Molecular profiling of pediatric and young adult colorectal cancer reveals a distinct genomic landscapes and potential therapeutic avenues

Abstract

Colorectal cancer (CRC) is a global health concern, and the incidence of early onset (EO) CRC, has an upward trend. This study delves into the genomic landscape of EO-CRC, specifically focusing on pediatric (PED) and young adult (YA) patients, comparing them with adult (AD) CRC. In this retrospective monocentric investigation, we performed targeted next-generation sequencing to compare the mutational profile of 38 EO-CRCs patients (eight PED and 30 YA) to those of a 'control group' consisting of 56 AD-CRCs. Our findings reveal distinct molecular profiles in EO-CRC, notably in the WNT and PI3K-AKT pathways. In pediatrics, we observed a significantly higher frequency of RNF43 mutations, whereas APC mutations were more prevalent in adult cases. These observations suggest age-related differences in the activation of the WNT pathway. Pathway and copy number variation analysis reveal that AD-CRC and YA-CRC have more similarities than the pediatric patients. PED shows a peculiar profile with CDK6 amplification and the enrichment of lysine degradation pathway. These findings may open doors for personalized therapies, such as PI3K-AKT pathway inhibitors or CDK6 inhibitors for pediatric patients. Additionally, the distinct molecular signatures of EO-CRC underscore the need for age-specific treatment strategies and precision medicine. This study emphasizes the importance of comprehensive molecular investigations in EO-CRCs, which can potentially improve diagnostic accuracy, prognosis, and therapeutic decisions for these patients. Collaboration between the pediatric and adult oncology community is fundamental to improve oncological outcomes for this rare and challenging pediatric tumor.

Figure 1

(A) Heatmap of top 30 altered genes in PED group, color green on the left (0–19 years); YA group, color purple in the middle (20–39 years) and AD group, color orange on the right (over 60 years). Information related to TMB and MSI (MSS, grey; H-MSI, white; L-MSI dark grey) were reported on the top while patient group association on the bottom. The types of alterations were indicated by different colors. Each column represented one patient. (B) Top 10 altered genes in PED-CRC (green, A), YA-CRC (purple, B) AD-CRC (orange, C).

Figure 2

Distribution of genes enriched among the cohorts. Genes with* were significantly enriched (*Fisher exact test, p < 0.050; ** Fisher exact test, fdr < 0.050).

Figure 3

Oncogenic pathway enriched in PED (left), YA (middle) and AD-CRCs (right). The pathways analyzed are: (1) cell cycle, (2) Hippo signaling, (3) Myc signaling, (4) Notch signaling, (5) oxidative stress response/NRF2, (6) PI-3-Kinase signaling, (7) receptor-tyrosine kinase (RTK)/RAS/MAP-Kinase signaling, (8) TGFβ signaling, (9) P53 and (10) β-catenin/WNT signaling. (A) Barplots on the left show the fraction of mutated genes in the pathway; panels on the right show the fraction of samples with mutated genes in the pathway. (B) Oncoplot panels show the variants in WNT pathway in each group.

Figure 4

Pathway enrichment analysis using KEGG database. Significantly altered signaling pathways obtained from KEGG database and the three groups of patients characterizing the cohort are reported on y-axis and x-axis respectively. For each group, the fraction of altered genes composing the pathway (GeneRatio) is reported as dot where the size represents the magnitude of the ratio. The level of significance of each pathway within the groups is reported as color scale (blue = higher significance; red = lower significance).

Figure 5

Copy number variation analysis. Heatmap of top 31 altered genes in PED-CRC, color green on the left (0–19 years); YA-CRC, color purple in the middle (20–39 years) and AD-CRC, color orange on the right (over 60 years). Red and blue colors refer to amplification and deletion events respectively. Each column represented one patient.