9 results on '"Multiregional sequencing"'
Search Results
2. Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST.
- Author
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Chattopadhyay, Subhayan, Karlsson, Jenny, Valind, Anders, Andersson, Natalie, and Gisselsson, David
- Subjects
- *
GENE frequency - Abstract
Clonal deconvolution of mutational landscapes is crucial to understand the evolutionary dynamics of cancer. Two limiting factors for clonal deconvolution that have remained unresolved are variation in purity and chromosomal copy number across different samples of the same tumor. We developed a semi-supervised algorithm that tracks variant calls through multi-sample spatiotemporal tumor data. While normalizing allele frequencies based on purity, it also adjusts for copy number changes at clonal deconvolution. Absent à priori copy number data, it renders in silico copy number estimations from bulk sequences. Using published and simulated tumor sequences, we reliably segregated clonal/subclonal variants even at a low sequencing depth (~50×). Given at least one pure tumor sample (>70% purity), we could normalize and deconvolve paired samples down to a purity of 40%. This renders a reliable clonal reconstruction well adapted to multi-regionally sampled solid tumors, which are often aneuploid and contaminated by non-cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
3. Multiregional sequencing and circulating tumour DNA analysis provide complementary approaches for comprehensive disease profiling of small lymphocytic lymphoma.
- Author
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Moia, Riccardo, Favini, Chiara, Ferri, Valentina, Forestieri, Gabriela, Terzi Di Bergamo, Lodovico, Schipani, Mattia, Sagiraju, Sruthi, Andorno, Annalisa, Rasi, Silvia, Adhinaveni, Ramesh, Talotta, Donatella, Al Essa, Wael, De Paoli, Lorenzo, Margiotta Casaluci, Gloria, Patriarca, Andrea, Boldorini, Renzo L., Rossi, Davide, and Gaidano, Gianluca
- Subjects
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DNA analysis , *CIRCULATING tumor DNA , *LYMPHOMAS , *GENETIC mutation , *LYMPH nodes - Abstract
Summary: We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and circulating cells, as well as plasma‐circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20·4% and 36·4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
4. Multiregional sequence revealed SMARCA4 R1192C mutant clones acquired EGFR C797S mutation in the metastatic site of an EGFR-mutated NSCLC patient.
- Author
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Kunimasa, Kei, Hirotsu, Yosuke, Miyashita, Yoshihiro, Goto, Taichiro, Amemiya, Kenji, Mochizuki, Hitoshi, Samamoto, Ikuko, Ohki, Takamasa, Oyama, Toshio, Honma, Keiichiro, Imamura, Fumio, Nishino, Kazumi, Kumagai, Toru, and Omata, Masao
- Subjects
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TREATMENT effectiveness , *CLONE cells , *NON-small-cell lung carcinoma , *MOLECULAR cloning , *LUNG cancer - Abstract
• Intratumor heterogeneity (ITH) is involved in clinical course and treatment efficacy. • Multiregional sequence (MRS) analysis with next generation sequence reveals ITH. • MRS analysis of pre- and post-EGFR-TKI lesions revealed resistant clone trajectory. • SMARCA4 R1192C mutant clone metastasized and acquired EGFR C797S mutation. • Local treatment can be effective for cancer with attenuated progression pattern. Intratumor heterogeneity (ITH) is reportedly involved in the clinical course and in the response to treatment, although the detailed mechanism underlying this effect remains unclear. In this study, we investigated the effect of epithelial growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment on ITH with an EGFR -mutated lung cancer patient using the multiregional sequence (MRS) analysis of surgical specimens both before and after EGFR-TKI treatment. We performed the MRS analysis of primary lung and resistant metastatic lesions, respectively through targeted sequencing, covering whole exons of 53 significantly mutated, lung cancer-associated genes. Through the comparison of primary lung and metastatic lesion mutation profiles, along with PyClone analysis of sequence data, we revealed the trajectory of resistant clones from a primary to metastatic site. MRS revealed high ITH at the primary lung lesion and low ITH at the metastatic site, suggesting that the EGFR-TKI treatment followed an attenuated progression pattern. Tumor cell clones harboring EGFR G719S, L861R, SMARCA4 R1192C and KMT2D Q1139R mutations in the primary lesion metastasized and acquired the EGFR-TKI-resistant EGFR C797S mutation. MRS revealed attenuated progression pattern and clonal evolution. In the case of high ITH with attenuated progression pattern, as observed in the present case, local treatment may be effective when oligometastasis emerged. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
5. Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium.
- Author
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Suda, Kazuaki, Nakaoka, Hirofumi, Yoshihara, Kosuke, Ishiguro, Tatsuya, Tamura, Ryo, Mori, Yutaro, Yamawaki, Kaoru, Adachi, Sosuke, Takahashi, Tomoko, Kase, Hiroaki, Tanaka, Kenichi, Yamamoto, Tadashi, Motoyama, Teiichi, Inoue, Ituro, and Enomoto, Takayuki
- Abstract
Summary Endometriosis is characterized by ectopic endometrial-like epithelium and stroma, of which molecular characteristics remain to be fully elucidated. We sequenced 107 ovarian endometriotic and 82 normal uterine endometrial epithelium samples isolated by laser microdissection. In both endometriotic and normal epithelium samples, numerous somatic mutations were identified within genes frequently mutated in endometriosis-associated ovarian cancers. KRAS is frequently mutated in endometriotic epithelium, with a higher mutant allele frequency (MAF) accompanied by arm-level allelic imbalances. Analyses of MAF, combined with multiregional sequencing, illuminated spatiotemporal evolution of the endometriosis and uterine endometrium genomes. We sequenced 109 single endometrial glands and found that each gland carried distinct cancer-associated mutations, demonstrating the heterogeneity of the genomic architecture of endometrial epithelium. Remarkable increases in MAF of mutations in cancer-associated genes in endometriotic epithelium suggest retrograde flow of endometrial cells already harboring cancer-associated mutations, with selective advantages at ectopic sites, leading to the development of endometriosis. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
6. Multiregional sequencing and circulating tumour DNA analysis provide complementary approaches for comprehensive disease profiling of small lymphocytic lymphoma
- Author
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Gabriela Forestieri, Lorenzo De Paoli, Silvia Rasi, Sruthi Sagiraju, Annalisa Andorno, Gianluca Gaidano, Ramesh Adhinaveni, Lodovico Terzi di Bergamo, Riccardo Moia, Valentina Ferri, Chiara Favini, Davide Rossi, Wael Al Essa, Donatella Talotta, Gloria Margiotta Casaluci, Andrea Patriarca, Mattia Schipani, and Renzo Boldorini
- Subjects
Male ,DNA Copy Number Variations ,Biopsy ,Short Report ,Lymph node biopsy ,small lymphocytic lymphoma ,Disease ,Biology ,Gene mutation ,Lymphocytic lymphoma ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,multiregional sequencing ,medicine ,Humans ,Liquid biopsy ,Haematological malignancy–Clinical ,Aged ,030304 developmental biology ,Chromosome Aberrations ,0303 health sciences ,Chromosomes, Human, Pair 12 ,Chromosomes, Human, Pair 13 ,Genes, Immunoglobulin ,liquid biopsy ,medicine.diagnostic_test ,Adenine ,DNA, Neoplasm ,Hematology ,Middle Aged ,Leukemia, Lymphocytic, Chronic, B-Cell ,Predictive value ,3. Good health ,chemistry ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Female ,Immunotherapy ,Lymph Nodes ,Chromosome Deletion ,Immunoglobulin Heavy Chains ,DNA ,Chromosomes, Human, Pair 17 - Abstract
Summary We aimed at molecularly dissecting the anatomical heterogeneity of small lymphocytic lymphoma (SLL), by analysing a cohort of 12 patients for whom paired DNA from a lymph node biopsy and circulating cells, as well as plasma‐circulating tumour DNA (ctDNA) was available. Notably, the analyses of the lymph node biopsy and of circulating cells complement each other since a fraction of mutations (20·4% and 36·4%, respectively) are unique to each compartment. Plasma ctDNA identified two additional unique mutations. Consistently, the different synchronous sources of tumour DNA complement each other in informing on driver gene mutations in SLL harbouring potential prognostic and/or predictive value.
- Published
- 2021
- Full Text
- View/download PDF
7. Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History
- Author
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Riccardo Vannozzi, Martina Modena, Mariangela Morelli, Geoffrey J. Pilkington, Sara Franceschi, Prospero Civita, Serena Barachini, Paolo Aretini, Orazio Santonocito, Francesco Pasqualetti, Francesca Lessi, Chiara Maria Mazzanti, Valerio Ortenzi, and Antonio Giuseppe Naccarato
- Subjects
0301 basic medicine ,Cancer Research ,clonal evolution ,tumor progression ,Computational biology ,Biology ,Somatic evolution in cancer ,Article ,03 medical and health sciences ,Therapeutic approach ,0302 clinical medicine ,multiregional sequencing ,temporal heterogeneity ,Clonal evolution ,Glioblastoma ,Multiregional sequencing ,Spatial heterogeneity ,Temporal heterogeneity ,Tumor phylogeny ,Tumor progression ,Copy-number variation ,Evolutionary dynamics ,RC254-282 ,Exome sequencing ,Genetic heterogeneity ,glioblastoma ,spatial heterogeneity ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Precision medicine ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,tumor phylogeny - Abstract
Simple Summary Glioblastoma is the most common and aggressive primary brain malignancy in adults. In addition to extensive inter-patient heterogeneity, glioblastoma shows intra-tumor extensive cellular and molecular heterogeneity, both spatially and temporally. This heterogeneity is one of the main reasons for the poor prognosis and overall survival. Moreover, it raises the important question of whether the molecular characterization of a single biopsy sample, as performed in standard diagnostics, actually represents the entire lesion. In this study, we sequenced the whole exome of nine spatially different cancer regions of three primary glioblastomas. We characterized their mutational profiles and copy number alterations, with implications for our understanding of tumor biology in relation to clonal architecture and evolutionary dynamics, as well as therapeutically relevant alterations. Abstract Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option.
- Published
- 2021
- Full Text
- View/download PDF
8. Multiregional Sequencing of IDH-WT Glioblastoma Reveals High Genetic Heterogeneity and a Dynamic Evolutionary History.
- Author
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Franceschi, Sara, Civita, Prospero, Pasqualetti, Francesco, Lessi, Francesca, Modena, Martina, Barachini, Serena, Morelli, Mariangela, Santonocito, Orazio, Vannozzi, Riccardo, Pilkington, Geoffrey J., Ortenzi, Valerio, Naccarato, Antonio Giuseppe, Aretini, Paolo, Mazzanti, Chiara Maria, and Katyal, Sachin
- Subjects
- *
SEQUENCE analysis , *GLIOMAS - Abstract
Simple Summary: Glioblastoma is the most common and aggressive primary brain malignancy in adults. In addition to extensive inter-patient heterogeneity, glioblastoma shows intra-tumor extensive cellular and molecular heterogeneity, both spatially and temporally. This heterogeneity is one of the main reasons for the poor prognosis and overall survival. Moreover, it raises the important question of whether the molecular characterization of a single biopsy sample, as performed in standard diagnostics, actually represents the entire lesion. In this study, we sequenced the whole exome of nine spatially different cancer regions of three primary glioblastomas. We characterized their mutational profiles and copy number alterations, with implications for our understanding of tumor biology in relation to clonal architecture and evolutionary dynamics, as well as therapeutically relevant alterations. Glioblastoma is one of the most common and lethal primary neoplasms of the brain. Patient survival has not improved significantly over the past three decades and the patient median survival is just over one year. Tumor heterogeneity is thought to be a major determinant of therapeutic failure and a major reason for poor overall survival. This work aims to comprehensively define intra- and inter-tumor heterogeneity by mapping the genomic and mutational landscape of multiple areas of three primary IDH wild-type (IDH-WT) glioblastomas. Using whole exome sequencing, we explored how copy number variation, chromosomal and single loci amplifications/deletions, and mutational burden are spatially distributed across nine different tumor regions. The results show that all tumors exhibit a different signature despite the same diagnosis. Above all, a high inter-tumor heterogeneity emerges. The evolutionary dynamics of all identified mutations within each region underline the questionable value of a single biopsy and thus the therapeutic approach for the patient. Multiregional collection and subsequent sequencing are essential to try to address the clinical challenge of precision medicine. Especially in glioblastoma, this approach could provide powerful support to pathologists and oncologists in evaluating the diagnosis and defining the best treatment option. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
9. Multiregion Sequence Analysis to Predict Intratumor Heterogeneity and Clonal Evolution.
- Author
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Ahn S and Huang H
- Subjects
- Cross-Sectional Studies, Exome genetics, Genetic Heterogeneity, Humans, Mutation genetics, Clonal Evolution genetics, Neoplasms genetics, Sequence Analysis, DNA methods
- Abstract
Multiregion sequencing can advance our understanding of the intratumor heterogeneity and the clonal evolution. Here, we introduced multiple aspects of multiregion sequencing and its analysis, including the study design and sampling strategy, current understanding of the tumor evolution model, and a protocol for multiregion sequencing analysis of DNA-sequencing data.
- Published
- 2021
- Full Text
- View/download PDF
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