Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Toomey, Sinéad; Gunther, Jillian R.; Carr, Aoife; Weksberg, David C.; Thomas, Valentina; Salvucci, Manuela; Bacon, Orna; Sherif, El Masry; Fay, Joanna; Kay, Elaine W.; Sheehan, Katherine M.; McNamara, Deborah A.; Sanders, Kevin E.; Mathew, Geena; Breathnach, Oscar S.; Grogan, Liam; Morris, Patrick G.; Foo, Wai Chin; You, Yi Qian Nancy; Prehn, Jochen H M; O’Neill, Brian; Krishnan, Sunil; Hennessy, Bryan T.; Furney, Simon J.

doi:10.3390/cancers12071808

Cited by 15 publications

(16 citation statements)

References 56 publications

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“…For instance, multi-gene expression assays developed on the NanoString nCounter system may provide more accurate prediction to nCRT response in LARC [ 39 , 40 ]. DNA-based molecular markers, including mutations in KRAS or TP53 and microsatellite instability (MSI), may also be associated with responses to neoadjuvant treatment in LARC [ 41 , 42 , 43 ]. Other promising tissue-based predictive biomarkers, including the expression of microRNAs [ 38 ], differentially methylated CpGs [ 44 ], immune profiles [ 45 , 46 ], multi-protein expression assays by immunohistochemistry [ 47 ], are necessary to be validated on large, retrospective, and prospective cohorts of pre-treatment LARC biopsies, although the translation of biomarkers into clinical practice remains challenging.…”

Section: Discussionmentioning

confidence: 99%

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Momma

Okayama

Kanke

et al. 2021

Cancers

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Background: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is widely used for patients with locally advanced rectal cancer. However, response to nCRT varies substantially among patients, highlighting the need for predictive biomarkers that can distinguish non-responsive from responsive patients before nCRT. This study aimed to build novel multi-gene assays for predicting nCRT response, and to validate our signature and previously-reported signatures in multiple independent cohorts. Methods: Three microarray datasets of pre-therapeutic biopsies containing a total of 61 non-responders and 53 responders were used as the discovery cohorts to screen for genes that were consistently associated with nCRT response. The predictive values of signatures were tested in a meta-analysis using six independent datasets as the validation cohorts, consisted of a total of 176 non-responders and 99 responders. Results: We identified four genes, including BRCA1, GPR110, TNIK, and WDR4 in the discovery cohorts. Although our 4-gene signature and nine published signatures were evaluated, they were unable to predict nCRT response in the validation cohorts. Conclusions: Although this is one of the largest studies addressing the validity of gene expression-based classifiers using pre-treatment biopsies from patients with rectal cancer, our findings do not support their clinically meaningful values to be predictive of nCRT response.

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Section: Discussionmentioning

confidence: 99%

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Momma

Okayama

Kanke

et al. 2021

Cancers

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“…Samples were sequenced to a mean coverage of 83× using 91bp paired end reads on the Illumina HiSeq 2000. Somatic single nucleotide variants (SNVs), short insertions and deletions (indels) and copy number alterations (CNAs) were identified by comparing each tumour sample and involved lymph node with the blood sample as a matched normal, as previously described [ 19 ].…”

Section: Case Presentation and Resultsmentioning

confidence: 99%

Tumour Genome Characterization of a Rare Case of Pulmonary Enteric Adenocarcinoma and Prior Colon Adenocarcinoma

Smyth

Thomas

Fay

et al. 2021

JPM

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Pulmonary enteric adenocarcinoma (PEAC) is a rare variant of lung adenocarcinoma first described in the early 1990s in a lung tumour with overlapping lung and small intestine features. It is a rare tumour with fewer than 300 cases described in the published literature and was only formally classified in 2011. Given these characteristics the diagnosis is challenging, but even more so in a patient with prior gastrointestinal malignancy. A 68-year-old Caucasian female presented with a cough and was found to have a right upper lobe mass. Her history was significant for a pT3N1 colon adenocarcinoma. The resected lung tumour showed invasive lung adenocarcinoma but also features of colorectal origin. Immuno-stains were strongly and diffusely positive for lung and enteric markers. Multi-region, whole-exome sequencing of the mass and archival tissue from the prior colorectal cancer showed distinct genomic signatures with higher mutational burden in the PEAC and very minimal overlap in mutations between the two tumours. This case highlights the challenge of diagnosing rare lung tumours, but more specifically PEAC in a patient with prior gastro-intestinal cancer. Our use of multi-region, next-generation sequencing revealed distinct genomic signatures between the two tumours further supporting our diagnosis, and evidence of PEAC intra-tumour heterogeneity.

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“…Recently, NT has emerged as the standard treatment for LARC patients[ 11 - 14 ]. Patients who cannot achieve a pCR usually undergo surgery and receive adjuvant therapy.…”

Section: Discussionmentioning

confidence: 99%

Nomograms and risk score models for predicting survival in rectal cancer patients with neoadjuvant therapy

Wei¹,

Mei²,

Chen³

et al. 2020

WJG

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BACKGROUND Colorectal cancer is a common digestive cancer worldwide. As a comprehensive treatment for locally advanced rectal cancer (LARC), neoadjuvant therapy (NT) has been increasingly used as the standard treatment for clinical stage II/III rectal cancer. However, few patients achieve a complete pathological response, and most patients require surgical resection and adjuvant therapy. Therefore, identifying risk factors and developing accurate models to predict the prognosis of LARC patients are of great clinical significance. AIM To establish effective prognostic nomograms and risk score prediction models to predict overall survival (OS) and disease-free survival (DFS) for LARC treated with NT. METHODS Nomograms and risk factor score prediction models were based on patients who received NT at the Cancer Hospital from 2015 to 2017. The least absolute shrinkage and selection operator regression model were utilized to screen for prognostic risk factors, which were validated by the Cox regression method. Assessment of the performance of the two prediction models was conducted using receiver operating characteristic curves, and that of the two nomograms was conducted by calculating the concordance index (C-index) and calibration curves. The results were validated in a cohort of 65 patients from 2015 to 2017. RESULTS Seven features were significantly associated with OS and were included in the OS prediction nomogram and prediction model: Vascular_tumors_bolt, cancer nodules, yN, body mass index, matchmouth distance from the edge, nerve aggression and postoperative carcinoembryonic antigen. The nomogram showed good predictive value for OS, with a C-index of 0.91 (95%CI: 0.85, 0.97) and good calibration. In the validation cohort, the C-index was 0.69 (95%CI: 0.53, 0.84). The risk factor prediction model showed good predictive value. The areas under the curve for 3- and 5-year survival were 0.811 and 0.782. The nomogram for predicting DFS included ypTNM and nerve aggression and showed good calibration and a C-index of 0.77 (95%CI: 0.69, 0.85). In the validation cohort, the C-index was 0.71 (95%CI: 0.61, 0.81). The prediction model for DFS also had good predictive value, with an AUC for 3-year survival of 0.784 and an AUC for 5-year survival of 0.754. CONCLUSION We established accurate nomograms and prediction models for predicting OS and DFS in patients with LARC after undergoing NT.

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Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Cited by 15 publications

References 56 publications

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

Tumour Genome Characterization of a Rare Case of Pulmonary Enteric Adenocarcinoma and Prior Colon Adenocarcinoma

Nomograms and risk score models for predicting survival in rectal cancer patients with neoadjuvant therapy

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