Easton, Douglas F [0000-0003-2444-3247], Chenevix-Trench, Georgia [0000-0002-1878-2587], Ottini, Laura [0000-0001-8030-0449], and Apollo - University of Cambridge Repository

Subjects
Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract

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 1318 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 3 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 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios 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 informing clinical management.

Published
2022

3. AND I’LL SEE YOU IN THE HIGH AND LOW. The ontogenetic origins of sensitivity to facial cues to trustworthiness and emotion

Author

SILVESTRI, VALENTINA, Silvestri, V, and MACCHI CASSIA, VIOLA MARINA

Subjects
affidabilità, sviluppo, M-PSI/04 - PSICOLOGIA DELLO SVILUPPO E PSICOLOGIA DELL'EDUCAZIONE, percezione visiva, spatial frequencie, emotion, visual perception, trustworthine, emozioni, frequenze spaziali
Abstract

Una componente fondamentale della competenza sociale degli esseri umani è l'abilità di estrarre rapidamente e in modo spontaneo i segnali sociali che provengono dal volto, quali per esempio i tratti emotivi e di affidabilità. Il fatto che le risposte a queste configurazioni facciali siano rapide e automatiche suggerisce come esse derivino dalla pressione evolutiva a rilevare segnali di pericolo per aumentare le possibilità di sopravvivenza. Tuttavia, le origini ontogenetiche di queste abilità sociali sono ancora oggetto di dibattito. La presente tesi di dottorato si pone l'obiettivo di indagare la natura dell’informazione visiva che media la discriminazione delle emozioni e/o la percezione dell'affidabilità dai volti utilizzando l'approccio del filtraggio spaziale, ossia la rimozione selettiva di bande di frequenze spaziali contenute nell'immagine. Nello specifico, l’elaborato comprende 5 studi volti a indagare (1) la natura dell'informazione visiva sui cui si basano i giudizi espliciti di affidabilità degli adulti (Studio 1) (2) se la percezione di affidabilità di adulti (Studio 2) e bambini (Studio 3) è generalizzata a volti di un'etnia differente dalla propria e la natura dell'informazione visiva coinvolta, (3) la natura dell'informazione visiva che determina la discriminazione neurale di affidabilità dai volti nei preverbali (Studio 4), e (4) la natura dell'informazione visiva su cui si basa la discriminazione visiva delle emozioni alla nascita (Studio 5a e 5b). I risultati dello Studio 1 mostrano che sebbene sia le informazioni visive globali, veicolate dalle frequenze spaziali basse, che le informazioni visive locali, veicolate dalle frequenze spaziali alte, sono sufficienti per discriminare tra livelli di affidabilità, l'informazione globale gioca un ruolo cruciale. Gli Studi 2 e 3 estendono le considerazioni sulla natura dell'informazione visiva coinvolta nella percezione di affidabilità a volti meno presenti nell'ambiente sociale dell'individuo, volti di un'altra etnia. Dunque, l'obiettivo è indagare se la percezione di affidabilità nei bambini (Studio 3) si basa sulle stesse informazioni visive su cui si basa negli adulti (Studio 2) e se la stessa differisca in base all'etnia del volto. I risultati mostrano che le informazioni visive coinvolte nella percezione di affidabilità dai volti della propria o altrui etnia cambiano in relazione al grado di familiarità del volto durante lo sviluppo. Nello Studio 4, attraverso un nuovo paradigma di registrazione della risposta neurale, la Fast Periodic Visual Stimulation, viene esplorata l'informazione visiva che i bambini di 6 mesi utilizzano per discriminare tra volti affidabili e inaffidabili. I bambini di 6 mesi discriminano tra volti affidabili e non affidabili sulla base di informazioni visive differenti. Le informazioni locali mediano la discriminazione di volti affidabili mentre la discriminazione di volti non affidabili si basa su informazione visiva locale. I risultati vengono discussi alla luce delle eventuali implicazioni per la comprensione dei meccanismi percettivi e neurali coinvolti nella discriminazione di volti a valenza positiva e negativa. Lo Studio 5 ha indagato il ruolo dell'informazione visiva nella percezione delle emozioni alla nascita. I neonati a 2 giorni di vita discriminano tra volti felici e impauriti sia quando rimangono solo le frequenze spaziali alte che quando rimangono solo le frequenze spaziali basse. Tuttavia, i neonati preferiscono i volti felici ai volti impauriti solo quando nell’immagine rimangono le frequenze spaziali alte. Dunque, l'informazione visiva presente nell'immagine modula la salienza dei segnali sociali dai volti fin dalle prime ore di vita. Nel complesso, i risultati suggeriscono che la percezione di affidabilità ed emotiva si basa su una sensibilità adattiva ed evoluzionistica che si raffina nel corso dello sviluppo come risultato dell'esperienza nell'ambiente sociale. One fundamental component of humans' social competence is the ability to rapidly and spontaneously extrapolate facial cues of emotion and trustworthiness - i.e., whether others are likely to approach us friendly or hostilely. The fast and automatic nature of these responses to facial configurations has led to the claim that they derive from evolutionary pressure to detect signals of potential harm, and distinguish between friends or foes to enhance our chances of survival. However, the ontogenetic origins of these fundamental social skills are still debated. To explore this question, the studies reported in this doctoral dissertation investigated the nature of the visual information driving emotion discrimination and/or trustworthiness perception across the life span using the spatial filtering approach - i.e., the selective removal of portions of the spatial frequencies (SF) information contained in the image. Specifically, this doctoral dissertation includes 5 studies aimed at investigating (1) the nature of the visual information on which adults' explicit judgments of trustworthiness are based (Study 1), (2) whether trustworthiness perception in adults (Study 2) and children (Study 3) generalizes across face-race and/or the nature of the visual information on which trustworthiness judgments are based differs for more versus less familiar face categories, (3) the nature of the visual information that triggers neural discrimination of facial cues to trustworthiness in preverbal infants (Study 4), and (4) the nature of the visual information that mediates visual discrimination of emotional facial expressions at birth (Study 5a and 5b). Results of Study 1 showed that, although both global visual cues, conveyed by low-spatial frequency bands, and local visual cues, conveyed by high-spatial frequency bands, are sufficient to discriminate between levels of trustworthiness, the selective removal of global information negatively impacts trustworthiness perception. Study 2 and 3 extended evidence on the nature of visual information involved in trustworthiness perception to faces underrepresented in the individual's social environment, other-race faces, in adults and preschool and school children. Results showed that in the course of development the visual information involved in own- and other-race trustworthiness perception changes. Study 4 used a newly developed Electroencephalographic (EEG) visual discrimination paradigm, the Fast Periodic Visual Stimulation, to investigate which visual information 6-month-old infants use to discriminate between trustworthy and untrustworthy faces. The infants’ brain discriminated between high-trustworthy and low-trustworthy faces based on different types of visual information. Results are discussed for their implications for the understanding of the perceptual/neural mechanisms involved in early discrimination between positive and negative valence faces. Study 5 explored the role of visual information in emotion perception at birth. 2-days-old newborns discriminate between happy and fearful facial expressions with both high and low spatial frequency information but they prefer happy faces when only high spatial frequencies remain. The visual information present in the image modulates the salience of the facial cues to emotions from the first hours of life. Altogether, the evidence gathered from the current studies adds to the existing literature suggesting that emotion and trustworthiness perception are based on an adaptive and evolutionary sensitivity early in life that is refined over the course of development as a result of the quantity and quality of facial experience in the social environment.

Published
2022

4. Cancer Risks Associated With BRCA1 and BRCA2 Pathogenic Variants

Author

Li, Shuai, Silvestri, Valentina, Leslie, Goska, Rebbeck, Timothy R, Neuhausen, Susan L, Hopper, John L, Nielsen, Henriette Roed, Lee, Andrew, Yang, Xin, McGuffog, Lesley, Parsons, Michael T, Andrulis, Irene L, Arnold, Norbert, Belotti, Muriel, Borg, Åke, Buecher, Bruno, Buys, Saundra S, Caputo, Sandrine M, Chung, Wendy K, Colas, Chrystelle, Colonna, Sarah V, Cook, Jackie, Daly, Mary B, de la Hoya, Miguel, de Pauw, Antoine, Delhomelle, Hélène, Eason, Jacqueline, Engel, Christoph, Evans, D Gareth, Faust, Ulrike, Fehm, Tanja N, Fostira, Florentia, Fountzilas, George, Frone, Megan, Garcia-Barberan, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Gehrig, Andrea, Glendon, Gord, Goldgar, David E, Golmard, Lisa, Greene, Mark H, Hahnen, Eric, Hamann, Ute, Hanson, Helen, Hassan, Tiara, Hentschel, Julia, Horvath, Judit, Izatt, Louise, Janavicius, Ramunas, Jiao, Yue, John, Esther M, Karlan, Beth Y, Kim, Sung-Won, Konstantopoulou, Irene, Kwong, Ava, Laugé, Anthony, Lee, Jong Won, Lesueur, Fabienne, Mebirouk, Noura, Meindl, Alfons, Mouret-Fourme, Emmanuelle, Musgrave, Hannah, Ngeow Yuen Yie, Joanne, Niederacher, Dieter, Park, Sue K, Pedersen, Inge Sokilde, Ramser, Juliane, Ramus, Susan J, Rantala, Johanna, Rashid, Muhammad U, Reichl, Florian, Ritter, Julia, Rump, Andreas, Santamariña, Marta, Saule, Claire, Schmidt, Gunnar, Schmutzler, Rita K, Senter, Leigha, Shariff, Saba, Singer, Christian F, Southey, Melissa C, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen, Teo, Soo Hwang, Terry, Mary Beth, Thomassen, Mads, Tischkowitz, Marc, Toland, Amanda E, Torres, Diana, Vega, Ana, Wagner, Sebastian A, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weber, Bernhard HF, Yannoukakos, Drakoulis, Spurdle, Amanda B, Easton, Douglas F, and Chenevix-Trench, Georgia

Subjects
Male, Risk, Urologic Diseases, Heterozygote, Aging, Clinical Sciences, Oncology and Carcinogenesis, Breast Neoplasms, Rare Diseases, Breast Cancer, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Cancer, Ovarian Neoplasms, BRCA2 Protein, BRCA1 Protein, Prevention, Infant, Newborn, Ovarian Cancer, Pancreatic Neoplasms, Mutation, Female, Digestive Diseases
Abstract

PurposeTo provide precise age-specific risk estimates of cancers other than female breast and ovarian cancers associated with pathogenic variants (PVs) in BRCA1 and BRCA2 for effective cancer risk management.MethodsWe used data from 3,184 BRCA1 and 2,157 BRCA2 families in the Consortium of Investigators of Modifiers of BRCA1/2 to estimate age-specific relative (RR) and absolute risks for 22 first primary cancer types adjusting for family ascertainment.ResultsBRCA1 PVs were associated with risks of male breast (RR = 4.30; 95% CI, 1.09 to 16.96), pancreatic (RR = 2.36; 95% CI, 1.51 to 3.68), and stomach (RR = 2.17; 95% CI, 1.25 to 3.77) cancers. Associations with colorectal and gallbladder cancers were also suggested. BRCA2 PVs were associated with risks of male breast (RR = 44.0; 95% CI, 21.3 to 90.9), stomach (RR = 3.69; 95% CI, 2.40 to 5.67), pancreatic (RR = 3.34; 95% CI, 2.21 to 5.06), and prostate (RR = 2.22; 95% CI, 1.63 to 3.03) cancers. The stomach cancer RR was higher for females than males (6.89 v 2.76; P = .04). The absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers.ConclusionIn addition to female breast and ovarian cancers, BRCA1 and BRCA2 PVs are associated with increased risks of male breast, pancreatic, stomach, and prostate (only BRCA2 PVs) cancers, but not with the risks of other previously suggested cancers. The estimated age-specific risks will refine cancer risk management in men and women with BRCA1/2 PVs.

Published
2022

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

Author

Rizzolo, Piera, Silvestri, Valentina, Valentini, Virginia, Zelli, Veronica, Bucalo, Agostino, Zanna, Ines, Bianchi, Simonetta, Tibiletti, Maria Grazia, Russo, Antonio, Varesco, Liliana, Tedaldi, Gianluca, Bonanni, Bernardo, Azzollini, Jacopo, Manoukian, Siranoush, Coppa, Anna, Giannini, Giuseppe, Cortesi, Laura, Viel, Alessandra, Montagna, Marco, Peterlongo, Paolo, Radice, Paolo, Palli, Domenico, and Ottini, Laura

Subjects
Oncology, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, PALB2, Disease, male breast cancer, Hyperestrogenism, lcsh:Diseases of the endocrine glands. Clinical endocrinology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Breast cancer, Internal medicine, Genotype, CYP17A1, Internal Medicine, Genetic predisposition, Medicine, 030212 general & internal medicine, skin and connective tissue diseases, Estrogen Receptor Status, CYP1B1, polymorphisms, male breast cancer risk, lcsh:RC648-665, business.industry, Research, medicine.disease, 030220 oncology & carcinogenesis, Male breast cancer, medicine.symptom, business
Abstract

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.

Published
2019

12. Common Susceptibility Loci for Male Breast Cancer

Author

Maguire, Sarah, Perraki, Eleni, Tomczyk, Katarzyna, Jones, Michael E, Fletcher, Olivia, Pugh, Matthew, Winter, Timothy, Thompson, Kyle, Cooke, Rosie, KConFab Consortium, Trainer, Alison, James, Paul, Bojesen, Stig, Flyger, Henrik, Nevanlinna, Heli, Mattson, Johanna, Friedman, Eitan, Laitman, Yael, Palli, Domenico, Masala, Giovanna, Zanna, Ines, Ottini, Laura, Silvestri, Valentina, Hollestelle, Antoinette, Hooning, Maartje J, Novaković, Srdjan, Krajc, Mateja, Gago-Dominguez, Manuela, Castelao, Jose Esteban, Olsson, Hakan, Hedenfalk, Ingrid, Saloustros, Emmanouil, Georgoulias, Vasilios, Easton, Douglas F, Pharoah, Paul, Dunning, Alison M, Bishop, D Timothy, Neuhausen, Susan L, Steele, Linda, Ashworth, Alan, Garcia Closas, Montserrat, Houlston, Richard, Swerdlow, Anthony, Orr, Nick, Easton, Douglas [0000-0003-2444-3247], Pharoah, Paul [0000-0001-8494-732X], Dunning, Alison [0000-0001-6651-7166], and Apollo - University of Cambridge Repository

Subjects
Male, Quantitative Trait Loci, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Breast Neoplasms, Male, Receptors, Estrogen, Case-Control Studies, polycyclic compounds, Confidence Intervals, Linear Models, Odds Ratio, Humans, Female, Genetic Predisposition to Disease, skin and connective tissue diseases, Genome-Wide Association Study
Abstract

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.

Published
2020
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13. 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)

Author

Silvestri, Valentina, Leslie, Goska, Barnes, Daniel R, CIMBA Group, Agnarsson, Bjarni A, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Barkardottir, Rosa B, Barroso, Alicia, Barrowdale, Daniel, Benitez, Javier, Bonanni, Bernardo, Borg, Ake, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Capalbo, Carlo, Campbell, Ian, Chung, Wendy K, Claes, Kathleen BM, Colonna, Sarah V, Cortesi, Laura, Couch, Fergus J, De La Hoya, Miguel, Diez, Orland, Ding, Yuan Chun, Domchek, Susan, Easton, Douglas F, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Feliubadalò, Lidia, Foretova, Lenka, Fostira, Florentia, Géczi, Lajos, Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Hahnen, Eric, Hogervorst, Frans BL, Hopper, John L, Hulick, Peter J, Isaacs, Claudine, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M, Joseph, Vijai, Konstantopoulou, Irene, Kurian, Allison W, Kwong, Ava, Landucci, Elisabetta, Lesueur, Fabienne, Loud, Jennifer T, Machackova, Eva, Mai, Phuong L, Majidzadeh-A, Keivan, Manoukian, Siranoush, Montagna, Marco, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L, Nevanlinna, Heli, Ngeow, Joanne, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Osorio, Ana, Papi, Laura, Park, Sue K, Pedersen, Inge Sokilde, Perez-Segura, Pedro, Petersen, Annabeth H, Pinto, Pedro, Porfirio, Berardino, Pujana, Miquel Angel, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U, Rosenzweig, Barak, Rossing, Maria, Santamariña, Marta, Schmutzler, Rita K, Senter, Leigha, Simard, Jacques, Singer, Christian F, Solano, Angela R, Southey, Melissa C, Steele, Linda, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Tan, Yen Yen, Teixeira, Manuel R, Teo, Soo H, Terry, Mary Beth, Thomassen, Mads, Toland, Amanda E, Torres-Esquius, Sara, Tung, Nadine, Van Asperen, Christi J, Vega, Ana, Viel, Alessandra, Vierstraete, Jeroen, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wieme, Greet, Yoon, Sook-Yee, Zorn, Kristin K, McGuffog, Lesley, Parsons, Michael T, Hamann, Ute, Greene, Mark H, Kirk, Judy A, Neuhausen, Susan L, Rebbeck, Timothy R, Tischkowitz, Marc, Chenevix-Trench, Georgia, Antoniou, Antonis C, Friedman, Eitan, Ottini, Laura, Leslie, Goska [0000-0001-5756-6222], Barnes, Daniel [0000-0002-3781-7570], Easton, Douglas [0000-0003-2444-3247], Tischkowitz, Marc [0000-0002-7880-0628], Antoniou, Antonis [0000-0001-9223-3116], and Apollo - University of Cambridge Repository

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Male, endocrine system diseases, Adolescent, BRCA1 Protein, Middle Aged, Young Adult, Phenotype, Neoplasms, Humans, skin and connective tissue diseases, Germ-Line Mutation, Aged, Retrospective Studies
Abstract

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.

Published
2020
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16. Characterization of the cancer spectrum in men with germline BRCA1 and BRCA2 pathogenic variants

Author

Silvestri, Valentina, Leslie, Goska, Barnes, Daniel R., Agnarsson, Bjarni A., Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L., Barkardottir, Rosa B., Barroso, Alicia, Barrowdale, Daniel, Benitez, Javier, Bonanni, Bernardo, Borg, Ake, Buys, Saundra S., Caldés, Trinidad, Caligo, Maria A., Capalbo, Carlo, Campbell, Ian, Chung, Wendy K., Claes, Kathleen B. M., Colonna, Sarah V., Cortesi, Laura, Couch, Fergus J., de la Hoya, Miguel, Diez, Orland, Ding, Yuan Chun, Domchek, Susan, Easton, Douglas F., Ejlertsen, Bent, Engel, Christoph, Evans, D. Gareth, Feliubadalò, Lidia, Foretova, Lenka, Fostira, Florentia, Géczi, Lajos, Gerdes, Anne-Marie, Glendon, Gord, Godwin, Andrew K., Goldgar, David E., Hahnen, Eric, Hogervorst, Frans B. L., Hopper, John L., Hulick, Peter J., Isaacs, Claudine, Izquierdo, Angel, James, Paul A., Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Joseph, Vijai, Konstantopoulou, Irene, Kurian, Allison W., Kwong, Ava, Landucci, Elisabetta, Lesueur, Fabienne, Loud, Jennifer T., Machackova, Eva, Mai, Phuong L., Majidzadeh-A, Keivan, Manoukian, Siranoush, Montagna, Marco, Moserle, Lidia, Mulligan, Anna Marie, Nathanson, Katherine L., Nevanlinna, Heli, Ngeow Yuen Ye, Joanne, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I., Osorio, Ana, Papi, Laura, Park, Sue K., Pedersen, Inge Sokilde, Perez-Segura, Pedro, Petersen, Annabeth H., Pinto, Pedro, Porfirio, Berardino, Pujana, Miquel Angel, Radice, Paolo, Rantala, Johanna, Rashid, Muhammad U., Rosenzweig, Barak, Rossing, Maria, Santamariña, Marta, Schmutzler, Rita K., Senter, Leigha, Simard, Jacques, Singer, Christian F., Solano, Angela R., Southey, Melissa C., Steele, Linda, Steinsnyder, Zoe, Stoppa-Lyonnet, Dominique, Tan, Yen Yen, Teixeira, Manuel R., Teo, Soo H., Terry, Mary Beth, Thomassen, Mads, Toland, Amanda E., Torres-Esquius, Sara, Tung, Nadine, van Asperen, Christi J., Vega, Ana, Viel, Alessandra, Vierstraete, Jeroen, Wappenschmidt, Barbara, Weitzel, Jeffrey N., Wieme, Greet, Yoon, Sook-Yee, Zorn, Kristin K., Mcguffog, Lesley, Parsons, Michael T., Hamann, Ute, Greene, Mark H., Kirk, Judy A., Neuhausen, Susan L., Rebbeck, Timothy R., Tischkowitz, Marc, Chenevix-Trench, Georgia, Antoniou, Antonis C., Friedman, Eitan, and Ottini, Laura

Subjects
male cancers, BRCA, cancer spectrum
Published
2020

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

Author

Lecarpentier, Julie, Silvestri, Valentina, Kuchenbaecker, Karoline B, Barrowdale, Daniel, Dennis, Joe, McGuffog, Lesley, Soucy, Penny, Leslie, Goska, Rizzolo, Piera, Navazio, Anna Sara, Valentini, Virginia, Zelli, Veronica, Lee, Andrew, Amin Al Olama, Ali, Tyrer, Jonathan P, Southey, Melissa, John, Esther M, Conner, Thomas A, Goldgar, David E, Buys, Saundra, Janavicius, Ramunas, Steele, Linda, Ding, Yuan Chun, Neuhausen, Susan L, Hansen, Thomas V O, Osorio, Ana, Weitzel, Jeffrey N, Toss, Angela, Medici, Veronica, Cortesi, Laura, Zanna, Ines, Palli, Domenico, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Azzollini, Jacopo, Viel, Alessandra, Cini, Giulia, Damante, Giuseppe, Tommasi, Stefania, Peterlongo, Paolo, Fostira, Florentia, Hamann, Ute, Evans, D Gareth, Bojesen, Anders, Nielsen, Henriette Roed, Skytte, Anne-Bine, Krogh, Lotte, Kruse, Torben A, and Thomassen, Mads

Subjects
OVERDIAGNOSIS, SUSCEPTIBILITY LOCI, IDENTIFICATION, GENETIC-VARIANTS, Journal Article, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, skin and connective tissue diseases
Abstract

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(-6)). 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(-9)). 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.

Published
2017
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21. Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores

Author

Lecarpentier, Julie, Silvestri, Valentina, Kuchenbaecker, Karoline B., Barrowdale, Daniel, Dennis, Joe, McGuffog, Lesley, Soucy, Penny, Leslie, Goska, Rizzolo, Piera, Navazio, Anna Sara, Valentini, Virginia, Zelli, Veronica, Lee, Andrew, Al Olama, Ali Amin, Tyrer, Jonathan P., Southey, Melissa, John, Esther M., Conner, Thomas A., Goldgar, David E., Buys, Saundra S., Janavicius, Ramunas, Steele, Linda, Ding, Yuan Chun, Neuhausen, Susan L., Hansen, Thomas V. O., Osorio, Ana, Weitzel, Jeffrey N., Toss, Angela, Medici, Veronica, Cortesi, Laura, Zanna, Ines, Palli, Domenico, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Azzollini, Jacopo, Viel, Alessandra, Cini, Giulia, Damante, Giuseppe, Tommasi, Stefania, Peterlongo, Paolo, Fostira, Florentia, Hamann, Ute, Evans, D. Gareth, Henderson, Alex, Brewer, Carole, Kiiski, Johanna I., Aittomäki, Kristiina, Khan, Sofia, Nevanlinna, Heli, EMBRACE, GEMO Study Collaborators, HEBON, kConFab Investigators, Clinicum, Department of Obstetrics and Gynecology, Kristiina Aittomäki / Principal Investigator, HUSLAB, Department of Medical and Clinical Genetics, and HUS Gynecology and Obstetrics

Subjects
OVERDIAGNOSIS, SUSCEPTIBILITY LOCI, IDENTIFICATION, GENETIC-VARIANTS, 3122 Cancers, GENOME-WIDE ASSOCIATION, FUNCTIONAL VARIANTS, skin and connective tissue diseases
Abstract

PurposeBRCA1/2 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 investigatedfor the first time to our knowledgeassociations 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 MethodsWe 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.ResultsIn 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 x 10(-6)). 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 x 10(-9)). 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.ConclusionPRSs 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.

Published
2017

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

Author

Lecarpentier, Julie, Silvestri, Valentina, Kuchenbaeker, Karoline B., Barrowdale, Daniel, Dennis, Joe, McGuffog, Lesley, Soucy, Penny, Leslie, Goska, Rizzolo, Piera, and Orr, Nicholas

Subjects
SDG 3 - Good Health and Well-being
Abstract

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2mutations. 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 MethodsWe 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.ResultsIn 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 × 10−6). 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 × 10−9). 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 BRCA1mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs 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.

Published
2017
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24. Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna Marie, Neuhausen, Susan L, Fox, Stephen, Karlan, Beth Y, Mitchell, Gillian, James, Paul, Thull, Darcy L, Zorn, Kristin K, Carter, Natalie J, Nathanson, Katherine L, Domchek, Susan M, Rebbeck, Timothy R, Ramus, Susan J, Nussbaum, Robert L, Olopade, Olufunmilayo I, Rantala, Johanna, Yoon, Sook-Yee, Caligo, Maria A, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge Sokilde, Thomassen, Mads, Jensen, Uffe Birk, Toland, Amanda Ewart, Senter, Leigha, Andrulis, Irene L, Glendon, Gord, Hulick, Peter J, Imyanitov, Evgeny N, Greene, Mark H, Mai, Phuong L, Singer, Christian F, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus J, Hallberg, Emily, Ruddy, Kathryn J, Sharma, Priyanka, Kim, Sung-Won, kConFab Investigators, Teixeira, Manuel R, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Arason, Adalgeir, Johannsson, Oskar Th, Barkardottir, Rosa B, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel Angel, Balmaña, Judith, Diez, Orland, Ivady, Gabriella, Papp, Janos, Olah, Edith, Kwong, Ava, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Nevanlinna, Heli, Aittomäki, Kristiina, Perez Segura, Pedro, Caldes, Trinidad, Van Maerken, Tom, Poppe, Bruce, Claes, Kathleen BM, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Varon-Mateeva, Raymonda, Wand, Dorothea, Godwin, Andrew K, Evans, D Gareth, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, and Platte, Radka

Subjects
Male, Adult, endocrine system diseases, Oncology and Carcinogenesis, Breast Neoplasms, Genotype-phenotype correlations, EMBRACE, Histologic grade, BRCA1/2, Breast Cancer, polycyclic compounds, Pathology, Humans, 2.1 Biological and endogenous factors, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Aetiology, Polymorphism, skin and connective tissue diseases, Neoplasm Staging, Aged, Cancer, BRCA2 Protein, BRCA1 Protein, Single Nucleotide, Middle Aged, Male breast cancer, Mutation, kConFab Investigators, Female, Hereditary Breast and Ovarian Cancer Research Group Netherlands
Abstract

BackgroundBRCA1 and, more commonly, BRCA2 mutations are associated with increased risk of male breast cancer (MBC). However, only a paucity of data exists on the pathology of breast cancers (BCs) in men with BRCA1/2 mutations. Using the largest available dataset, we determined whether MBCs arising in BRCA1/2 mutation carriers display specific pathologic features and whether these features differ from those of BRCA1/2 female BCs (FBCs).MethodsWe characterised the pathologic features of 419 BRCA1/2 MBCs and, using logistic regression analysis, contrasted those with data from 9675 BRCA1/2 FBCs and with population-based data from 6351 MBCs in the Surveillance, Epidemiology, and End Results (SEER) database.ResultsAmong BRCA2 MBCs, grade significantly decreased with increasing age at diagnosis (P = 0.005). Compared with BRCA2 FBCs, BRCA2 MBCs were of significantly higher stage (P for trend = 2 × 10(-5)) and higher grade (P for trend = 0.005) and were more likely to be oestrogen receptor-positive [odds ratio (OR) 10.59; 95 % confidence interval (CI) 5.15-21.80] and progesterone receptor-positive (OR 5.04; 95 % CI 3.17-8.04). With the exception of grade, similar patterns of associations emerged when we compared BRCA1 MBCs and FBCs. BRCA2 MBCs also presented with higher grade than MBCs from the SEER database (P for trend = 4 × 10(-12)).ConclusionsOn the basis of the largest series analysed to date, our results show that BRCA1/2 MBCs display distinct pathologic characteristics compared with BRCA1/2 FBCs, and we identified a specific BRCA2-associated MBC phenotype characterised by a variable suggesting greater biological aggressiveness (i.e., high histologic grade). These findings could lead to the development of gender-specific risk prediction models and guide clinical strategies appropriate for MBC management.

Published
2016

25. Prosthetic Vascular Graft Infection Imaging

Author

Silvestri, Valentina

Subjects
genetic structures, Vascular, education, Infection, Diagnostic procedure, CT-Angiography
Abstract

Learning objectives Background Findings and procedure details Conclusion Personal information References, Learning objectives: To identify the radiologic findings that suggest vascular prostethic graft infection...

Published
2016
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26. Breast Cancer: Not Only a 'Womans' Disease

Author

Ottini Laura, Silvestri Valentina, Falchetti Mario, Rizzolo Piera, and Gulino Matteo

Subjects
Oncology, medicine.medical_specialty, Breast cancer, business.industry, Internal medicine, medicine, Obstetrics and Gynecology, Disease, business, medicine.disease
Published
2012
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27. Comprehensive CT cardiothoracic imaging: a new challenge for chest imaging

Author

Marano, Riccardo, Pirro, Federica, Silvestri, Valentina, Merlino, Biagio, Savino, Giancarlo, Rutigliano, Claudia, Meduri, Agostino, Natale, Luigi, and Bonomo, Lorenzo

Subjects
Heart Diseases, Multidetector Computed Tomography, Humans, Pulmonary Edema, Radiography, Thoracic, cardiothoracic imaging, chest imaging, Coronary Angiography, Tomography, X-Ray Computed, Coronary Vessels, Settore MED/36 - DIAGNOSTICA PER IMMAGINI E RADIOTERAPIA
Abstract

In the past, thoracic and cardiac imaging were two distinct specialties of radiology. The technical evolution, however, has changed their boundaries with an important impact on CT imaging practices and has opened the new era of "cardiothoracic" imaging, due to the strong anatomic, mechanical, physiologic, physiopathologic, and therapeutic cardiopulmonary correlations. Modern thoracic radiologists can no longer avoid the assessment of heart and coronary arteries, as they used to do with earlier generations of CT scanner. The advent of ECG gating and state-of-art CT scanner faster rotation speed, high spatial and temporal resolution, high-pitch mode, shorter acquisition time, and dedicated cardiac reconstruction algorithms has opened new possibilities for chest imaging, integrating cardiac morphologic and even functional information within a diagnostic chest CT scan. The aim of this review is to briefly show and summarize the concept of integrated cardiothoracic imaging, which redefines the boundaries of chest CT imaging, opening the door to a new radiologic specialty.

Published
2015

28. Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy

Author

Ottini, Laura, Rizzolo, Piera, Zanna, I, Silvestri, Valentina, Saieva, C, Falchetti, M, Masala, G, Navazio, ANNA SARA, Capalbo, Carlo, Bianchi, S, Manoukian, S, Barile, M, Peterlongo, P, Caligo, Ma, Varesco, L, Tommasi, S, Russo, A, Giannini, Giuseppe, Cortesi, L, Cini, G, Montagna, M, Radice, P, and Palli, D.

Subjects
Male, Genotype, Receptor, ErbB-2, Middle Aged, Arylsulfotransferase, Polymorphism, Single Nucleotide, Breast Neoplasms, Male, Gene Expression Regulation, Neoplastic, Asian People, Gene Frequency, Italy, Risk Factors, Humans, Genetic Predisposition to Disease, Genetic Association Studies
Abstract

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638GA) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Published
2014

31. Inherited and acquired alterations in development of breast cancer

Author

Ottini, Laura, Rizzolo,Piera, Silvestri,Valentina, and Falchetti,M

Subjects
The Application of Clinical Genetics, skin and connective tissue diseases
Abstract

Piera Rizzolo, Valentina Silvestri, Mario Falchetti, Laura OttiniDepartment of Molecular Medicine, "La Sapienza" University of Rome, Rome, ItalyAbstract: Breast cancer is the most common cancer among women, accounting for about 30% of all cancers. In contrast, breast cancer is a rare disease in men, accounting for less than 1% of all cancers. Up to 10% of all breast cancers are hereditary forms, caused by inherited germ-line mutations in "high-penetrance," "moderate-penetrance," and "low-penetrance" breast cancer susceptibility genes. The remaining 90% of breast cancers are due to acquired somatic genetic and epigenetic alterations. A heterogeneous set of somatic alterations, including mutations and gene amplification, are reported to be involved in the etiology of breast cancer. Promoter hypermethylation of genes involved in DNA repair and hormone-mediated cell signaling, as well as altered expression of micro RNAs predicted to regulate key breast cancer genes, play an equally important role as genetic factors in development of breast cancer. Elucidation of the inherited and acquired genetic and epigenetic alterations involved in breast cancer may not only clarify molecular pathways involved in the development and progression of breast cancer itself, but may also have an important clinical and therapeutic impact on improving the management of patients with the disease.Keywords: breast cancer, inherited susceptibility, acquired alterations, epigenetics

Published
2011

32. Mutation analysis of in male breast cancer cases: a population-based study in Central Italy

Author

Silvestri, Valentina, Rizzolo, Piera, Falchetti, Mario, Zanna, Ines, Masala, Giovanna, Bianchi, Simonetta, Palli, Domenico, Ottini, Laura, Department of Molecular Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute-ISPO, Department of Pathology, and Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)

Subjects
Male Breast Cancer, Germ-line mutations
Abstract

International audience; Breast cancer (BC) in men is rare compared with BC in women, but its incidence is increasing along with attention toward this uncommon disease. Although with some differences, male and female BC share similar genetic predisposition factors, including , , and mutations. As other functionally related DNA repair genes, such as and , is considered a moderate-penetrance BC susceptibility gene. At present, the role of on BC susceptibility in men is unknown. In this study, we aimed to assess whether variants may contribute to male BC (MBC) risk, by screening 97 MBC cases, all negative for , , and mutations, selected from a population-based series of 126 MBCs from Central Italy. A total of five germ-line sequence alterations, three coding, and two non-coding variants, were detected in our series. The two non-coding variants IVS4-28G > A and 3′UTR 4049C > T were classified as neutral by analysis. Of the three coding variants, one was a silent variant (E879E) and two resulted in amino acid substitution (R264W and P919S) showing a putative pathogenic role by analysis. However, further analysis of tumor-associated loss of heterozygosity and the frequency of variant alleles, tested in 203 male population controls, suggested a neutral effect for both of these variants. Overall, our results indicate that variants may not play a relevant role in MBC predisposition.

Published
2010
Full Text
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33. mutations in male breast cancer: a population-based study in Central Italy

Author

Silvestri, Valentina, Rizzolo, Piera, Zanna, Ines, Falchetti, Mario, Masala, Giovanna, Bianchi, Simonetta, Papi, Laura, Giannini, Giuseppe, Palli, Domenico, Ottini, Laura, Department of Experimental Medicine, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Department of Pathology, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), and Medical Genetics Unit, Department of Clinical Physiopathology

Subjects
Medicine, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2010
Full Text
View/download PDF

37. Additional file 1: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
endocrine system diseases, skin and connective tissue diseases, neoplasms, female genital diseases and pregnancy complications, 3. Good health
Abstract

Male BRCA1 and BRCA2 mutation carriers by study group/country. (DOCX 21 kb)

38. Additional file 2: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
3. Good health
Abstract

List of local ethics committees that granted approval for the access and use of the data in present study. (DOCX 23 kb)

39. Additional file 3: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
3. Good health
Abstract

Methods and thresholds used to define the final marker variables for study groups providing MBC cases. (DOCX 20 kb)

40. Additional file 6: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
polycyclic compounds, bacteria, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, skin and connective tissue diseases, 3. Good health
Abstract

Pathology of invasive MBCs in the general population from SEER and BRCA1 MBCs and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)

41. Additional file 4: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
endocrine system diseases, polycyclic compounds, skin and connective tissue diseases, neoplasms, female genital diseases and pregnancy complications, 3. Good health
Abstract

Pathology of BRCA1 and BRCA2 MBCs and ORs in predicting BRCA2 mutation carrier status. (DOCX 20 kb)

42. Association of Genomic Domains in BRCA1 and BRCA2 with Prostate Cancer Risk and Aggressiveness

Author

Patel, Vivek L, Busch, Evan L, Friebel, Tara M, Cronin, Angel, Leslie, Goska, McGuffog, Lesley, Adlard, Julian, Agata, Simona, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Alducci, Elisa, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Artioli, Grazia, Arver, Brita, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barnes, Daniel R, Barroso, Alicia, Barrowdale, Daniel, Belotti, Muriel, Benitez, Javier, Bertelsen, Birgitte, Blok, Marinus J, Bodrogi, Istvan, Bonadona, Valérie, Bonanni, Bernardo, Bondavalli, Davide, Boonen, Susanne E, Borde, Julika, Borg, Ake, Bradbury, Angela R, Brady, Angela, Brewer, Carole, Brunet, Joan, Buecher, Bruno, Buys, Saundra S, Cabezas-Camarero, Santiago, Caldés, Trinidad, Caliebe, Almuth, Caligo, Maria A, Calvello, Mariarosaria, Campbell, Ian G, Carnevali, Ileana, Carrasco, Estela, Chan, Tsun L, Chu, Annie TW, Chung, Wendy K, Claes, Kathleen BM, Collaborators, Gemo Study, Collaborators, Embrace, Cook, Jackie, Cortesi, Laura, Couch, Fergus J, Daly, Mary B, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, De La Hoya, Miguel, Puppa, Lara Della, Dennis, Joe, Díez, Orland, Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M, Donaldson, Alan, Dworniczak, Bernd, Easton, Douglas F, Eccles, Diana M, Eeles, Rosalind A, Ehrencrona, Hans, Ejlertsen, Bent, Engel, Christoph, Evans, D Gareth, Faivre, Laurence, Faust, Ulrike, Feliubadaló, Lídia, Foretova, Lenka, Fostira, Florentia, Fountzilas, George, Frost, Debra, García-Barberán, Vanesa, Garre, Pilar, Gauthier-Villars, Marion, Géczi, Lajos, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gutierrez-Barrera, Angelica M, Hahnen, Eric, Hamann, Ute, Hauke, Jan, Herold, Natalie, Hogervorst, Frans BL, Honisch, Ellen, Hopper, John L, Hulick, Peter J, Investigators, KConFab, Investigators, Hebon, Izatt, Louise, Jager, Agnes, James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, Jensen, Thomas Dyrso, Johannsson, Oskar Th, John, Esther M, Joseph, Vijai, Kang, Eunyoung, Kast, Karin, Kiiski, Johanna I, Kim, Sung-Won, Kim, Zisun, Ko, Kwang-Pil, Konstantopoulou, Irene, Kramer, Gero, Krogh, Lotte, Kruse, Torben A, Kwong, Ava, Larsen, Mirjam, Lasset, Christine, Lautrup, Charlotte, Lazaro, Conxi, Lee, Jihyoun, Lee, Jong Won, Lee, Min Hyuk, Lemke, Johannes, Lesueur, Fabienne, Liljegren, Annelie, Lindblom, Annika, Llovet, Patricia, Lopez-Fernández, Adria, Lopez-Perolio, Irene, Lorca, Victor, Loud, Jennifer T, Ma, Edmond SK, Mai, Phuong L, Manoukian, Siranoush, Mari, Veronique, Martin, Lynn, Matricardi, Laura, Mebirouk, Noura, Medici, Veronica, Meijers-Heijboer, Hanne EJ, Meindl, Alfons, Mensenkamp, Arjen R, Miller, Clare, Gomes, Denise Molina, Montagna, Marco, Mooij, Thea M, Moserle, Lidia, Mouret-Fourme, Emmanuelle, Mulligan, Anna Marie, Nathanson, Katherine L, Navratilova, Marie, Nevanlinna, Heli, Niederacher, Dieter, Nielsen, Finn C Cilius, Nikitina-Zake, Liene, Offit, Kenneth, Olah, Edith, Olopade, Olufunmilayo I, Ong, Kai-Ren, Osorio, Ana, Ott, Claus-Eric, Palli, Domenico, Park, Sue K, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Peixoto, Ana, Pérez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth Høgh, Porteous, Mary E, Pujana, Miguel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Rashid, Muhammad U, Rhiem, Kerstin, Rizzolo, Piera, Robson, Mark E, Rookus, Matti A, Rossing, Caroline M, Ruddy, Kathryn J, Santos, Catarina, Saule, Claire, Scarpitta, Rosa, Schmutzler, Rita K, Schuster, Hélène, Senter, Leigha, Seynaeve, Caroline M, Shah, Payal D, Sharma, Priyanka, Shin, Vivian Y, Silvestri, Valentina, Simard, Jacques, Singer, Christian F, Skytte, Anne-Bine, Snape, Katie, Solano, Angela R, Soucy, Penny, Southey, Melissa C, Spurdle, Amanda B, Steele, Linda, Steinemann, Doris, Stoppa-Lyonnet, Dominique, Stradella, Agostina, Sunde, Lone, Sutter, Christian, Tan, Yen Y, Teixeira, Manuel R, Teo, Soo Hwang, Thomassen, Mads, Tibiletti, Maria Grazia, Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda E, Tommasi, Stefania, Torres, Diana, Toss, Angela, Trainer, Alison H, Tung, Nadine, Van Asperen, Christi J, Van Der Baan, Frederieke H, Van Der Kolk, Lizet E, Van Der Luijt, Rob B, Van Hest, Liselotte P, Varesco, Liliana, Varon-Mateeva, Raymonda, Viel, Alessandra, Vierstraete, Jeroen, Villa, Roberta, Von Wachenfeldt, Anna, Wagner, Philipp, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Weitzel, Jeffrey N, Wieme, Greet, Yadav, Siddhartha, Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zorn, Kristin K, D'Amico, Anthony V, Freedman, Matthew L, Pomerantz, Mark M, Chenevix-Trench, Georgia, Antoniou, Antonis C, Neuhausen, Susan L, Ottini, Laura, Nielsen, Henriette Roed, and Rebbeck, Timothy R

Subjects
Adult, Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, endocrine system diseases, Adolescent, BRCA1 Protein, Prostatic Neoplasms, Genomics, Middle Aged, Prognosis, 3. Good health, Young Adult, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases, Genetic Association Studies, Aged
Abstract

Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3' region of BRCA2 (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; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63-5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71-4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12-11.54; P = 0.0002). No genotype-phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 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.

43. Additional file 5: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
endocrine system diseases, skin and connective tissue diseases, 3. Good health
Abstract

Pathology of invasive BRCA1 female and male breast tumours and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)

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

Author

Barnes, Daniel R, Silvestri, Valentina, Leslie, Goska, McGuffog, Lesley, Dennis, Joe, Yang, Xin, Adlard, Julian, Agnarsson, Bjarni A, Ahmed, Munaza, Aittomäki, Kristiina, Andrulis, Irene L, Arason, Adalgeir, Arnold, Norbert, Auber, Bernd, Azzollini, Jacopo, Balmaña, Judith, Barkardottir, Rosa B, Barrowdale, Daniel, Barwell, Julian, Belotti, Muriel, Benitez, Javier, Berthet, Pascaline, Boonen, Susanne E, Borg, Åke, Bozsik, Aniko, Brady, Angela F, Brennan, Paul, Brewer, Carole, Brunet, Joan, Bucalo, Agostino, Buys, Saundra S, Caldés, Trinidad, Caligo, Maria A, Campbell, Ian, Cassingham, Hayley, Christensen, Lise Lotte, Cini, Giulia, Claes, Kathleen BM, GEMO Study Collaborators, EMBRACE Collaborators, Cook, Jackie, Coppa, Anna, Cortesi, Laura, Damante, Giuseppe, Darder, Esther, Davidson, Rosemarie, De La Hoya, Miguel, De Leeneer, Kim, De Putter, Robin, Del Valle, Jesús, Diez, Orland, Ding, Yuan Chun, Domchek, Susan M, Donaldson, Alan, Eason, Jacqueline, Eeles, Ros, Engel, Christoph, Evans, D Gareth, Feliubadaló, Lidia, Fostira, Florentia, Frone, Megan, Frost, Debra, Gallagher, David, Gehrig, Andrea, Giraud, Sophie, Glendon, Gord, Godwin, Andrew K, Goldgar, David E, Greene, Mark H, Gregory, Helen, Gross, Eva, Hahnen, Eric, Hamann, Ute, Hansen, Thomas VO, Hanson, Helen, Hentschel, Julia, Horvath, Judit, KConFab Investigators, HEBON Investigators, Izatt, Louise, Izquierdo, Angel, James, Paul A, Janavicius, Ramunas, Jensen, Uffe Birk, Johannsson, Oskar Th, John, Esther M, Kramer, Gero, Kroeldrup, Lone, Kruse, Torben A, Lautrup, Charlotte, Lazaro, Conxi, Lesueur, Fabienne, Lopez-Fernández, Adria, Mai, Phuong L, Manoukian, Siranoush, Matrai, Zoltan, Matricardi, Laura, Maxwell, Kara N, Mebirouk, Noura, Meindl, Alfons, Montagna, Marco, Monteiro, Alvaro N, Morrison, Patrick J, Muranen, Taru A, Murray, Alex, Nathanson, Katherine L, Neuhausen, Susan L, Nevanlinna, Heli, Nguyen-Dumont, Tu, Niederacher, Dieter, Olah, Edith, Olopade, Olufunmilayo I, Palli, Domenico, Parsons, Michael T, Pedersen, Inge Sokilde, Peissel, Bernard, Perez-Segura, Pedro, Peterlongo, Paolo, Petersen, Annabeth H, Pinto, Pedro, Porteous, Mary E, Pottinger, Caroline, Pujana, Miquel Angel, Radice, Paolo, Ramser, Juliane, Rantala, Johanna, Robson, Mark, Rogers, Mark T, Rønlund, Karina, Rump, Andreas, Sánchez De Abajo, Ana María, Shah, Payal D, Sharif, Saba, Side, Lucy E, Singer, Christian F, Stadler, Zsofia, Steele, Linda, Stoppa-Lyonnet, Dominique, Sutter, Christian, Tan, Yen Yen, Teixeira, Manuel R, Teulé, Alex, Thull, Darcy L, Tischkowitz, Marc, Toland, Amanda E, Tommasi, Stefania, Toss, Angela, Trainer, Alison H, Tripathi, Vishakha, Valentini, Virginia, Van Asperen, Christi J, Venturelli, Marta, Viel, Alessandra, Vijai, Joseph, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Whaite, Anna, Zanna, Ines, Offit, Kenneth, Thomassen, Mads, Couch, Fergus J, Schmutzler, Rita K, Simard, Jacques, Easton, Douglas F, Chenevix-Trench, Georgia, Antoniou, Antonis C, Ottini, Laura, and Consortium Of Investigators Of Modifiers Of BRCA1 And BRCA2

Subjects
Aged, 80 and over, BRCA2 Protein, Male, Heterozygote, BRCA1 Protein, Prostatic Neoplasms, Breast Neoplasms, Polymorphism, Single Nucleotide, Risk Assessment, 3. Good health, Risk Factors, Mutation, Humans, Genetic Predisposition to Disease, skin and connective tissue diseases
Abstract

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 1318 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 3 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 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios 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 informing clinical management.

45. Additional file 4: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
endocrine system diseases, polycyclic compounds, skin and connective tissue diseases, neoplasms, female genital diseases and pregnancy complications, 3. Good health
Abstract

Pathology of BRCA1 and BRCA2 MBCs and ORs in predicting BRCA2 mutation carrier status. (DOCX 20 kb)

46. Additional file 3: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
3. Good health
Abstract

Methods and thresholds used to define the final marker variables for study groups providing MBC cases. (DOCX 20 kb)

47. Additional file 6: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
polycyclic compounds, bacteria, biochemical phenomena, metabolism, and nutrition, bacterial infections and mycoses, skin and connective tissue diseases, 3. Good health
Abstract

Pathology of invasive MBCs in the general population from SEER and BRCA1 MBCs and ORs in predicting male BRCA1 mutation carrier status. (DOCX 19 kb)

48. Additional file 1: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
endocrine system diseases, skin and connective tissue diseases, neoplasms, female genital diseases and pregnancy complications, 3. Good health
Abstract

Male BRCA1 and BRCA2 mutation carriers by study group/country. (DOCX 21 kb)

49. Additional file 2: of Male breast cancer in BRCA1 and BRCA2 mutation carriers: pathology data from the Consortium of Investigators of Modifiers of BRCA1/2

Author

Silvestri, Valentina, Barrowdale, Daniel, Mulligan, Anna, Neuhausen, Susan, Fox, Stephen, Karlan, Beth, Mitchell, Gillian, James, Paul, Thull, Darcy, Zorn, Kristin, Carter, Natalie, Nathanson, Katherine, Domchek, Susan, Rebbeck, Timothy, Ramus, Susan, Nussbaum, Robert, Olufunmilayo Olopade, Rantala, Johanna, Sook-Yee Yoon, Caligo, Maria, Spugnesi, Laura, Bojesen, Anders, Pedersen, Inge, Thomassen, Mads, Jensen, Uffe, Toland, Amanda, Leigha Senter, Andrulis, Irene, Gord Glendon, Hulick, Peter, Imyanitov, Evgeny, Greene, Mark, Mai, Phuong, Singer, Christian, Rappaport-Fuerhauser, Christine, Kramer, Gero, Vijai, Joseph, Offit, Kenneth, Robson, Mark, Lincoln, Anne, Jacobs, Lauren, Machackova, Eva, Foretova, Lenka, Navratilova, Marie, Vasickova, Petra, Couch, Fergus, Hallberg, Emily, Ruddy, Kathryn, Sharma, Priyanka, Kim, Sung-Won, Teixeira, Manuel, Pinto, Pedro, Montagna, Marco, Matricardi, Laura, Adalgeir Arason, Johannsson, Oskar, Barkardottir, Rosa, Jakubowska, Anna, Lubinski, Jan, Izquierdo, Angel, Pujana, Miguel, Balmaùa, Judith, Diez, Orland, Ivady, Gabriella, Janos Papp, Olah, Edith, Kwong, Ava, Nevanlinna, Heli, AittomäKi, Kristiina, Segura, Pedro Perez, Caldes, Trinidad, Maerken, Tom Van, Poppe, Bruce, Claes, Kathleen, Isaacs, Claudine, Elan, Camille, Lasset, Christine, Stoppa-Lyonnet, Dominique, Barjhoux, Laure, Belotti, Muriel, Meindl, Alfons, Gehrig, Andrea, Sutter, Christian, Engel, Christoph, Niederacher, Dieter, Steinemann, Doris, Hahnen, Eric, Kast, Karin, Arnold, Norbert, Raymonda Varon-Mateeva, Wand, Dorothea, Godwin, Andrew, D. Evans, Frost, Debra, Perkins, Jo, Adlard, Julian, Izatt, Louise, Platte, Radka, Eeles, Ros, Ellis, Steve, Hamann, Ute, Garber, Judy, Fostira, Florentia, Fountzilas, George, Pasini, Barbara, Giannini, Giuseppe, Rizzolo, Piera, Russo, Antonio, Cortesi, Laura, Papi, Laura, Varesco, Liliana, Palli, Domenico, Zanna, Ines, Savarese, Antonella, Radice, Paolo, Manoukian, Siranoush, Peissel, Bernard, Barile, Monica, Bonanni, Bernardo, Viel, Alessandra, Pensotti, Valeria, Tommasi, Stefania, Peterlongo, Paolo, Weitzel, Jeffrey, Osorio, Ana, Benitez, Javier, McGuffog, Lesley, Healey, Sue, Gerdes, Anne-Marie, Ejlertsen, Bent, Hansen, Thomas, Steele, Linda, Ding, Yuan, Tung, Nadine, Ramunas Janavicius, Goldgar, David, Buys, Saundra, Daly, Mary, Bane, Anita, Terry, Mary, John, Esther, Southey, Melissa, Easton, Douglas, Chenevix-Trench, Georgia, Antoniou, Antonis, and Ottini, Laura

Subjects
3. Good health
Abstract

List of local ethics committees that granted approval for the access and use of the data in present study. (DOCX 23 kb)

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

Author

Silvia Corbetta, Vittoria Disciglio, Martina Lepore Signorile, Alberto Del Rio, Natale Porta, Valentina Grossi, Stefania Bertora, Valeria Di Maio, Manuela Bartolini, Valentina Silvestri, Giovanna Forte, Cristiano Simone, Paola Sanese, Giuseppina Caretti, Katia De Marco, Giacomo Buscemi, Laura Ottini, Cinzia Bottino, Candida Fasano, Virginia Valentini, Elisabetta Manoni, Gianluigi Giannelli, Ummu Guven, Edoardo Fabini, Sanese, Paola, Fasano, Candida, Buscemi, Giacomo, Bottino, Cinzia, Corbetta, Silvia, Fabini, Edoardo, Silvestri, Valentina, Valentini, Virginia, Disciglio, Vittoria, Forte, Giovanna, Lepore Signorile, Martina, De Marco, Katia, Bertora, Stefania, Grossi, Valentina, Guven, Ummu, Porta, Natale, Di Maio, Valeria, Manoni, Elisabetta, Giannelli, Gianluigi, Bartolini, Manuela, Del Rio, Alberto, Caretti, Giuseppina, Ottini, Laura, and Simone, Cristiano

Subjects
0301 basic medicine, Mutant, RAD51, 02 engineering and technology, Synthetic lethality, medicine.disease_cause, Article, 03 medical and health sciences, medicine, carcinogenesi, lcsh:Science, Molecular Biology, Cancer, SMYD3, Multidisciplinary, Chemistry, cancer, cell biology, molecular biology, Cell Biology, 021001 nanoscience & nanotechnology, medicine.disease, Synthetic Lethality, 030104 developmental biology, PARP-dependent DNA damage, Cancer cell, Cancer research, Phosphorylation, lcsh:Q, 0210 nano-technology, Carcinogenesis, Homologous recombination
Abstract

Summary SMYD3 is frequently overexpressed in a wide variety of cancers. Indeed, its inactivation reduces tumor growth in preclinical in vivo animal models. However, extensive characterization in vitro failed to clarify SMYD3 function in cancer cells, although confirming its importance in carcinogenesis. Taking advantage of a SMYD3 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., Graphical Abstract, Highlights • SMYD3 phosphorylation by ATM favors the formation of HR complexes during DSB response • SMYD3 mediates DSB repair by promoting RAD51 recruitment at DNA damage sites • SMYD3 inhibition triggers a compensatory PARP-dependent DNA damage response • Co-targeting SMYD3/PARP leads to synthetic lethality in HR-proficient cancer cells, Molecular Biology; Cell Biology; Cancer

Published
2020

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