Data from Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer Article Swipe

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Gillian Vandekerkhove , Tilman Todenhöfer , Matti Annala , Werner J. Struss , Amanda Wong , Kevin Beja , Elie Ritch , Sonal Brahmbhatt , Stanislav Volik , Jörg Hennenlotter , Matti Nykter , Kim N. , Scott North , Arnulf Stenzl , Colin C. Collins , Bernhard J. Eigl , Peter C. Black , Alexander W. Wyatt ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1158/1078-0432.c.6526847.v1

Purpose: Targeted agents and immunotherapies promise to transform the treatment of metastatic bladder cancer, but therapy selection will depend on practical tumor molecular stratification. Circulating tumor DNA (ctDNA) is established in several solid malignancies as a minimally invasive tool to profile the tumor genome in real-time, but is critically underexplored in bladder cancer.Experimental Design: We applied a combination of whole-exome sequencing and targeted sequencing across 50 bladder cancer driver genes to plasma cell-free DNA (cfDNA) from 51 patients with aggressive bladder cancer, including 37 with metastatic disease.Results: The majority of patients with metastasis, but only 14% of patients with localized disease, had ctDNA proportions above 2% of total cfDNA (median 16.5%, range 3.9%–72.6%). Twelve percent of estimable samples had evidence of genome hypermutation. We reveal an aggressive mutational landscape in metastatic bladder cancer with 95% of patients harboring deleterious alterations to TP53, RB1, or MDM2, and 70% harboring a mutation or disrupting rearrangement affecting chromatin modifiers such as ARID1A. Targetable alterations in MAPK/ERK or PI3K/AKT/mTOR pathways were robustly detected, including amplification of ERBB2 (20% of patients) and activating hotspot mutations in PIK3CA (20%), with the latter mutually exclusive to truncating mutations in TSC1. A novel FGFR3 gene fusion was identified in consecutive samples from one patient.Conclusions: Our study demonstrates that ctDNA provides a practical and cost-effective snapshot of driver gene status in metastatic bladder cancer. The identification of a wide spectrum of clinically informative somatic alterations nominates ctDNA as a tool to dissect disease pathogenesis and guide therapy selection in patients with metastatic bladder cancer. Clin Cancer Res; 23(21); 6487–97. ©2017 AACR.

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ARID1A Cancer research Somatic hypermutation Bladder cancer Targeted therapy Metastasis Exome sequencing Exome PI3K/AKT/mTOR pathway Cancer Medicine Biology Oncology Internal medicine Gene Mutation Immunology Genetics B cell Antibody Signal transduction

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1158/1078-0432.c.6526847.v1
OA Status: gold
Related Works: 10
OpenAlex ID: https://openalex.org/W4361952909

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DOI: https://doi.org/10.1158/1078-0432.c.6526847.v1

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Title: Data from Circulating Tumor DNA Reveals Clinically Actionable Somatic Genome of Metastatic Bladder Cancer

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Language: en

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Publication year: 2023

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Publication date: 2023-03-31

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Authors: Gillian Vandekerkhove, Tilman Todenhöfer, Matti Annala, Werner J. Struss, Amanda Wong, Kevin Beja, Elie Ritch, Sonal Brahmbhatt, Stanislav Volik, Jörg Hennenlotter, Matti Nykter, Kim N., Scott North, Arnulf Stenzl, Colin C. Collins, Bernhard J. Eigl, Peter C. Black, Alexander W. Wyatt

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Landing page: https://doi.org/10.1158/1078-0432.c.6526847.v1

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Concepts: ARID1A, Cancer research, Somatic hypermutation, Bladder cancer, Targeted therapy, Metastasis, Exome sequencing, Exome, PI3K/AKT/mTOR pathway, Cancer, Medicine, Biology, Oncology, Internal medicine, Gene, Mutation, Immunology, Genetics, B cell, Antibody, Signal transduction

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abstract_inverted_index.70%	146
abstract_inverted_index.95%	134
abstract_inverted_index.DNA	26, 73
abstract_inverted_index.Our	206
abstract_inverted_index.The	87, 225
abstract_inverted_index.and	3, 61, 145, 176, 214, 245
abstract_inverted_index.but	14, 46, 93
abstract_inverted_index.had	101, 118
abstract_inverted_index.one	204
abstract_inverted_index.the	8, 41, 184
abstract_inverted_index.was	198
abstract_inverted_index.(20%	173
abstract_inverted_index.Res;	257
abstract_inverted_index.from	75, 203
abstract_inverted_index.gene	196, 219
abstract_inverted_index.only	94
abstract_inverted_index.such	156
abstract_inverted_index.that	209
abstract_inverted_index.tool	38, 240
abstract_inverted_index.were	166
abstract_inverted_index.wide	229
abstract_inverted_index.will	17
abstract_inverted_index.with	78, 84, 91, 98, 133, 183, 251
abstract_inverted_index.above	104
abstract_inverted_index.cfDNA	108
abstract_inverted_index.ctDNA	102, 210, 237
abstract_inverted_index.genes	69
abstract_inverted_index.guide	246
abstract_inverted_index.novel	194
abstract_inverted_index.range	111
abstract_inverted_index.solid	32
abstract_inverted_index.study	207
abstract_inverted_index.total	107
abstract_inverted_index.tumor	21, 25, 42
abstract_inverted_index.(20%),	182
abstract_inverted_index.16.5%,	110
abstract_inverted_index.Cancer	256
abstract_inverted_index.Twelve	113
abstract_inverted_index.across	64
abstract_inverted_index.agents	2
abstract_inverted_index.cancer	67, 132
abstract_inverted_index.depend	18
abstract_inverted_index.driver	68, 218
abstract_inverted_index.fusion	197
abstract_inverted_index.genome	43, 121
abstract_inverted_index.latter	185
abstract_inverted_index.plasma	71
abstract_inverted_index.reveal	124
abstract_inverted_index.status	220
abstract_inverted_index.©2017	260
abstract_inverted_index.(cfDNA)	74
abstract_inverted_index.(ctDNA)	27
abstract_inverted_index.(median	109
abstract_inverted_index.23(21);	258
abstract_inverted_index.applied	55
abstract_inverted_index.bladder	12, 51, 66, 80, 131, 223, 253
abstract_inverted_index.cancer,	13, 81
abstract_inverted_index.cancer.	224, 254
abstract_inverted_index.disease	243
abstract_inverted_index.dissect	242
abstract_inverted_index.hotspot	178
abstract_inverted_index.percent	114
abstract_inverted_index.profile	40
abstract_inverted_index.promise	5
abstract_inverted_index.samples	117, 202
abstract_inverted_index.several	31
abstract_inverted_index.somatic	234
abstract_inverted_index.therapy	15, 247
abstract_inverted_index.MAPK/ERK	162
abstract_inverted_index.Targeted	1
abstract_inverted_index.disease,	100
abstract_inverted_index.evidence	119
abstract_inverted_index.invasive	37
abstract_inverted_index.majority	88
abstract_inverted_index.mutation	149
abstract_inverted_index.mutually	186
abstract_inverted_index.pathways	165
abstract_inverted_index.patients	77, 90, 97, 136, 250
abstract_inverted_index.provides	211
abstract_inverted_index.robustly	167
abstract_inverted_index.snapshot	216
abstract_inverted_index.spectrum	230
abstract_inverted_index.targeted	62
abstract_inverted_index.affecting	153
abstract_inverted_index.cell-free	72
abstract_inverted_index.chromatin	154
abstract_inverted_index.detected,	168
abstract_inverted_index.estimable	116
abstract_inverted_index.exclusive	187
abstract_inverted_index.harboring	137, 147
abstract_inverted_index.including	82, 169
abstract_inverted_index.landscape	128
abstract_inverted_index.localized	99
abstract_inverted_index.minimally	36
abstract_inverted_index.modifiers	155
abstract_inverted_index.molecular	22
abstract_inverted_index.mutations	179, 190
abstract_inverted_index.nominates	236
abstract_inverted_index.patients)	175
abstract_inverted_index.practical	20, 213
abstract_inverted_index.selection	16, 248
abstract_inverted_index.transform	7
abstract_inverted_index.treatment	9
abstract_inverted_index.6487–97.	259
abstract_inverted_index.Targetable	159
abstract_inverted_index.activating	177
abstract_inverted_index.aggressive	79, 126
abstract_inverted_index.clinically	232
abstract_inverted_index.critically	48
abstract_inverted_index.disrupting	151
abstract_inverted_index.identified	199
abstract_inverted_index.metastatic	11, 85, 130, 222, 252
abstract_inverted_index.mutational	127
abstract_inverted_index.real-time,	45
abstract_inverted_index.sequencing	60, 63
abstract_inverted_index.truncating	189
abstract_inverted_index.Circulating	24
abstract_inverted_index.alterations	139, 160, 235
abstract_inverted_index.combination	57
abstract_inverted_index.consecutive	201
abstract_inverted_index.deleterious	138
abstract_inverted_index.established	29
abstract_inverted_index.informative	233
abstract_inverted_index.metastasis,	92
abstract_inverted_index.proportions	103
abstract_inverted_index.whole-exome	59
abstract_inverted_index.demonstrates	208
abstract_inverted_index.malignancies	33
abstract_inverted_index.pathogenesis	244
abstract_inverted_index.<i>Clin	255
abstract_inverted_index.PI3K/AKT/mTOR	164
abstract_inverted_index.amplification	170
abstract_inverted_index.rearrangement	152
abstract_inverted_index.underexplored	49
abstract_inverted_index.<i>TP53,	141
abstract_inverted_index.3.9%–72.6%).	112
abstract_inverted_index.RB1</i>,	142
abstract_inverted_index.cost-effective	215
abstract_inverted_index.hypermutation.	122
abstract_inverted_index.identification	226
abstract_inverted_index.immunotherapies	4
abstract_inverted_index.stratification.	23
abstract_inverted_index.Design:</b>	53
abstract_inverted_index.<i>ERBB2</i>	172
abstract_inverted_index.<i>FGFR3</i>	195
abstract_inverted_index.<i>MDM2</i>,	144
abstract_inverted_index.<i>TSC1</i>.	192
abstract_inverted_index.<i>PIK3C</i>A	181
abstract_inverted_index.<i>ARID1A</i>.	158
abstract_inverted_index.AACR</i>.</p></div>	261
abstract_inverted_index.cancer.</p><p><b>Experimental	52
abstract_inverted_index.disease.</p><p><b>Results:</b>	86
abstract_inverted_index.<div>Abstract<p><b>Purpose:</b>	0
abstract_inverted_index.patient.</p><p><b>Conclusions:</b>	205
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