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https://www.readbyqxmd.com/read/28819011/tp53-mutations-identify-younger-mantle-cell-lymphoma-patients-who-do-not-benefit-from-intensive-chemoimmunotherapy
#1
Christian W Eskelund, Christina Dahl, Jakob W Hansen, Maj Westman, Arne Kolstad, Lone B Pedersen, Carmen P Montano-Almendras, Simon Husby, Catja Freiburghaus, Sara Ek, Anja Pedersen, Carsten Niemann, Riikka Räty, Peter Brown, Christian H Geisler, Mette K Andersen, Per Guldberg, Mats Jerkeman, Kirsten Grønbæk
Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67>30%); however, in multivariate analyses only TP53 mutations (HR=6...
August 17, 2017: Blood
https://www.readbyqxmd.com/read/28818438/cancer-risks-and-survival-in-patients-with-multiple-primary-melanomas-association-with-family-history-of-melanoma-and-germline-cdkn2a-mutation-status
#2
Hildur Helgadottir, Rainer Tuominen, Håkan Olsson, Johan Hansson, Veronica Höiom
BACKGROUND: Worse outcomes have been noted in patients with multiple primary melanomas (MPMs) than in patients with single primary melanomas. OBJECTIVE: We investigated how family history of melanoma and germline CDKN2A mutation status of MPM patients affects risks of developing subsequent melanomas and other cancers and survival outcomes. METHODS: Comprehensive data on cancer diagnoses and deaths of MPM patients, their first-degree relatives, and matched controls were obtained through Swedish national health care and population registries...
August 14, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28815047/whole-blood-rna-transcript-based-models-can-predict-clinical-response-in-two-large-independent-clinical-studies-of-patients-with-advanced-melanoma-treated-with-the-checkpoint-inhibitor-tremelimumab
#3
Philip Friedlander, Karl Wassmann, Alan M Christenfeld, David Fisher, Chrisann Kyi, John M Kirkwood, Nina Bhardwaj, William K Oh
BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions. METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset)...
2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28812223/prognostic-potential-of-klotho-and-sfrp1-promoter-methylation-in-head-and-neck-squamous-cell-carcinoma
#4
Abeer A Alsofyani, Rawiah A Alsiary, Alaa Samkari, Baraa T Alhaj-Hussain, Jalaluddin Azam Khan, Jaudah Al-Maghrabi, Aisha Elaimi, Mohammed H Al-Qahtani, Adel M Abuzenadah, Ashraf Dallol
Hypermethylation in the CpG island promoter regions of tumor suppressors is known to play a significant role in the development of HNSCC and the detection of which can aid the classification and prognosis of HNSCC. This study aims to profile the methylation patterns in a panel of key genes including CDKN2A, CDKN2B, KLOTHO (KL), RASSF1A, RARB, SLIT2, and SFRP1, in a group of HNSCC samples from Saudi Arabia. The extent of methylation in these genes is determined using the MethyLight assay and correlated with known clinicopathological parameters in our samples of 156 formalin-fixed and paraffin-embedded HNSCC tissues...
August 16, 2017: Journal of Applied Genetics
https://www.readbyqxmd.com/read/28810144/integrated-genomic-characterization-of-pancreatic-ductal-adenocarcinoma
#5
(no author information available yet)
We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations...
August 14, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28809762/elucidation-of-novel-chromosomal-abnormalities-in-pancreatic-cancer-conventional-and-molecular-cytogenetic-characterization-of-16-pancreatic-cell-lines
#6
David Shabsovich, Carlos A Tirado
Pancreatic carcinoma is a major cause of cancer-related death in the United States, with a five-year survival rate of approximately 5%. Cytogenetic analysis has identified clinically significant chromosomal abnormalities in numerous malignancies, but it is not utilized in the clinical management of pancreatic carcinoma. We performed conventional and molecular cytogenetic analysis of 16 pancreatic carcinoma cell lines using Giemsa banding and DNA-based fluorescence in situ hybridization (FISH). Conventional cytogenetic analysis revealed a diversity of recurrent and clonal numerical and structural abnormalities in all cell lines analyzed, many of which occurred at loci of genes implicated in pancreatic or related cancers...
2017: Journal of the Association of Genetic Technologists
https://www.readbyqxmd.com/read/28807052/whole-blood-rna-transcript-based-models-can-predict-clinical-response-in-two-large-independent-clinical-studies-of-patients-with-advanced-melanoma-treated-with-the-checkpoint-inhibitor-tremelimumab
#7
Philip Friedlander, Karl Wassmann, Alan M Christenfeld, David Fisher, Chrisann Kyi, John M Kirkwood, Nina Bhardwaj, William K Oh
BACKGROUND: Tremelimumab is an antibody that blocks CTLA-4 and demonstrates clinical efficacy in a subset of advanced melanoma patients. An unmet clinical need exists for blood-based response-predictive gene signatures to facilitate clinically effective and cost-efficient use of such immunotherapeutic interventions. METHODS: Peripheral blood samples were collected in PAXgene® tubes from 210 treatment-naïve melanoma patients receiving tremelimumab in a worldwide, multicenter phase III study (discovery dataset)...
August 15, 2017: Journal for Immunotherapy of Cancer
https://www.readbyqxmd.com/read/28802642/prognostic-value-of-tert-alterations-and-mutational-and-copy-number-alteration-burden-in-urothelial-carcinoma
#8
Sumit Isharwal, François Audenet, Esther Drill, Eugene J Pietzak, Gopa Iyer, Irina Ostrovnaya, Eugene Cha, Timothy Donahue, Maria Arcila, Gowtham Jayakumaran, Michael F Berger, Jonathan E Rosenberg, Dean F Bajorin, Jonathan Coleman, Guido Dalbagni, Victor E Reuter, Bernard H Bochner, David B Solit, Hikmat A Al-Ahmadie
Missense mutations in the TERT gene promoter occur at high frequency in multiple cancers, including urothelial carcinoma (UC). However, the relationship between TERT promoter mutations and UC patient outcomes is unclear due to conflicting reports in the literature. In this study, we examined the association of TERT alterations, tumor mutational burden per megabase (Mb), and copy number alteration (CNA) burden with clinical parameters and their prognostic value in a cohort of 398 urothelial tumors. The majority of TERT mutations were located at two promoter region hotspots (chromosome 5, 1 295 228 C>T and 1 295 250 C>T)...
August 9, 2017: European Urology Focus
https://www.readbyqxmd.com/read/28792678/modeling-glaucoma-retinal-ganglion-cells-generated-from-induced-pluripotent-stem-cells-of-patients-with-six6-risk-allele-show-developmental-abnormalities
#9
Pooja Teotia, Matthew J Van Hook, Christopher S Wichman, R Rand Allingham, Michael A Hauser, Iqbal Ahmad
Glaucoma represents a group of multifactorial diseases with a unifying pathology of progressive retinal ganglion cell (RGC) degeneration, causing irreversible vision loss. To test the hypothesis that RGCs are intrinsically vulnerable in glaucoma we have developed an in vitro model using the SIX6 risk allele carrying glaucoma patient-specific induced pluripotent stem cells (iPSCs) for generating functional RGCs. Here, we demonstrate that the efficiency of RGC generation by SIX6 risk allele iPSCs is significantly lower than iPSCs-derived from healthy, age-and sex-matched controls...
August 9, 2017: Stem Cells
https://www.readbyqxmd.com/read/28783718/integrative-clinical-genomics-of-metastatic-cancer
#10
Dan R Robinson, Yi-Mi Wu, Robert J Lonigro, Pankaj Vats, Erin Cobain, Jessica Everett, Xuhong Cao, Erica Rabban, Chandan Kumar-Sinha, Victoria Raymond, Scott Schuetze, Ajjai Alva, Javed Siddiqui, Rashmi Chugh, Francis Worden, Mark M Zalupski, Jeffrey Innis, Rajen J Mody, Scott A Tomlins, David Lucas, Laurence H Baker, Nithya Ramnath, Ann F Schott, Daniel F Hayes, Joseph Vijai, Kenneth Offit, Elena M Stoffel, J Scott Roberts, David C Smith, Lakshmi P Kunju, Moshe Talpaz, Marcin Cieślik, Arul M Chinnaiyan
Metastasis is the primary cause of cancer-related deaths. Although The Cancer Genome Atlas has sequenced primary tumour types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here we perform whole-exome and -transcriptome sequencing of 500 adult patients with metastatic solid tumours of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1...
August 2, 2017: Nature
https://www.readbyqxmd.com/read/28780132/commentary-on-comprehensive-molecular-characterization-of-papillary-renal-cell-carcinoma-cancer-genome-atlas-research-network-n-engl-j-med-2016-jan-14-374-2-135-45
#11
Byron H Lee
BACKGROUND: Papillary renal-cell carcinoma, which accounts for 15%-20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation, and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist. METHODS: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis...
August 2, 2017: Urologic Oncology
https://www.readbyqxmd.com/read/28776573/pancreatic-intraductal-tubulopapillary-neoplasm-is-genetically-distinct-from-intraductal-papillary-mucinous-neoplasm-and-ductal-adenocarcinoma
#12
Olca Basturk, Michael F Berger, Hiroshi Yamaguchi, Volkan Adsay, Gokce Askan, Umesh K Bhanot, Ahmet Zehir, Fatima Carneiro, Seung-Mo Hong, Giuseppe Zamboni, Esra Dikoglu, Vaidehi Jobanputra, Kazimierz O Wrzeszczynski, Serdar Balci, Peter Allen, Naoki Ikari, Shoko Takeuchi, Hiroyuki Akagawa, Atsushi Kanno, Tooru Shimosegawa, Takanori Morikawa, Fuyuhiko Motoi, Michiaki Unno, Ryota Higuchi, Masakazu Yamamoto, Kyoko Shimizu, Toru Furukawa, David S Klimstra
Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28776571/expanded-molecular-profiling-of-myxofibrosarcoma-reveals-potentially-actionable-targets
#13
Ellen Heitzer, Sandra Sunitsch, Magdalena M Gilg, Birgit Lohberger, Beate Rinner, Karl Kashofer, Nicole Stündl, Peter Ulz, Joanna Szkandera, Andreas Leithner, Bernadette Liegl-Atzwanger
Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated...
August 4, 2017: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
https://www.readbyqxmd.com/read/28768142/contributions-of-ikzf1-ddc-cdkn2a-cebpe-and-lmo1-gene-polymorphisms-to-acute-lymphoblastic-leukemia-in-a-yemeni-population
#14
Boshra Al-Absi, Muhammad F M Razif, Suzita M Noor, Riyadh Saif-Ali, Mohammed Aqlan, Sameer D Salem, Radwan H Ahmed, Sekaran Muniandy
BACKGROUND: Genome-wide and candidate gene association studies have previously revealed links between acute lymphoblastic leukemia (ALL) predisposition and genetic polymorphisms in these genes: IKZF1 (7p12.2; ID: 10320), DDC (7p12.2; ID: 1644), CDKN2A (9p21.3; ID: 1029), CEBPE (14q11.2; ID: 1053), and LMO1 (11p15; ID: 4004). In this study, we aimed to conduct an investigation into the possible association between polymorphisms in these genes and ALL within a sample of Yemeni children of Arab-Asian descent...
August 2, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/28767289/deleterious-germline-mutations-in-patients-with-apparently-sporadic-pancreatic-adenocarcinoma
#15
Koji Shindo, Jun Yu, Masaya Suenaga, Shahriar Fesharakizadeh, Christy Cho, Anne Macgregor-Das, Abdulrehman Siddiqui, P Dane Witmer, Koji Tamura, Tae Jun Song, Jose Alejandro Navarro Almario, Aaron Brant, Michael Borges, Madeline Ford, Thomas Barkley, Jin He, Matthew J Weiss, Christopher L Wolfgang, Nicholas J Roberts, Ralph H Hruban, Alison P Klein, Michael Goggins
Purpose Deleterious germline mutations contribute to pancreatic cancer susceptibility and are well documented in families in which multiple members have had pancreatic cancer. Methods To define the prevalence of these germline mutations in patients with apparently sporadic pancreatic cancer, we sequenced 32 genes, including known pancreatic cancer susceptibility genes, in DNA prepared from normal tissue obtained from 854 patients with pancreatic ductal adenocarcinoma, 288 patients with other pancreatic and periampullary neoplasms, and 51 patients with non-neoplastic diseases who underwent pancreatic resection at Johns Hopkins Hospital between 2000 and 2015...
August 2, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28765905/mir-663-promotes-npc-cell-proliferation-by-directly-targeting-cdkn2a
#16
Shaoqiang Liang, Ning Zhang, Yanming Deng, Lusi Chen, Yang Zhang, Zhenhe Zheng, Weijun Luo, Zhiqian Lv, Shaoen Li, Tao Xu
MicroRNAs (miRs) act as important regulators during the development and progression of human cancer; however, the regulatory mechanism of miR-663 in nasopharyngeal carcinoma (NPC) remains unclear. The present study demonstrated that serum miR‑663 levels were significantly increased in patients with NPC compared with healthy controls. In addition, the serum levels of miR‑663 were associated with the grade, lymph node metastasis and clinical stage of NPC. The expression of miR‑663 was increased in NPC C666‑1 cells, compared with normal nasopharyngeal epithelial NP69 cells...
August 1, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28765326/outcome-of-azacitidine-therapy-in-acute-myeloid-leukemia-is-not-improved-by-concurrent-vorinostat-therapy-but-is-predicted-by-a-diagnostic-molecular-signature
#17
Charles Craddock, Aimee E Houlton, Lynn S Quek, Paul Ferguson, Emmanouela Gbandi, Corran Roberts, Marlen Metzner, Natalia Garcia-Martin, Alison Kennedy, Angela Hamblin, Manoj Raghavan, Sandeep Nagra, Louise Dudley, Keith Wheatley, Mary Frances McMullin, Srinivas Pillai, Richard J Kelly, Shamyla Siddique, Michael Dennis, Jamie D Cavenagh, Paresh Vyas
Purpose: Azacitidine (AZA) is a novel therapeutic option in older patients with acute myeloid leukemia (AML) but its rational utilization is compromised by the fact that neither the determinants of clinical response nor its mechanism of action are defined. Co-administration of histone deacetylase inhibitors, such as vorinostat (VOR), is reported to improve the clinical activity of AZA but this has not been prospectively studied in AML. Experimental Design: We compared outcomes in 259 adults with AML (n=217) and MDS (n=42) randomized to receive either AZA monotherapy (75 mg/m(2) × seven days every 28 days) or AZA combined with VOR 300 mg bd on days 3-9 po...
August 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28758283/copy-number-profiling-of-adult-relapsed-b-cell-precursor-acute-lymphoblastic-leukemia-reveals-potential-leukemia-progression-mechanisms
#18
Jordi Ribera, Lurdes Zamora, Mireia Morgades, Mar Mallo, Neus Solanes, Montserrat Batlle, Susana Vives, Isabel Granada, Jordi Juncà, Roberto Malinverni, Eulàlia Genescà, Ramon Guàrdia, Santiago Mercadal, Lourdes Escoda, Joaquín Martinez-Lopez, Mar Tormo, Jordi Esteve, Marta Pratcorona, Carmen Martinez-Losada, Francesc Solé, Evarist Feliu, Josep Maria Ribera
The outcome of relapsed adult acute lymphoblastic leukemia (ALL) remains dismal despite new therapeutic approaches. Previous studies analyzing relapse samples have shown a high degree of heterogeneity regarding gene alterations without an evident relapse signature. Bone marrow or peripheral blood samples from 31 adult B-cell precursor ALL patients at first relapse, and 21 paired diagnostic samples were analyzed by multiplex ligation probe-dependent amplification (MLPA). Nineteen paired diagnostic and relapse samples of these 21 patients were also analyzed by SNP arrays...
July 30, 2017: Genes, Chromosomes & Cancer
https://www.readbyqxmd.com/read/28753586/development-of-zebrafish-medulloblastoma-like-pnet-model-by-talen-mediated-somatic-gene-inactivation
#19
Jaegal Shim, Jung-Hwa Choi, Moon-Hak Park, Hyena Kim, Jong Hwan Kim, Seon-Young Kim, Dongwan Hong, Sunshin Kim, Ji Eun Lee, Cheol-Hee Kim, Jeong-Soo Lee, Young-Ki Bae
Genetically engineered animal tumor models have traditionally been generated by the gain of single or multiple oncogenes or the loss of tumor suppressor genes; however, the development of live animal models has been difficult given that cancer phenotypes are generally induced by somatic mutation rather than by germline genetic inactivation. In this study, we developed somatically mutated tumor models using TALEN-mediated somatic gene inactivation of cdkn2a/b or rb1 tumor suppressor genes in zebrafish. One-cell stage injection of cdkn2a/b-TALEN mRNA resulted in malignant peripheral nerve sheath tumors with high frequency (about 39%) and early onset (about 35 weeks of age) in F0 tp53e7/e7 mutant zebrafish...
July 21, 2017: Oncotarget
https://www.readbyqxmd.com/read/28753554/histone-modification-alteration-coordinated-with-acquisition-of-promoter-dna-methylation-during-epstein-barr-virus-infection
#20
Sayaka Funata, Keisuke Matsusaka, Ryota Yamanaka, Shogo Yamamoto, Atsushi Okabe, Masaki Fukuyo, Hiroyuki Aburatani, Masashi Fukayama, Atsushi Kaneda
Aberrant DNA hypermethylation is a major epigenetic mechanism to inactivate tumor suppressor genes in cancer. Epstein-Barr virus positive gastric cancer is the most frequently hypermethylated tumor among human malignancies. Herein, we performed comprehensive analysis of epigenomic alteration during EBV infection, by Infinium HumanMethylation 450K BeadChip for DNA methylation and ChIP-sequencing for histone modification alteration during EBV infection into gastric cancer cell line MKN7. Among 7,775 genes with increased DNA methylation in promoter regions, roughly half were "DNA methylation-sensitive" genes, which acquired DNA methylation in the whole promoter regions and thus were repressed...
July 21, 2017: Oncotarget
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