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https://www.readbyqxmd.com/read/28319063/compromised-brca1-palb2-interaction-is-associated-with-breast-cancer-risk
#1
T K Foo, M Tischkowitz, S Simhadri, T Boshari, N Zayed, K A Burke, S H Berman, P Blecua, N Riaz, Y Huo, Y C Ding, S L Neuhausen, B Weigelt, J S Reis-Filho, W D Foulkes, B Xia
The major breast cancer suppressor proteins BRCA1 and BRCA2 play essential roles in homologous recombination (HR)-mediated DNA repair, which is thought to be critical for tumor suppression. The two BRCA proteins are linked by a third tumor suppressor, PALB2, in the HR pathway. While truncating mutations in these genes are generally pathogenic, interpretation of missense variants remains a challenge. To date, patient-derived missense variants that disrupt PALB2 binding have been identified in BRCA1 and BRCA2; however, there has not been sufficient evidence to prove their pathogenicity in humans, and no variants in PALB2 that disrupt either its BRCA1 or BRCA2 binding have been reported...
March 20, 2017: Oncogene
https://www.readbyqxmd.com/read/28279176/palb2-mutations-in-brca1-2-mutation-negative-breast-and-ovarian-cancer-patients-from-poland
#2
Anna Kluska, Aneta Balabas, Magdalena Piatkowska, Katarzyna Czarny, Katarzyna Paczkowska, Dorota Nowakowska, Michal Mikula, Jerzy Ostrowski
BACKGROUND: The PALB2 gene encodes a protein that plays a crucial role in maintaining genomic integrity. Germline inactivating mutations in PALB2 are associated with an increased risk of breast and ovarian cancer. The prevalence and spectrum of recurrent PALB2 germline mutations in breast and ovarian cancer patients from Poland is not clearly defined. METHODS: PALB2 exons were amplified from 460 BRCA1/2-mutation negative women with familial breast and/or ovarian cancer and early-onset breast cancer using AmpliSeq technology and sequenced on an Ion Torrent PGM sequencer...
March 9, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28254358/specific-killing-of-dna-damage-response-deficient-cells-with-inhibitors-of-poly-adp-ribose-glycohydrolase
#3
Polly Gravells, Emma Grant, Kate M Smith, Dominic I James, Helen E Bryant
Poly(ADP-ribosylation) of proteins following DNA damage is well studied and the use of poly(ADP-ribose) polymerase (PARP) inhibitors as therapeutic agents is an exciting prospect for the treatment of many cancers. Poly(ADP-ribose) glycohydrolase (PARG) has endo- and exoglycosidase activities which can cleave glycosidic bonds, rapidly reversing the action of PARP enzymes. Like addition of poly(ADP-ribose) (PAR) by PARP, removal of PAR by PARG is also thought to be required for repair of DNA strand breaks and for continued replication at perturbed forks...
February 17, 2017: DNA Repair
https://www.readbyqxmd.com/read/28240985/a-palb2-interacting-domain-in-rnf168-couples-homologous-recombination-to-dna-break-induced-chromatin-ubiquitylation
#4
Martijn S Luijsterburg, Dimitris Typas, Marie-Christine Caron, Wouter W Wiegant, Diana van den Heuvel, Rick A Boonen, Anthony M Couturier, Leon H Mullenders, Jean-Yves Masson, Haico van Attikum
DNA double-strand breaks (DSB) elicit a ubiquitylation cascade that controls DNA repair pathway choice. This cascade involves the ubiquitylation of histone H2A by the RNF168 ligase and the subsequent recruitment of RIF1, which suppresses homologous recombination (HR) in G1 cells. The RIF1-dependent suppression is relieved in S/G2 cells, allowing PALB2-driven HR to occur. With the inhibitory impact of RIF1 relieved, it remains unclear how RNF168-induced ubiquitylation influences HR. Here, we uncover that RNF168 links the HR machinery to H2A ubiquitylation in S/G2 cells...
February 27, 2017: ELife
https://www.readbyqxmd.com/read/28194609/a-high-frequency-of-palb2-mutations-in-jamaican-patients-with-breast-cancer
#5
Jordan Lerner-Ellis, Talia Donenberg, Humayun Ahmed, Sophia George, Gilian Wharfe, Sheray Chin, Dwight Lowe, Robert Royer, Shiyu Zhang, Steven Narod, Judith Hurley, Mohammad R Akbari
PURPOSE: Jamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer. METHODS: We sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects...
April 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28158555/cancer-causing-mutations-in-the-tumor-suppressor-palb2-reveal-a-novel-cancer-mechanism-using-a-hidden-nuclear-export-signal-in-the-wd40-repeat-motif
#6
Joris Pauty, Anthony M Couturier, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Graham Dellaire, Jean-Yves Masson
No abstract text is available yet for this article.
February 1, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28135145/cancer-susceptibility-gene-mutations-in-individuals-with-colorectal-cancer
#7
Matthew B Yurgelun, Matthew H Kulke, Charles S Fuchs, Brian A Allen, Hajime Uno, Jason L Hornick, Chinedu I Ukaegbu, Lauren K Brais, Philip G McNamara, Robert J Mayer, Deborah Schrag, Jeffrey A Meyerhardt, Kimmie Ng, John Kidd, Nanda Singh, Anne-Renee Hartman, Richard J Wenstrup, Sapna Syngal
Purpose Hereditary factors play an important role in colorectal cancer (CRC) risk, yet the prevalence of germline cancer susceptibility gene mutations in patients with CRC unselected for high-risk features (eg, early age at diagnosis, personal/family history of cancer or polyps, tumor microsatellite instability [MSI], mismatch repair [MMR] deficiency) is unknown. Patients and Methods We recruited 1,058 participants who received CRC care in a clinic-based setting without preselection for age at diagnosis, personal/family history, or MSI/MMR results...
January 30, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28124401/brca1-alterations-with-additional-defects-in-dna-damage-response-genes-may-confer-chemoresistance-to-brca-like-breast-cancers-treated-with-neoadjuvant-chemotherapy
#8
Mamoru Takada, Shigenori Nagai, Masayuki Haruta, Ryuichi P Sugino, Katsunori Tozuka, Hiroyuki Takei, Fumie Ohkubo, Kenichi Inoue, Masafumi Kurosumi, Masaru Miyazaki, Aiko Sato-Otsubo, Yusuke Sato, Seishi Ogawa, Yasuhiko Kaneko
The BRCA-like phenotype is a feature that some sporadic breast cancers share with those occurring in BRCA1 or BRCA2 mutation carriers. As tumors with the phenotype have defects in the DNA damage response pathway, which may increase sensitivity to drugs such as DNA cross-linking agents and PARP inhibitors, a method to identify this phenotype is important. The prediction of chemoresistance, which frequently develops in these tumors, is also crucial for improving therapy. We examined genomic aberrations and BRCA1 promoter methylation in tumors of 73 breast cancer (20 HR-/HER2- and 53 HR+/HER2-) patients, who received neoadjuvant chemotherapy with anthracycline, cyclophosphamide, and taxane, using SNP array CGH and quantitative PCR...
May 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28090623/palb2-positive-breast-cancer-in-a-40-year-old-man
#9
Pritish Iyer, Jagar Jasem, Michelle A Springer, Catherine E Klein, Peter Kabos
No abstract text is available yet for this article.
January 15, 2017: Oncology (Williston Park, NY)
https://www.readbyqxmd.com/read/28089683/coupling-of-homologous-recombination-and-the-checkpoint-by-atr
#10
Rémi Buisson, Joshi Niraj, Amélie Rodrigue, Chu Kwen Ho, Johannes Kreuzer, Tzeh Keong Foo, Emilie J-L Hardy, Graham Dellaire, Wilhelm Haas, Bing Xia, Jean-Yves Masson, Lee Zou
ATR is a key regulator of cell-cycle checkpoints and homologous recombination (HR). Paradoxically, ATR inhibits CDKs during checkpoint responses, but CDK activity is required for efficient HR. Here, we show that ATR promotes HR after CDK-driven DNA end resection. ATR stimulates the BRCA1-PALB2 interaction after DNA damage and promotes PALB2 localization to DNA damage sites. ATR enhances BRCA1-PALB2 binding at least in part by inhibiting CDKs. The optimal interaction of BRCA1 and PALB2 requires phosphorylation of PALB2 at S59, an ATR site, and hypo-phosphorylation of S64, a CDK site...
January 19, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28027327/mutational-profile-of-metastatic-breast-cancers-a-retrospective-analysis
#11
Celine Lefebvre, Thomas Bachelot, Thomas Filleron, Marion Pedrero, Mario Campone, Jean-Charles Soria, Christophe Massard, Christelle Lévy, Monica Arnedos, Magali Lacroix-Triki, Julie Garrabey, Yannick Boursin, Marc Deloger, Yu Fu, Frédéric Commo, Véronique Scott, Ludovic Lacroix, Maria Vittoria Dieci, Maud Kamal, Véronique Diéras, Anthony Gonçalves, Jean-Marc Ferrerro, Gilles Romieu, Laurence Vanlemmens, Marie-Ange Mouret Reynier, Jean-Christophe Théry, Fanny Le Du, Séverine Guiu, Florence Dalenc, Gilles Clapisson, Hervé Bonnefoi, Marta Jimenez, Christophe Le Tourneau, Fabrice André
BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials...
December 2016: PLoS Medicine
https://www.readbyqxmd.com/read/28024868/germline-mutations-in-palb2-brca1-and-rad51c-which-regulate-dna-recombination-repair-in-patients-with-gastric-cancer
#12
Ruta Sahasrabudhe, Paul Lott, Mabel Bohorquez, Ted Toal, Ana P Estrada, John J Suarez, Alejandro Brea-Fernández, José Cameselle-Teijeiro, Carla Pinto, Irma Ramos, Alejandra Mantilla, Rodrigo Prieto, Alejandro Corvalan, Enrique Norero, Carolina Alvarez, Teresa Tapia, Pilar Carvallo, Luz M Gonzalez, Alicia Cock-Rada, Angela Solano, Florencia Neffa, Adriana Della Valle, Chris Yau, Gabriela Soares, Alexander Borowsky, Nan Hu, Li-Ji He, Xiao-You Han, Philip R Taylor, Alisa M Goldstein, Javier Torres, Magdalena Echeverry, Clara Ruiz-Ponte, Manuel R Teixeira, Luis G Carvajal-Carmona
Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination...
December 23, 2016: Gastroenterology
https://www.readbyqxmd.com/read/28011157/increased-identification-of-candidates-for-high-risk-breast-cancer-screening-through-expanded-genetic-testing
#13
Eric T Rosenthal, Brent Evans, John Kidd, Krystal Brown, Heidi Gorringe, Michael van Orman, Susan Manley
PURPOSE: Breast MRI screening is recommended for women with a >20% lifetime risk for breast cancer on the basis of estimates derived from risk models dependent largely on family history. Alternatively, a >20% lifetime risk can be established through genetic testing of BRCA1 and BRCA2, as well as a growing selection of other genes associated with inherited breast cancer risk. The aim of this study was to quantify the impact of testing for genes other than BRCA1/2 and the extent to which mutation carriers in these genes would have been identified as candidates for enhanced screening on the basis of family history alone...
December 20, 2016: Journal of the American College of Radiology: JACR
https://www.readbyqxmd.com/read/28008555/male-breast-cancer-in-a-multi-gene-panel-testing-cohort-insights-and-unexpected-results
#14
Mary Pritzlaff, Pia Summerour, Rachel McFarland, Shuwei Li, Patrick Reineke, Jill S Dolinsky, David E Goldgar, Hermela Shimelis, Fergus J Couch, Elizabeth C Chao, Holly LaDuca
PURPOSE: Genetic predisposition to male breast cancer (MBC) is not well understood. The aim of this study was to better define the predisposition genes contributing to MBC and the utility of germline multi-gene panel testing (MGPT) for explaining the etiology of MBCs. METHODS: Clinical histories and molecular results were retrospectively reviewed for 715 MBC patients who underwent MGPT from March 2012 to June 2016. RESULTS: The detection rate of MGPT was 18...
February 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/27978560/prevalence-and-spectrum-of-germline-cancer-susceptibility-gene-mutations-among-patients-with-early-onset-colorectal-cancer
#15
Rachel Pearlman, Wendy L Frankel, Benjamin Swanson, Weiqiang Zhao, Ahmet Yilmaz, Kristin Miller, Jason Bacher, Christopher Bigley, Lori Nelsen, Paul J Goodfellow, Richard M Goldberg, Electra Paskett, Peter G Shields, Jo L Freudenheim, Peter P Stanich, Ilene Lattimer, Mark Arnold, Sandya Liyanarachchi, Matthew Kalady, Brandie Heald, Carla Greenwood, Ian Paquette, Marla Prues, David J Draper, Carolyn Lindeman, J Philip Kuebler, Kelly Reynolds, Joanna M Brell, Amy A Shaper, Sameer Mahesh, Nicole Buie, Kisa Weeman, Kristin Shine, Mitchell Haut, Joan Edwards, Shyamal Bastola, Karen Wickham, Karamjit S Khanduja, Rosemary Zacks, Colin C Pritchard, Brian H Shirts, Angela Jacobson, Brian Allen, Albert de la Chapelle, Heather Hampel
Importance: Hereditary cancer syndromes infer high cancer risks and require intensive cancer surveillance, yet the prevalence and spectrum of these conditions among unselected patients with early-onset colorectal cancer (CRC) is largely undetermined. Objective: To determine the frequency and spectrum of cancer susceptibility gene mutations among patients with early-onset CRC. Design, Setting, and Participants: Overall, 450 patients diagnosed with colorectal cancer younger than 50 years were prospectively accrued from 51 hospitals into the Ohio Colorectal Cancer Prevention Initiative from January 1, 2013, to June 20, 2016...
December 15, 2016: JAMA Oncology
https://www.readbyqxmd.com/read/27974172/advances-in-structural-studies-of-recombination-mediator-proteins
#16
S Korolev
Recombination mediator proteins (RMPs) are critical for genome integrity in all organisms. They include phage UvsY, prokaryotic RecF, -O, -R (RecFOR) and eukaryotic Rad52, Breast Cancer susceptibility 2 (BRCA2) and Partner and localizer of BRCA2 (PALB2) proteins. BRCA2 and PALB2 are tumor suppressors implicated in cancer. RMPs regulate binding of RecA-like recombinases to sites of DNA damage to initiate the most efficient non-mutagenic repair of broken chromosome and other deleterious DNA lesions. Mechanistically, RMPs stimulate a single-stranded DNA (ssDNA) hand-off from ssDNA binding proteins (ssbs) such as gp32, SSB and RPA, to recombinases, activating DNA repair only at the time and site of the damage event...
December 6, 2016: Biophysical Chemistry
https://www.readbyqxmd.com/read/27924011/roles-for-aprin-pds5b-in-homologous-recombination-and-in-ovarian-cancer-prediction
#17
Anthony M Couturier, Hubert Fleury, Anne-Marie Patenaude, Victoria L Bentley, Amélie Rodrigue, Yan Coulombe, Joshi Niraj, Joris Pauty, Jason N Berman, Graham Dellaire, Javier M Di Noia, Anne-Marie Mes-Masson, Jean-Yves Masson
APRIN (PDS5 cohesin associated factor B) interacts with both the cohesin complex and the BRCA2 tumor suppressor. How APRIN influences cohesion and DNA repair processes is not well understood. Here, we show that APRIN is recruited to DNA damage sites. We find that APRIN interacts directly with RAD51, PALB2 and BRCA2. APRIN stimulates RAD51-mediated DNA strand invasion. APRIN also binds DNA with an affinity for D-loop structures and single-strand (ss) DNA. APRIN is a new homologous recombination (HR) mediator as it counteracts the RPA inhibitory effect on RAD51 loading to ssDNA...
December 15, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27902704/methylation-of-breast-cancer-predisposition-genes-in-early-onset-breast-cancer-australian-breast-cancer-family-registry
#18
Cameron M Scott, JiHoon Eric Joo, Neil O'Callaghan, Daniel D Buchanan, Mark Clendenning, Graham G Giles, John L Hopper, Ee Ming Wong, Melissa C Southey
DNA methylation can mimic the effects of both germline and somatic mutations for cancer predisposition genes such as BRCA1 and p16INK4a. Constitutional DNA methylation of the BRCA1 promoter has been well described and is associated with an increased risk of early-onset breast cancers that have BRCA1-mutation associated histological features. The role of methylation in the context of other breast cancer predisposition genes has been less well studied and often with conflicting or ambiguous outcomes. We examined the role of methylation in known breast cancer susceptibility genes in breast cancer predisposition and tumor development...
2016: PloS One
https://www.readbyqxmd.com/read/27878467/outcomes-of-retesting-brca-negative-patients-using-multigene-panels
#19
Siddhartha Yadav, Ashley Reeves, Sarah Campian, Amy Paine, Dana Zakalik
The utility of multigene panels in retesting patients who previously tested negative for a pathogenic mutation by BRCA1/2 testing is not well established. Patients who previously tested negative for a pathogenic BRCA1/2 mutation by standard sequencing, and who were seen in cancer genetics center between November 1, 2012 and June 30, 2015 for additional testing utilizing multigene panels, were identified using our genetic testing registry. Data on demographics, personal and family history of cancer, results of panel testing and the impact on patient management was collected retrospectively...
November 22, 2016: Familial Cancer
https://www.readbyqxmd.com/read/27803004/mismatch-repair-deficient-metastatic-pancreatic-ductal-adenocarcinoma-with-a-germline-palb2-mutation-unusual-genetics-unusual-clinical-course
#20
Stefan Boeck, Yasmin Mehraein, Steffen Ormanns, Stephan Kruger, C Benedikt Westphalen, Michael Haas, Andreas Jung, Thomas Kirchner, Volker Heinemann
No abstract text is available yet for this article.
November 1, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
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