Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

TY - JOUR

T1 - Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

AU - Taber, Ann

AU - Christensen, Emil

AU - Lamy, Philippe

AU - Nordentoft, Iver

AU - Prip, Frederik

AU - Lindskrog, Sia Viborg

AU - Birkenkamp-Demtröder, Karin

AU - Okholm, Trine Line Hauge

AU - Knudsen, Michael

AU - Pedersen, Jakob Skou

AU - Steiniche, Torben

AU - Agerbæk, Mads

AU - Jensen, Jørgen Bjerggaard

AU - Dyrskjøt, Lars

PY - 2020/9

Y1 - 2020/9

N2 - Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.

AB - Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.

KW - ASSOCIATION

KW - CARCINOMA

KW - CLONAL EVOLUTION

KW - CYSTECTOMY

KW - GEMCITABINE PLUS CISPLATIN

KW - NEOADJUVANT CHEMOTHERAPY

KW - SENSITIVITY

KW - SIGNATURES

KW - SOMATIC ERCC2 MUTATIONS

KW - SURVIVAL

KW - Genomic Instability

KW - Humans

KW - Drug Therapy

KW - Transcriptome

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Biomarkers, Tumor

KW - Urinary Bladder Neoplasms/drug therapy

KW - Programmed Cell Death 1 Receptor/genetics

KW - BRCA2 Protein/genetics

KW - Cisplatin/pharmacology

KW - DNA Methylation

KW - Neoadjuvant Therapy

KW - Chemotherapy, Adjuvant

KW - Mutation

UR - http://www.scopus.com/inward/record.url?scp=85091566862&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-18640-0

DO - 10.1038/s41467-020-18640-0

M3 - Journal article

C2 - 32978382

AN - SCOPUS:85091566862

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4858

ER -