Background:

Recent data show that patients with left-sided colon tumors (LT) have better survival and respond differently to biologics compared to patients with right-sided tumors (RT), likely due to molecular differences. We sought to examine these differences.

Methods:

Primary colorectal tumors (n = 1730) with origins clearly defined as RT (cecum to hepatic flexure; n = 273), LT (splenic flexure to sigmoid colon; n = 585), or rectal (RC; n = 872) were examined by NextGen sequencing, protein expression, and gene amplification. Tumor mutational load (TML) was calculated in 1001 of these tumors using only somatic nonsynonymous missense mutations. Chi-square test was used for comparison.

Results:

When compared to LT, RT carried a significantly higher rate of BRAF (25% vs. 7%; p < 0.0001), PTEN (5.4% vs. 1.3%; p = 0.008), and ATM (4% vs. 1%; p = 0.04) mutations. RT were likely to have more MSI-high tumors (22% vs. 5%; p < 0.0001) and PD-1 overexpression (58% vs. 44%; p = 0.01). There were no differences in the rate of KRAS (50% vs. 42%; p = 0.07) or NRAS mutations (2.2% vs. 3.4%; p = 0.4). When compared to RC, RT had a higher rate of BRAF (25% vs. 3%; p = 7E-07), PIK3CA (22% vs. 11%; p = 0.001), CTNNB1 (3% vs. 0.3%; p = 0.02); ATM (3% vs. 1%; p = 0.04), PTEN (5% vs. 1%; p = 0.004), and BRCA1 mutations (4% vs. 0%; p = 0.02). However, a lower rate of TP53 (56% vs. 71%; p = 0.001) and APC (53% vs. 66%; p = 0.003) mutations were observed in RT than RC. When compared to RC, LT showed higher rates of BRAF (6.7% vs. 3.2%; p = 0.04) mutations, CTNNB1 (2.1% vs. 0.3%; p = 0.04) mutations, and MSI-high tumors (4.6% vs. 0.7%; p = 0.04); however RC had a higher rate of KRAS mutations (50% vs. 42%; p = 0.04). There were no differences between RT, LT, and RC for the frequency of PD-L1 (2%, 2%, and 1%) or Her-2 (1%, 2%, and 3%) overexpression, although Her-2 amplification was significantly different (1%, 3%, and 5%, RT vs. RC; p = 0.03). Mean TML was 12, 11, and 8 mutations/megabase for RT, LT, and RC (RT vs. RC; p = 0.01), respectively. There was a correlation between TML and PD-L1 expression (p = 0.04), and TML and PD-1 expression (p = 0.01).

Conclusions:

Tumors arising in the right colon carry genetic alterations that are different from LT as well as RC. However, it appears that CRCs carry a continuum of molecular alterations from the right to the left side, rather than displaying sharp, clear-cut differences