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Identification of protein clusters predictive of tumor response in rectal cancer patients receiving neoadjuvant chemo-radiotherapy.

ABSTRACT: Preoperative neoadjuvant chemoradiotherapy (nCRT) is the gold standard in locally advanced rectal cancer, only 10-30% of patients achieving benefits. Currently, there is a need of a reliable selection of markers for the identification of poor or non-responders prior to therapy. In this work, we compared protein profiles before therapy of patients differing in their responses to nCRT to find novel predictive markers of response to therapy. Patients were grouped into 3 groups according to their tumor regression grading (TRG) after surgery: 'TRG 1-2', good responders, 'TRG 3' and 'TRG 4', poor responders. Paired surgical specimens of rectal cancer and healthy (histologically confirmed) rectal tissues from 15 patients were analysed before nCRT by two dimensional difference in gel electrophoresis followed by mass spectrometry. Thirty spots were found as differentially expressed (p < 0.05). Among them, 3 spots (spots 471, 683 and 684) showed an increased amount of protein in poor responders compared with good responders, and they were more tumor associated compared with healthy tissues. Proteins of these spots were identified as fibrinogen ß chain fragment D, actin isoforms, B9 and B5 serpins, cathepsin D isoforms and peroxiredoxin-4. In an independent validation set of 20 rectal carcinomas we validated the increased fibrinogen ß chain abundance before nCRT in poor responders by immunoblotting. In conclusion, we propose a risk-stratification tool in predicting the response to nCRT treatment in rectal cancer based on the quantity of these proteins.

SUBMITTER: Repetto O

PROVIDER: S-EPMC5438653 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Identification of protein clusters predictive of tumor response in rectal cancer patients receiving neoadjuvant chemo-radiotherapy.

Repetto Ombretta O De Re Valli V De Paoli Antonino A Belluco Claudio C Alessandrini Lara L Canzonieri Vincenzo V Cannizzaro Renato R

Oncotarget 20170401 17

Preoperative neoadjuvant chemoradiotherapy (nCRT) is the gold standard in locally advanced rectal cancer, only 10-30% of patients achieving benefits. Currently, there is a need of a reliable selection of markers for the identification of poor or non-responders prior to therapy. In this work, we compared protein profiles before therapy of patients differing in their responses to nCRT to find novel predictive markers of response to therapy. Patients were grouped into 3 groups according to their tu ...[more]

PMID: 28423701

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Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific M-bM-^@M-^\signatureM-bM-^@M-^] associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (M-OM-^G2=11M-bM-^@M-"793; p= 0M-bM-^@M-"001) and TS expression (M-OM-^G2=10M-bM-^@M-"589; p= 0M-bM-^@M-"001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer. Experiments were performed on purified RNA from preoperatory biopsies of 38 patients with histological diagnosis of rectal adenocarcinoma invading through the intestinal wall and/or with pelvic lymph node involvement as evaluated by endorectal ultrasonography (uT3-T4 and/or uN+). Patients were treated with neoadjuvant chemo-radiotherapy (capecitabine + oxaliplatin in combination with 45 Gy of pelvic conformal radiotherapy). Patients have been divided in the following two groups: group A those who had obtained a pathologic complete response M-bM-^@M-^S TRG 1, including the patient without detectable disease who refused surgery, group B any pathologic response other than complete.

Project description:Background: MicroRNAs (miRNAs) are small, non-coding, RNA molecules which regulate numerous cellular processes. Specific miRNA may be abnormally down-regulated or up-regulated in colorectal cancer and have been found associated with prognosis or response to treatments. However, no study has ever addressed their predictive role in rectal cancer. Therefore, we used microarray technology and RT-PCR to profile miRNA expression patterns in patients (pts) with rectal cancer, with the aim to identify a specific “signature” associated with pathological complete response after neoadjuvant chemo-radiotherapy. Methods: 38 pts with locally advanced rectal cancer (cT3-4/N+) were treated with capecitabine-oxaliplatin and pelvic conformal radiotherapy (45 cGy) followed by surgery (after 6-8 weeks). Pathologic response was scored according to the tumor regression grade (TRG) scale. MiRNA expression profile was analysed by microarray on fresh frozen biopsies obtained before treatment start and confirmed by RT-PCR. The correlation between miRNA expression profile and the TRG coded as TRG1 (pathologic Complete Response-pCR) versus TRG >1 (no pCR) was assessed by statistical analysis methods specifically designed for this study. Findings: 14 miRNAs were selected by arrays analysis as differentially expressed in TRG1 pts and 13 were confirmed by RT-PCR. In particular, 11 miRNAs (miR-1183, miR-483-5p, miR-622, miR-125a-3p, miR-1224-5p, miR-188-5p, miR-1471, miR-671-5p, miR-1909*, miR-630 and miR-765) were significantly up-regulated in TRG1 pts, while 2 miRNAs were under -expressed (miR-1274b and miR-720). miR-622 and miR-630 showed 100% sensitivity and specificity in selecting TRG1 cases and were significantly correlated with EGFR (χ2=11•793; p= 0•001) and TS expression (χ2=10•589; p= 0•001). Interpretation: A set of 13 miRNAs is strongly associated with pathologic complete response and may represent a specific marker of response to chemo-radiotherapy in locally advanced rectal cancer.

Dataset Information

Identification of protein clusters predictive of tumor response in rectal cancer patients receiving neoadjuvant chemo-radiotherapy.

Publications

Identification of protein clusters predictive of tumor response in rectal cancer patients receiving neoadjuvant chemo-radiotherapy.

Similar Datasets

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