584P - Genomic and transcriptomic characterization of peritoneal, lung and liver metastases of colorectal carcinoma reveals site-specific differences

Background

Metastasis in colorectal cancer (CRC) is a critical factor in patient outcomes. Despite the growing importance of metastatic sites as independent predictors of overall survival and the ongoing development of new treatments, there has been limited effort to personalize systemic treatment based on specific metastatic locations. This study aims to compare the genomic landscape of different metastatic sites in CRC to detect novel diagnostic and therapeutic targets.

Methods

DNA whole-genome-sequencing and RNA expression data from 484 CRC samples derived from liver metastases (n=380), peritoneal metastases (PM, n=66) and lung metastases (n=38) retrieved from the Hartwig Medical Foundation (HMF) were included. We compared DNA mutation frequencies using two-sided Mann-Whitney or Fisher-exact tests. We utilized gene expression information to identify coding structural variants that influence tumor biology.

Results

PM displayed less genomic instability, featuring lower fraction genome altered (median 0.54 vs 0.64 in liver (p=0.008); vs 0.68 in lung (p=0.016)) as well as lower fractions of whole genome doubling (median 0.59 vs 0.72 in liver (p=0.046); vs 0.76 in lung (p=0.122)). PM had lower frequencies of non-silent SNVs in the APC gene compared to liver and lung (65% vs 86% in liver (FDR=0.020); 86% in lung (FDR =0.091)). Analysis of targetable variants, revealed that PM were more frequently MSI (12.1%) compared to liver (2.9%, p=0.002) and lung (2.6%, p=0.15). All MSI peritoneal metastases had a mutation in ERBB2. In the whole cohort, PM showed the highest frequency of this mutation (13.6% vs. 5.2% in liver (p=0.025); vs. 7.9% in lung (p=0.528)). 29.7% of the lung metastases had a high TMB despite the MSS status Integrative transcriptomic analysis reveals genes in PM that are affected by a structural variation in a coding region and have a high influence on tumor biology and are located on chromosome 8q: FAM150 A, RP11 and TACC1.

Conclusions

The higher proportion of MSI and ERBB2 mutations could make PM a good candidate for immunotherapy. The genes FAM150 A, RP11 and TACC1 on chromosome arm 8q could have an influence on distinct biology in PM. Lung metastasis have high TMB despite a MSS status.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Deutsche Forschungsgemeinschaft.

Disclosure

R. de Wit: Non-Financial Interests, Institutional, Other, nonfinancial support: Cergentis. G. Meijer: Financial Interests, Personal and Institutional, Advisory Board: CRCbioscreen BV; Non-Financial Interests, Institutional, Other, collaboration: CZ Health Insurances; Other, Institutional, Other, collaboration: Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi, Hartwig Medical Foundation; Other, Institutional, Other, Several patents pending: Several patents pending. S. Abeln: Financial Interests, Institutional, Funding: Cergentis BV, Olink Proteomics AB, Quanterix Corporation. R. Fijneman: Financial Interests, Institutional, Funding: Personal Genome Diagnostics, Delfi Diagnostics, Natera, Merck BV; Other, Institutional, Other, Several patents pending: Several patents pending. All other authors have declared no conflicts of interest.