Increased APC mutations in MRI risk‐stratified colorectal liver metastases
Authors: Seth Arun , Amemiya Yutaka , Cheung Helen , Hsieh Eugene , Law Calvin , Milot Laurent 
Published: June 2021

Surgery is the treatment of choice of patients with colorectal liver metastases (CRCLM), often used in conjunction with chemotherapy. Individual tumor genomics play a key role in determining patient prognosis, response to chemotherapy and in guiding therapy. A recent study demonstrated that harboring two or more APC mutations is significantly associated with lower overall survival compared to none or one mutation and another study showed that the double mutation of APC and PIK3CA negatively affected survival after hepatectomy.

Earlier work by our group demonstrated that target tumour enhancement (TTE), defined as the mean contrast‐to‐noise ratio of target lesions on late‐phase gadobutrol‐enhanced MRI, was associated with overall survival following liver surgery. Strong TTE was associated with improved survival compared to weak TTE (3‐year survival: 88.4% vs. 58.8%, p = 0.003) with a hazard ratio of 0.32 (95% CI: 0.14–0.75, p = 0.008), after taking into account known prognostic variables. Inter‐rater reliability was very good with a relative intraclass correlation of 0.84 (95% CI: 0.77–0.89).

Here we show results of next generation deep sequencing in 20 patients from the cohort, clustered by MRI TTE, using an Ion AmpliSeq Custom Next‐Generation Sequencing Colorectal Cancer Panel. Matched tumor and adjacent normal tissue samples from 10 patients with weak TTE (CNR: −111.2 to −10.8) and 10 patients with strong TTE (CNR: 15.9 to 74.0) were analyzed to detect somatic mutations.

We detected a total of 41 non‐synonymous somatic mutations from 10 patients with weak TTE (mean of 4.1 mutations) and a total of 25 non‐synonymous somatic mutations from 10 patients with strong TTE (mean of 2.5 mutations) when compared with the respective normal tissue samples. The mutation burden between weak TTE and strong TTE tumors was statistically different using the t‐test (p=0.0149).

APC was the most commonly altered gene, 30 mutations in 17 patients (85.0%) followed by 11 KRAS mutations in 11 patients (55%) and 10 TP53 mutations in 10 patients (50.0%). Among total of 30 mutations detected in APC, 26 mutations (86.7%) were either nonsense or frameshift mutations which are predicted to cause protein truncation or nonsense‐mediated decay. Of 26 truncation mutations, 18 mutations (69.2%) are found in weak TTE and 8 mutations (30.8%) are in strong TTE group. There was also a significant difference in the number of patients with double truncation mutation in APC between the weak TTE group (8/10=80%) and the strong TTE group (2/10=20%) using the Fisher's exact test (p=0.01).

In contrast, 80% of patients (8/10) with strong TTE tumors had TP53 mutations compared to 20% of patients (2/10) with weak TTE tumors. TP53 mutations in strong TTE were also strongly associated with APC mutations (87.5%). These data suggest that a tumor with the MRI phenotype associated with the worst prognosis harbored mutations known to be associated with a poorer outcome.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.