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https://www.readbyqxmd.com/read/28503720/contribution-of-germline-mutations-in-cancer-predisposition-genes-to-tumor-etiology-in-young-women-diagnosed-with-invasive-breast-cancer
#1
Seth K Rummel, Leann Lovejoy, Craig D Shriver, Rachel E Ellsworth
PURPOSE: Although breast cancer in young women accounts for <10% of diagnoses annually, tumors in young patients exhibit more aggressive characteristics and higher mortality rates. Determination of the frequency of germline mutations in cancer predisposition genes is needed to improve the understanding of breast cancer etiology in young women. METHODS: All female patients enrolled in the Clinical Breast Cancer Project between 2001 and 2015 and diagnosed with invasive breast cancer before age 40 were included in this study...
May 13, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28488580/germline-mutations-in-pancreatic-cancer-and-potential-new-therapeutic-options
#2
REVIEW
Rille Pihlak, Juan W Valle, Mairéad G McNamara
Due to short-lived treatment responses in unresectable disease, pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest cancers. There is availability of new information about germline and sporadic mutations in the deoxyribonucleic acid (DNA) damage repair pathway in PDAC in recent decades and the expectation is that novel targeted therapies will thus be developed. A variety of germline mutations (BRCA2, BRCA1, PALB2, CDKN2A, ATM, TP53 and mismatch repair genes MLH1, MSH2, MSH6) have been reported in these patients with the highest prevalence being BRCA1/2...
April 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28486781/genomic-analysis-of-inherited-breast-cancer-among-palestinian-women-genetic-heterogeneity-and-a-founder-mutation-in-tp53
#3
Suhair Lolas Hamameh, Paul Renbaum, Lara Kamal, Dima Dweik, Mohammad Salahat, Tamara Jaraysa, Amal Abu Rayyan, Silvia Casadei, Jessica B Mandell, Suleyman Gulsuner, Ming K Lee, Tom Walsh, Mary-Claire King, Ephrat Levy-Lahad, Moein Kanaan
Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital-based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother, or aunt ("discovery series"); and 422 women diagnosed after age 40 and with negative family history ("older-onset sporadic patient series")...
May 9, 2017: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/28450425/circulating-free-dna-to-guide-prostate-cancer-treatment-with-parp-inhibition
#4
Jane Goodall, Joaquin Mateo, Wei Yuan, Helen Mossop, Nuria Porta, Susana Miranda, Raquel Perez-Lopez, David Dolling, Dan R Robinson, Shahneen Sandhu, Gemma Fowler, Berni Ebbs, Penny Flohr, George Seed, Daniel Nava Rodrigues, Gunther Boysen, Claudia Bertan, Mark Atkin, Matthew Clarke, Mateus Crespo, Ines Figueiredo, Ruth Riisnaes, Semini Sumanasuriya, Pasquale Rescigno, Zafeiris Zafeiriou, Adam Sharp, Nina Tunariu, Diletta Bianchini, Alexa Gillman, Christopher J Lord, Emma Hall, Arul M Chinnaiyan, Suzanne Carreira, Johann S de Bono
Biomarkers for a more precise patient care are needed in metastatic prostate cancer (mPC). We have reported a Phase II trial (TOPARP-A) of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib in mPC, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole exome sequencing of serial circulating-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0...
April 27, 2017: Cancer Discovery
https://www.readbyqxmd.com/read/28423363/multiple-gene-panel-analysis-in-a-case-series-of-255-women-with-hereditary-breast-and-ovarian-cancer
#5
Gianluca Tedaldi, Michela Tebaldi, Valentina Zampiga, Rita Danesi, Valentina Arcangeli, Mila Ravegnani, Ilaria Cangini, Francesca Pirini, Elisabetta Petracci, Andrea Rocca, Fabio Falcini, Dino Amadori, Daniele Calistri
As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS...
April 3, 2017: Oncotarget
https://www.readbyqxmd.com/read/28419251/evaluating-genetic-variants-associated-with-breast-cancer-risk-in-high-and-moderate-penetrance-genes-in-asians
#6
Mi-Ryung Han, Wei Zheng, Qiuyin Cai, Yu-Tang Gao, Ying Zheng, Manjeet K Bolla, Kyriaki Michailidou, Joe Dennis, Qin Wang, Alison M Dunning, Paul Brennan, Shou-Tung Chen, Ji-Yeob Choi, Mikael Hartman, Hidemi Ito, Artitaya Lophatananon, Keitaro Matsuo, Hui Miao, Kenneth Muir, Suleeporn Sangrajrang, Chen-Yang Shen, Soo Hwang Teo, Chiu-Chen Tseng, Anna H Wu, Cheng Har Yip, Daehee Kang, Yong-Bing Xiang, Douglas F Easton, Xiao-Ou Shu, Jirong Long
Over the past 20 years, high-penetrance pathogenic mutations in genes BRCA1, BRCA2, TP53, PTEN, STK11 and CDH1 and moderate-penetrance mutations in genes CHEK2, ATM, BRIP1, PALB2, RAD51C, RAD50 and NBN have been identified for breast cancer. In this study, we investigated whether there are additional variants in these 13 genes associated with breast cancer among women of Asian ancestry. We analyzed up to 654 single nucleotide polymorphisms (SNPs) from 6269 cases and 6624 controls of Asian descent included in the Breast Cancer Association Consortium (BCAC), and up to 236 SNPs from 5794 cases and 5529 controls included in the Shanghai Breast Cancer Genetics Study (SBCGS)...
May 1, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28418444/associations-between-cancer-predisposition-testing-panel-genes-and-breast-cancer
#7
Fergus J Couch, Hermela Shimelis, Chunling Hu, Steven N Hart, Eric C Polley, Jie Na, Emily Hallberg, Raymond Moore, Abigail Thomas, Jenna Lilyquist, Bingjian Feng, Rachel McFarland, Tina Pesaran, Robert Huether, Holly LaDuca, Elizabeth C Chao, David E Goldgar, Jill S Dolinsky
Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined. Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes. Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels...
April 13, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28413668/palb2-mutation-in-a-woman-with-bilateral-breast-cancer-a-case-report
#8
Hiroshi Nakagomi, Yosuke Hirotsu, Kenichiro Okimoto, Ikuko Sakamoto, Kenji Amemiya, Satoko Nakagomi, Takeo Kubota, Hitoshi Mochizuki, Masao Omata
Partner and localizer of breast cancer 2 (PALB2) was identified as a moderate-risk gene of breast and pancreas cancer. The present authors previously reported that no PALB2 germline mutations with a deleterious frameshift or stop codons were identified in 155 Japanese patients with breast and/or ovarian cancer who were estimated to be at risk of hereditary cancer, according to the National Comprehensive Cancer Network (NCCN) criteria. In the present study, one patient with a deleterious mutation of PALB2 (c...
April 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28407996/a-multigene-test-could-cost-effectively-help-extend-life-expectancy-for-women-at-risk-of-hereditary-breast-cancer
#9
COMPARATIVE STUDY
Yonghong Li, Andre R Arellano, Lance A Bare, Richard A Bender, Charles M Strom, James J Devlin
BACKGROUND: The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. OBJECTIVES: To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy...
April 2017: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
https://www.readbyqxmd.com/read/28398700/differential-requirements-for-dna-repair-proteins-in-immortalized-cell-lines-using-alternative-lengthening-of-telomere-mechanisms
#10
Alaina R Martinez, Zeenia Kaul, Jeffrey D Parvin, Joanna Groden
Cancer cells require telomere maintenance to enable uncontrolled growth. Most often telomerase is activated, although a subset of human cancers are telomerase-negative and depend on recombination-based mechanisms known as ALT (Alternative Lengthening of Telomeres). ALT depends on proteins that are essential for homologous recombination, including BLM and the MRN complex, to extend telomeres. This study surveyed the requirement for requisite homologous recombination proteins, yet to be studied in human ALT cell lines, by protein depletion using RNA interference...
April 11, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28398198/functional-and-mutational-landscapes-of-brca1-for-homology-directed-repair-and-therapy-resistance
#11
Rachel W Anantha, Srilatha Simhadri, Tzeh Keong Foo, Susanna Miao, Jingmei Liu, Zhiyuan Shen, Shridar Ganesan, Bing Xia
BRCA1 plays a critical role in homology-directed repair (HDR) of DNA double strand breaks, and the repair defect of BRCA1-mutant cancer cells is being targeted with platinum drugs and poly (ADP-ribose) polymerase (PARP) inhibitors. We have employed relatively simple and sensitive assays to determine the function of BRCA1 variants or mutants in two HDR mechanisms, homologous recombination (HR) and single strand annealing (SSA), and in conferring resistance to cisplatin and olaparib in human cancer cells. Our results define the functionality of the top 22 patient-derived BRCA1 missense variants and the contribution of different domains of BRCA1 and its E3 ubiquitin ligase activity to HDR and drug resistance...
April 11, 2017: ELife
https://www.readbyqxmd.com/read/28319063/compromised-brca1-palb2-interaction-is-associated-with-breast-cancer-risk
#12
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
#13
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
#14
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...
April 2017: DNA Repair
https://www.readbyqxmd.com/read/28240985/a-palb2-interacting-domain-in-rnf168-couples-homologous-recombination-to-dna-break-induced-chromatin-ubiquitylation
#15
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
#16
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
#17
Joris Pauty, Anthony M Couturier, Amélie Rodrigue, Marie-Christine Caron, Yan Coulombe, Graham Dellaire, Jean-Yves Masson
One typical mechanism to promote genomic instability, a hallmark of cancer, is to inactivate tumor suppressors, such as PALB2. It has recently been reported that mutations in PALB2 increase the risk of breast cancer by 8-9-fold by age 40 and the life time risk is ∼3-4-fold. To date, predicting the functional consequences of PALB2 mutations has been challenging as they lead to different cancer risks. Here, we performed a structure-function analysis of PALB2, using PALB2 truncated mutants (R170fs, L531fs, Q775X and W1038X), and uncovered a new mechanism by which cancer cells could drive genomic instability...
March 17, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28135145/cancer-susceptibility-gene-mutations-in-individuals-with-colorectal-cancer
#18
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...
April 1, 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
#19
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
#20
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)
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