المؤلفون: Agustinus, Albert S, Al-Rawi, Duaa, Dameracharla, Bhargavi, Raviram, Ramya, Jones, Bailey SCL, Stransky, Stephanie, Scipioni, Lorenzo, Luebeck, Jens, Di Bona, Melody, Norkunaite, Danguole, Myers, Robert M, Duran, Mercedes, Choi, Seongmin, Weigelt, Britta, Yomtoubian, Shira, McPherson, Andrew, Toufektchan, Eléonore, Keuper, Kristina, Mischel, Paul S, Mittal, Vivek, Shah, Sohrab P, Maciejowski, John, Storchova, Zuzana, Gratton, Enrico, Ly, Peter, Landau, Dan, Bakhoum, Mathieu F, Koche, Richard P, Sidoli, Simone, Bafna, Vineet, David, Yael, Bakhoum, Samuel F

المصدر: Nature. 619(7968)

مصطلحات موضوعية: Chromosomes, Chromatin, Animals, Humans, Mice, Neoplasms, Chromosomal Instability, Histones, Epigenesis, Genetic, Human Genome, Genetics, Cancer, General Science & Technology

الوصف: Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers1-4, but whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei5,6 and subsequent rupture of the micronuclear envelope7 profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice, as well as in cancer and non-transformed cells. Some of the changes in histone PTMs occur because of the rupture of the micronuclear envelope, whereas others are inherited from mitotic abnormalities before the micronucleus is formed. Using orthogonal approaches, we demonstrate that micronuclei exhibit extensive differences in chromatin accessibility, with a strong positional bias between promoters and distal or intergenic regions, in line with observed redistributions of histone PTMs. Inducing CIN causes widespread epigenetic dysregulation, and chromosomes that transit in micronuclei experience heritable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, as well as altering genomic copy number, CIN promotes epigenetic reprogramming and heterogeneity in cancer.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/25b0n7j7Test

المؤلفون: Bolton, Kelly L, Chen, Denise, de la Fuente, Rosario I Corona, Fu, Zhuxuan, Murali, Rajmohan, K�bel, Martin, Tazi, Yanis, Cunningham, Julie M, Chan, Irenaeus CC, Wiley, Brian J, Moukarzel, Lea A, Winham, Stacey J, Armasu, Sebastian M, Lester, Jenny, Elishaev, Esther, Laslavic, Angela, Kennedy, Catherine J, Piskorz, Anna, Sekowska, Magdalena, Brand, Alison H, Chiew, Yoke-Eng, Pharoah, Paul, Elias, Kevin M, Drapkin, Ronny, Churchman, Michael, Gourley, Charlie, DeFazio, Anna, Karlan, Beth, Brenton, James D, Weigelt, Britta, Anglesio, Michael S, Huntsman, David, Gayther, Simon A, Konner, Jason, Modugno, Francesmary, Lawrenson, Kate, Goode, Ellen L, Papaemmanuil, Elli

المصدر: Clinical Cancer Research. 28(22)

مصطلحات موضوعية: Rare Diseases, Ovarian Cancer, Genetics, Cancer, Clinical Research, Good Health and Well Being, Female, Humans, Ovarian Neoplasms, Adenocarcinoma, Clear Cell, Mutation, Endometriosis, Oncology and Carcinogenesis, Oncology & Carcinogenesis

الوصف: PurposeTo identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes.Experimental designWe profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival.ResultsWe detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy.ConclusionsOur study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3m9399p3Test

المؤلفون: Weigelt, Britta

مصطلحات موضوعية: Borstkanker Metastasering

الوصف: Proefschrift Universiteit van Amsterdam.
Met bibliogr., lit. opg. - Met samenvatting in het Nederlands en Duits.

الإتاحة: http://dare.uva.nl/document/88848Test

المؤلفون: Vahdatinia, Mahsa, Derakhshan, Fatemeh, Da Cruz Paula, Arnaud, Dopeso, Higinio, Marra, Antonio, Gazzo, Andrea M, Brown, David, Selenica, Pier, Ross, Dara S, Razavi, Pedram, Zhang, Hong, Weigelt, Britta, Wen, Hannah Y, Brogi, Edi, Reis-Filho, Jorge S, Pareja, Fresia

مصطلحات موضوعية: Original research

الوصف: Aims Activating somatic mutations or gene amplification of KIT result in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence of KIT genetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours. Methods A retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs with KIT alterations. A histological assessment of KIT -altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lacking KIT genetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type. Results We identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affecting KIT , including activating somatic mutations (n=4) or gene amplification (n=14). All KIT -altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lacking KIT genetic alterations, no distinctive genetic features were identified. In two metastatic KIT -altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, the KIT mutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers. Conclusions KIT genetic alterations are vanishingly rare in BC. KIT -altered BCs are of high grade but lack distinctive histological features. Genetic alterations in KIT might be late events in the evolution and/or progression of BC.

وصف الملف: text/html

العلاقة: http://jcp.bmj.com/cgi/content/short/77/1/40Test; http://dx.doi.org/10.1136/jcp-2022-208611Test

الإتاحة: https://doi.org/10.1136/jcp-2022-208611Test
http://jcp.bmj.com/cgi/content/short/77/1/40Test

المؤلفون: Gordhandas, Sushmita, Da Cruz Paula, Arnaud, Kertowidjojo, Elizabeth C., Pareja, Fresia, Dessources, Kimberly, da Silva, Edaise M., Derakhshan, Fatemeh, Mueller, Jennifer J., Abu-Rustum, Nadeem R., Herman Chui, M., Weigelt, Britta

المساهمون: Cycle for Survival, National Institutes of Health, Breast Cancer Research Foundation

المصدر: Gynecologic Oncology Reports ; volume 53, page 101391 ; ISSN 2352-5789

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.gore.2024.101391Test
https://api.elsevier.com/content/article/PII:S2352578924000705?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2352578924000705?httpAccept=text/plainTest

المؤلفون: Feinberg, Jacqueline, Da Cruz Paula, Arnaud, da Silva, Edaise M., Pareja, Fresia, Patel, Juber, Zhu, Yingjie, Selenica, Pier, Leitao, Mario M., Abu-Rustum, Nadeem R., Reis-Filho, Jorge S., Joehlin-Price, Amy, Weigelt, Britta

المساهمون: National Cancer Institute

المصدر: Gynecologic Oncology ; volume 185, page 58-67 ; ISSN 0090-8258

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.ygyno.2024.02.015Test
https://api.elsevier.com/content/article/PII:S0090825824001124?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0090825824001124?httpAccept=text/plainTest

المؤلفون: Derakhshan, Fatemeh, Da Cruz Paula, Arnaud, Selenica, Pier, da Silva, Edaise M., Grabenstetter, Anne, Jalali, Sahar, Gazzo, Andrea M., Dopeso, Higinio, Marra, Antonio, Brown, David N., Ross, Dara S., Mandelker, Diana, Razavi, Pedram, Chandarlapaty, Sarat, Wen, Hannah Y., Brogi, Edi, Zhang, Hong, Weigelt, Britta, Pareja, Fresia, Reis-Filho, Jorge S.

المصدر: Modern Pathology ; volume 37, issue 2, page 100375 ; ISSN 0893-3952

مصطلحات موضوعية: Pathology and Forensic Medicine

الإتاحة: https://doi.org/10.1016/j.modpat.2023.100375Test
https://api.elsevier.com/content/article/PII:S0893395223002806?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0893395223002806?httpAccept=text/plainTest

المؤلفون: Sia, Tiffany Y., Yaari, Zvi, Feiner, Ron, Smith, Evan, Da Cruz Paula, Arnaud, Selenica, Pier, Doddi, Sital, Chi, Dennis S., Abu-Rustum, Nadeem R., Levine, Douglas A., Weigelt, Britta, Fleisher, Martin, Ramanathan, Lakshmi V., Heller, Daniel A., Long Roche, Kara

المساهمون: Ovarian Cancer Research Fund, Congressionally Directed Medical Research Programs, Cycle for Survival, Breast Cancer Research Foundation, Honorable Tina Brozman Foundation, US Department of Defense, Memorial Sloan-Kettering Cancer Center, National Cancer Institute, National Institutes of Health

المصدر: Gynecologic Oncology Reports ; volume 51, page 101330 ; ISSN 2352-5789

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.gore.2024.101330Test
https://api.elsevier.com/content/article/PII:S2352578924000092?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2352578924000092?httpAccept=text/plainTest

المؤلفون: Praiss, Aaron M., White, Charlie, Iasonos, Alexia, Selenica, Pier, Zivanovic, Oliver, Chi, Dennis S., Abu-Rustum, Nadeem R., Weigelt, Britta, Aghajanian, Carol, Girshman, Jeffrey, Park, Kay J., Grisham, Rachel N.

المساهمون: National Cancer Institute, National Institutes of Health

المصدر: Gynecologic Oncology ; volume 182, page 32-38 ; ISSN 0090-8258

مصطلحات موضوعية: Obstetrics and Gynecology, Oncology

الإتاحة: https://doi.org/10.1016/j.ygyno.2024.01.015Test
https://api.elsevier.com/content/article/PII:S0090825824000222?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0090825824000222?httpAccept=text/plainTest

المؤلفون: Kahn, Ryan M., Selenica, Pier, Boerner, Thomas, Roche, Kara Long, Xiao, Yonghong, Sia, Tiffany Y., Maio, Anna, Kemel, Yelena, Sheehan, Margaret, Salo-Mullen, Erin, Breen, Kelsey E., Zhou, Qin, Iasonos, Alexia, Grisham, Rachel N., O’Cearbhaill, Roisin E., Chi, Dennis S., Berger, Michael F., Kundra, Ritika, Schultz, Nikolaus, Ellenson, Lora H., Stadler, Zsofia K., Offit, Kenneth, Mandelker, Diana, Aghajanian, Carol, Zamarin, Dmitriy, Sabbatini, Paul, Weigelt, Britta, Liu, Ying L.

المساهمون: National Cancer Institute, Breast Cancer Research Foundation, National Institutes of Health, Cycle for Survival

المصدر: Gynecologic Oncology ; volume 180, page 35-43 ; ISSN 0090-8258

الإتاحة: https://doi.org/10.1016/j.ygyno.2023.11.019Test
https://api.elsevier.com/content/article/PII:S0090825823015639?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0090825823015639?httpAccept=text/plainTest