TP53 Gain-of-Function Mutation is a Poor Prognostic Factor in High-Methylated Metastatic Colorectal Cancer

Abstract

<h2>Abstract</h2><h3>Background</h3> Neither <i>TP53</i> mutation nor DNA methylation status has been established as a biomarker alone of metastatic colorectal cancer. We analyzed the association between <i>TP53</i> mutation functional subtypes and genome-wide DNA methylation status (GWMS) as combined prognostic markers. <h3>Methods</h3> Patient clinical data were obtained from the TRICOLORE study, a randomized phase III trial. The <i>TP53</i> mutations were classified into wild-type, gain-of-function (GOF) mutations, and non-gain-of-function (non-GOF) mutations. GWMS of the tumor tissues classified them into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). Overall survival (OS) was compared based on these subgroups. <h3>Results</h3> Of the 209 patients, 60 (28.7%) were HMCC and 149 (71.3%) were LMCC, 35 (16.7%) were <i>TP53</i> wild-type and 174 (83.3%) were <i>TP53</i> mutants including 79 (45.4%) GOF mutations and 95 (54.6%) non-GOF mutations. The OS of the HMCC group was shorter than that of the LMCC group (median 25.3 vs. 40.3 months, <i>P</i> < .001, hazard ratio 1.87) in the total cohort. The combined subgroup analyses of GWMS and <i>TP53</i> mutation subtypes showed that the HMCC/GOF group had significantly shorter OS than the HMCC/non-GOF group, the LMCC/GOF group, and the LMCC/non-GOF group (median 17.7; 35.3, 40.3, and 41.2 months, <i>P</i> = .007, <i>P</i> < .001, and <i>P</i> < .001, respectively), regardless of the primary tumor location. By the multivariate analysis, only HMCC (<i>P</i> = .009) was a poor prognostic factor in the GOF mutation group. <h3>Conclusions</h3> <i>TP53</i> GOF with HMCC is a newly identified poorest prognostic molecular subset in metastatic colorectal cancer.

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