Tumor location matters, next generation sequencing mutation profiling of left-sided, rectal, and right-sided colorectal tumors in 552 patients

Abstract

Despite the introduction of new molecular classifications, advanced colorectal cancer (CRC) is treated with chemotherapy supplemented with anti-EGFR and anti-VEGF targeted therapy. In this study, 552 CRC cases with different primary tumor locations (250 left side, 190 rectum, and 112 right side) were retrospectively analyzed by next generation sequencing for mutations in 50 genes. The most frequently mutated genes were TP53 in left-sided tumors compared to right-sided tumors and BRAF in right-sided tumors compared to left-sided tumors. Mutations in KRAS, NRAS, and BRAF were not detected in 45% of patients with left-sided tumors and in 28.6% of patients with right-sided tumors. Liver metastases were more common in patients with left-sided tumors. Tumors on the right side were larger at diagnosis and had a higher grade (G3) than tumors on the left. Rectal tumors exhibit distinctive biological characteristics when compared to left-sided tumors, including a higher absence rate of KRAS, NRAS, and BRAF mutations (47.4% in rectal versus 42.8% in left-sided tumors). These rectal tumors are also unique in their primary metastasis site, which is predominantly the lungs, and they have varying mutation rates, particularly in genes such as BRAF, FBXW7, and TP53, that distinguish them from tumors found in other locations. Primary tumor location has implications for the potential treatment of CRC with anti-EGFR therapy.

Figure 1

Oncoplot depicting the most recurrent (> 1%) genomic alterations in 552 colorectal cancer cases. Each column represents a tumor, and the bar graph (tumor mutation burden -TMB) at the top shows the number/distribution of mutations detected per sample. The Oncoprint rows show the changes for each gene. The summarized gender information for each case is shown at the bottom of the graph. The bar graph on the right side of the panel shows the number and distribution of mutations for each gene. Mutation types and gender are color-coded according to the legend.

Figure 2

Exclusive/co-occurrence event analysis of the top 25 mutated genes (p < 0.05, pairwise Fisher’s Exact test).

Figure 3

Frequency of mutations detected in the selected genes (BRAF, FBXW7, KRAS, NRAS, PIK3CA, and TP53) according to primary tumor location. (A) (right side = 112 cases vs. left side = 440 cases): BRAF and TP53 show statistically significant differences. (B) (right side = 112 cases, left side = 250 cases, and rectum = 190 cases): BRAF, FBWX7, and TP53 show statistically significant differences.