Rectal cancer sub-clones respond differentially to neoadjuvant therapy

Area of Science:

• Oncology
• Genetics
• Cancer Research

Background:

• Patient responses to neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer are highly variable.
• Rectal tumors exhibit genetic heterogeneity with distinct sub-clones, potentially influencing treatment response.

Purpose of the Study:

• To analyze the impact of nCRT on intra-tumoral genetic heterogeneity in rectal cancer.
• To identify genetic alterations and sub-clones that persist or are enriched after nCRT, offering insights into resistance mechanisms.

Main Methods:

• Whole exome sequencing and deep sequencing of pre- and post-treatment rectal cancer tissue.
• Copy number variation analysis using OncoScan SNP arrays.
• Genomic data analysis with PyClone to identify and track tumor sub-clones before and after nCRT.

Main Results:

• Significant changes in sub-clone proportions were observed in all patients post-nCRT.
• Resistant sub-clones frequently harbored mutations in TP53, APC, ABCA13, MUC16, and THSD4.
• Pathway analysis revealed significant alterations, particularly involving APC and TP53, in resistant sub-clones.

Conclusions:

• Intra-tumoral heterogeneity in rectal cancer is modified by nCRT, leading to the selective enrichment of resistant sub-clones.
• Further research is needed to identify diagnostic alterations predicting nCRT resistance.