Exploration of molecular signalling underpinning the DNA Damage Response Deficiency (DDRD) assay in Colorectal Cancer; Data from the S:CORT consortium (Stratification in COlorRecTal cancer)


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Sudhir Malla1,Keara Redmond1,Andrew Blake2,Enric Domingo2,Susan Richman3,Michael Youdell2,Ian Tomlinson4,Louise Brown5,Tim Maughan2,Mark Lawler1,Philip Dunne1,S:cort Consortium6
1Queen's University Belfast, Belfast, UK,2University of Oxford, Oxford, UK,3University of Leeds, Leeds, UK,4University of Birmingham, Birmingham, UK,5University College London, London, UK,6S:CORT Consortium, Oxford, UK

Abstract

Background

The DNA Damage Response Deficiency (DDRD) assay was developed by Almac (Craigavon, Northern Ireland, UK) as a predictive tool in breast cancer (BC) for response to DNA-damaging chemotherapy, based on tumour biology associated with Fanconi Anaemia/BRCA pathway loss. Following studies in BC, the S:CORT consortium tested the hypothesis that the DDRD assay might also predict response to oxaliplatin in colorectal cancer (CRC). In addition to the clinical endpoints, this study also set out to describe the underlying tumour biology represented by DDRD-positivity in CRC.

Method

A comprehensive data analysis was performed on 361 primary FFPE samples from a subset of the FOCUS metastatic CRC clinical trial, including assessment of consensus molecular subtypes (CMS), colorectal intrinsic subtypes (CRIS), DDRD calls, and DDRD scores. To explore the tumour microenvironment (TME) content and biology, MCPcounter (R package) and gene set enrichment analysis (GSEA) using the ‘Hallmark’ collection from genepattern was used. Additionally, 198 BC samples from TRANSBIG cohort (GSE7390), used in the development of DDRD assay, were included for a comparative analysis with CRC GSEA finding.

Results

CMS1 subtypes are proportionally higher in DDRD-positives and CMS4 in DDRD-negatives (Fisher’s exact test, P = 0.0002). Additionally, DDRD-positives are significantly infiltrated with cytotoxic lymphocytes (t-test, P < 0.0001) with a moderate linear correlation against DDRD scores (Pearson’s correlation r = 0.43598, P < 0.00001). Allograft rejection, interferon-α, and interferon-γ response are the top three upregulated gene-sets in DDRD-positives (FDR adjusted, P < 0.25). Of note, we observe CRC-specific upregulation of apical surface and spermatogenesis in DDRD-positives, and Hedgehog signalling and NOTCH signalling gene-sets in DDRD-negatives.

Conclusion

Our finding suggests DDRD-positive tumours represents a similar biology between the two cancer types in terms of TME infiltrates with high tumour-infiltrating lymphocytes and activation of interferon-related signalling. This distinct immune-specific DDRD biology suggests a potential immunotherapeutic implication in CRC.