Abstract
BackgroundIn colorectal cancer (CRC), the consensus molecular subtype 4 (CMS4) is associated with therapy resistance and poor prognosis. Clinical diagnosis of CMS4 is hampered by locoregional and temporal variables influencing CMS classification. Diagnostic tools that comprehensively detect CMS4 are therefore urgently needed.MethodsTo identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. Heterogeneity of marker expression in relation to CMS4 status was assessed by analysing 3–5 tumour regions and 91.103 single-tumour cells (7 and 29 tumours, respectively). Candidate marker expression was validated in CMS4 peritoneal metastases (PM; n = 59). Molecular imaging was performed using the 68Ga-DOTA-FAPI-46 PET tracer.ResultsFibroblast activation protein (FAP) mRNA identified CMS4 with very high sensitivity and specificity (AUROC > 0.91), and was associated with significantly shorter relapse-free survival (P = 0.0038). Heterogeneous expression of FAP among and within tumour lesions correlated with CMS4 heterogeneity (AUROC = 1.00). FAP expression was homogeneously high in PM, a near-homogeneous CMS4 entity. FAPI-PET identified focal and diffuse PM that were missed using conventional imaging. Extra-peritoneal metastases displayed extensive heterogeneity of tracer uptake.ConclusionFAP expression identifies CMS4 CRC. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking.
Highlights
Transcriptional profiling of large cohorts of colorectal tumours has resulted in the generation of a consensus molecular classification (CMS) system for colorectal cancer (CRC), consisting of four distinct subtypes (CMS14) [1]
We provide evidence that FAPbinding tracers may serve as a comprehensive diagnostic tool to detect the highly heterogenous consensus molecular subtype 4 (CMS4) subtype and distinguish it from CMS1-3
Prior work had already shown that Fibroblast activation protein (FAP) expression in CRC is associated with poor prognosis [35–37] and that FAP is highly expressed in CMS4 [38]
Summary
Transcriptional profiling of large cohorts of colorectal tumours has resulted in the generation of a consensus molecular classification (CMS) system for CRC, consisting of four distinct subtypes (CMS14) [1]. A single biopsy from a primary tumour or a metastasis is sufficient to assess tumour MSI status of all tumour lesions in an individual patient [7]. This is presumably because dMMR is hard-wired into the DNA of all tumour lesions and not dependent on contextual or temporal variables. METHODS: To identify targets for molecular CMS4 imaging, RNA sequencing data of 3232 primary CRC patients were explored. FAPI-PET may have value in the comprehensive detection of CMS4 tumours in CRC. This is especially relevant in patients with PM, for whom effective imaging tools are currently lacking
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