Genomic instability and early-onset colorectal cancer: a new form of classifying the disease?

Background

Early-onset colorectal cancer (EOCRC) is an uncommon entity frequently associated with poor clinical outcomes. Therefore, advances in the understanding of its molecular basis are essential for the adequate management of the patients.

Methods

We used a high-resolution array comparative genomic hybridization (aCGH) platform to investigate the chromosomal instability (CIN) of 60 EOCRC (≤45 years at diagnosis), and submitted the data to an unsupervised hierarchical clustering analysis in order to unveil possible associations between the CIN profile and the clinical features of the tumors. We also evaluated the microsatellite instability (MSI) and CpG island methylator phenotype (CIMP) statuses with the aim of investigating a possible relationship between CIMP, MSI and CIN.

Results

Based on the similarity of the copy number alterations (CNAs), the unsupervised analysis stratified samples into two main clusters (A, B) and four secondary clusters (A1, A2, B3, B4). We observed a correspondence with the molecular classification of colorectal cancer, in such a way that the CIMP-High tumors were mostly contained in A1 or A2 depending on the CIN degree (with microsatellite and chromosome stable tumors [MACS, 1-3 whole chromosomes affected] mainly included in A1 and CIN- tumors [none whole chromosome affected] mainly included in A2), and the CIMP-Low/0 tumors were mostly contained in B3 or B4 depending on the presence/absence of MSI. Interestingly, each subcluster showed some distinctive clinicopathological features. But more interestingly, the CIN of each subcluster mainly affected particular chromosomes, providing evidence of the association between the three indicators of genomic instability evaluated.

Conclusions

We observed a correlation between the CIMP/MSI/CIN statuses in EOCRC which enabled us to outline an algorithm whereby tumors could be categorized according to these features. Our findings may provide a basis for a new form of classifying EOCRC according to the genomic status of the tumors.

Clinical trial identification

Legal entity responsible for the study

This work was funded by Projects PI10/0683, PI13/01741 and PI13/0127 from the Spanish Ministry of Health and Consumer Affairs and FEDER.

Funding

This work was funded by Mari Paz Jiménez Casado Foundation.

Disclosure

All authors have declared no conflicts of interest.