Dataset Information

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy.

ABSTRACT: Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

SUBMITTER: De Mattia E

PROVIDER: S-EPMC8740633 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy.

De Mattia Elena E Canzonieri Vincenzo V Polesel Jerry J Mezzalira Silvia S Dalle Fratte Chiara C Dreussi Eva E Roncato Rossana R Bignucolo Alessia A Innocente Roberto R Belluco Claudio C Pucciarelli Salvatore S De Paoli Antonino A Palazzari Elisa E Toffoli Giuseppe G Cecchin Erika E

Frontiers in pharmacology 20211224

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochem ...[more]

PMID: 35002714

Similar Datasets

Project description:Locally advanced rectal cancer (LARC) exhibits heterogeneous responses to neoadjuvant chemoradiotherapy (nCRT), patients resistant to nCRT failing to benefit from to nCRT. The aim of this pilot study is to identify proteins associated with LARC nCRT-resistance. This pilot study retrospectively enrolled 4 representative nCRT-resistant (stable disease/progressive disease) and 4 nCRT-sensitive (complete response/partial response) patients, of which a total of 15 formalin-fixed paraffin-embedded tumor tissues (before and after nCRT) were subjected to data-independent acquisition mass spectrometry for proteomic analysis. Spectronaut software was employed for protein identification and quantification. Principal component analysis (PCA) was used to visualize intergroup differences in detected proteins. Differently abundant proteins in resistant patients (fold change ≥ 1.2 or ≤ 0.83 compare to sensitive patients) were selected for analysis using hierarchical clustering, cluster of orthologous groups, subcellular location, gene ontology, and pathway enrichment assay. A total of 39052 peptides and 6006 proteins were identified. PCA showed PCA clear separation among four groups: pre-treatment sensitive (B_S), pre-treatment resistant (B_R), post-treatment sensitive (P_S), and post-treatment resistant (P_R). Intergroup comparisons revealed before nCRT, 133 proteins were upregulated in the resistant group compared to the sensitive group, mainly localized in cytoplasm (33.08%), secreted (24.81%), and nucleus (24.06%), with functions enriched in cell junctions and metabolic related pathways. Post nCRT, 290 proteins were upregulated in the resistant group compared to the sensitive group, mainly localized in the nucleus (36.55%) and cytoplasm (23.10%), with functions enriched in replication, transcription, translation, and metabolic pathways. This study characterized DAP signatures of LARC with nCRT resistance, specific DAPs in resistant tumor provide references for mechanistic studies on treatment resistance, could be potential biomarker for response and therapeutic targets after further validation in larger cohorts.

Dataset Information

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy.

Publications

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets