Early‑onset colorectal cancer: A distinct entity with unique genetic features

Abstract

The aim of the present study was to elucidate the genetic features of early-onset colorectal cancer (CRC), particularly the genetic mutations that may be regarded as prognostic and/or predictive markers in CRC and other malignancies. In total, 40 patients with non-polyposis CRC aged 35 or younger were selected. The formalin-fixed, paraffin-embedded tumors acquired were subjected to mismatch repair (MMR) protein immunochemical staining and gene analysis with next-generation sequencing (44 exons, 17 genes; Ion Torrent Sequencing Platform). A total of 11 (27.5%) tumors presented with MMR protein deficiency (dMMR) and 26 (65%) tumors harbored one or more genetic mutations, including K-RAS proto-oncogene (35%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA; 20%), B-Raf proto-oncogene (5%), erb-b2 receptor tyrosine kinase 2 (5%), discoidin domain receptor tyrosine kinase 2 (5%), N-RAS proto-oncogene (2.5%), KIT proto-oncogene (2.5%), TSC complex subunit 1 (2.5%), DNA methyltransferase 3 alpha (2.5%) and ABL proto-oncogene 1 (2.5%). Of the dMMR tumors, 81.8% (9/11) of cases presented with mutations in the tested genes, while only 58.6% (17/29) of the MMR-proficient (pMMR) tumors presented with these (P=0.158). PI3KCA was frequently mutated in dMMR tumors compared to pMMR tumors (P=0.025). In a subgroup with a family history of CRC, the dMMR status (P<0.001) and PIK3CA genetic mutation status (P=0.01) were more frequently observed compared to the other two groups (with a family history of other cancer types or no malignancy). Almost all patients who had relatives with CRC presented with both dMMR and other genetic mutations, while this was not observed in the patients who had relatives with other types of carcinoma. Certain genetic mutations that are rarely reported in CRC were only identified in those patients with a family history of carcinoma. In conclusion, non-polyposis CRC in young adults presents as a distinct entity with a unique set of genetic features. However, investigation of more cases in further studies is required to verify the present results.

Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review

“…Fifteen studies reported data on expression of MMR proteins, indicating MMR status. 21,23,24,26,27,33,37,41,43,[45][46][47][48][49][50] A combined meta-analysis of studies that had MSI and/or MMR results was performed, and this is shown in Figure 4A. Pooled analysis revealed a prevalence of 10% (95% CI 7%-14%) of MSI-H/dMMR in presumed sporadic EOCRCs.…”

“…Thirteen studies reported data on KRAS mutations, 22,24,27,[31][32][33]37,38,40,43,44,48 including our population-based cohort study. Pooled analysis revealed a prevalence of 32% (95% CI 23%-40%) for KRAS mutations in sporadic EOCRC (Figure 4C).…”

Early-Onset Colorectal Cancer: Current Insights

“…PIK3CA mutations are identified in 10–18% of CRC patients. These mutations confer a greater risk of transformation to cancer and predict poor response to treatment [ 99 ].…”