Dataset Information

Ena-DATASET-UAMS-17-03-2019-03:57:35:391-32 - samples

ABSTRACT: Series of 56 paired presentation, relapse and control samples from newly diagnosed, uniformly treated myeloma patients. Deep of treatment response and maintenance allocation (active observation or lenaldiomide) was determined for all. All samples underwent whole exome sequencing with additional baits to cover the myc and immunoglobulin loci. There are 168 (56 presentation, 56 relapse and 56 control) samples in this study. 131 are available as part of this dataset. The remaining 37 are available with dataset accession id EGAD00001001358.

PROVIDER: EGAD00001004846 | EGA |

REPOSITORIES: EGA

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Publications

Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients.

Jones John R JR Weinhold Niels N Ashby Cody C Walker Brian A BA Wardell Chris C Pawlyn Charlotte C Rasche Leo L Melchor Lorenzo L Cairns David A DA Gregory Walter M WM Johnson David D Begum Dil B DB Ellis Sidra S Sherborne Amy L AL Cook Gordon G Kaiser Martin F MF Drayson Mark T MT Owen Roger G RG Jackson Graham H GH Davies Faith E FE Greaves Mel M Morgan Gareth J GJ

Haematologica 20190207 7

The emergence of treatment resistant sub-clones is a key feature of relapse in multiple myeloma. Therapeutic attempts to extend remission and prevent relapse include maximizing response and the use of maintenance therapy. We used whole exome sequencing to study the genetics of paired samples taken at presentation and at relapse from 56 newly diagnosed patients, following induction therapy, randomized to receive either lenalidomide maintenance or observation as part of the Myeloma XI trial. Patie ...[more]

PMID: 30733268

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Project description:High-grade serous ovarian cancer (HGSOC) exhibits significant genomic heterogeneity within a patient at presentation. Recent work has suggested that this heterogeneity is linked to the development of resistance and disease progression in that chemotherapy selects for minor resistant subclones embodied in presentation disease leading to short progression-free survival and resistant relapse. Cell line models support this by showing that relapse is not an immediate descendant of presentation disease, but so far no immediate clinical evidence has been provided that convincingly demonstrates the origin of relapse. It is further still unclear what evolutionary processes shape the mutational landscape of HGSOC in vivo and to what extent the degree of genomic heterogeneity impacts a patient's clinical outcome. We address these questions by inferring evolutionary trees of metastatic disease from structural variations between 138 cancer samples obtained from 17 patients undergoing neoadjuvant chemotherapy for HGSOC. Using novel phylogenetic methods, we quantify genomic changes in the course of chemotherapy and the degree of clonal expansion and show that these indices determine patient outcome with high accuracy. We demonstrate that relapse is indeed a minor subclone of presentation disease by verifying that the focal NF1 deletion of a relapse case was already present at biopsy. By leveraging the information contained in the evolutionary trees, we unveil the etiology of genetic heterogeneity and the tumorigenic potential of HGSOC cell populations. This is the first comprehensive study showing the origin, strength and effect of genetic heterogeneity in HGSOC in a clinical setting. In addition to its immediate clinical significance, it strengthens previous statements that single sample biopsies are seemingly insufficient to predict disease progression and stresses the importance of establishing multiple sampling as a routine approach in the clinic. Clinical data and tissue samples were collected on the prospective CTCR-OV03 and CTCR-OV04 clinical studies designed to identify biomarkers of heterogeneity.

Dataset Information

Ena-DATASET-UAMS-17-03-2019-03:57:35:391-32 - samples

Publications

Clonal evolution in myeloma: the impact of maintenance lenalidomide and depth of response on the genetics and sub-clonal structure of relapsed disease in uniformly treated newly diagnosed patients.

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