Objectives The Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) consists of 40.3% (214/530) of TP53-mutants. TP53 mutation-spectrum consists of missense and truncated mutations yielding loss-of-function/gain-of-function (GOF) and only loss-of-function effects, respectively. of the four TCGA-defined molecular categories, namely, prognostically superior POLE, MSI, ‘copy number low’ and prognostically worst ‘copy number high’, the last includes TP53-mutants. We have compared progression free survival (PFS) among missense, truncated and most frequent GOF TP53-mutants, in the context of overlapping mutations in POLE and/or MSI-specific genes.
Methods Our study is based on mutation-analysis from TCGA-UCEC categorizing cases into TP53-mutants, POLE-mutants and MSI-specific gene-mutants. Mutational overlap is termed as ‘mixed’. MSI-status is based on mutations in MSH2/MSH3/MSH6/MLH1/MLH3/PMS1/PMS2.
Results PFS of TP53 truncated-only (n=37) and TP53 truncated-mixed (group-A) (n=12) differed significantly (p,log-rank=0.013) unlike that among TP53 missense-only (n=123), TP53 truncated-only, and TP53 missense-mixed (n=21) (p,log-rank=0.305). GOF TP53 Y220C (group-B) (n=6) depicted better PFS. There was no difference in PFS of group-A or group-B from those having POLE mutated wild-type TP53 (group-C) (p,log-rank=0.582) (n=9). Together, group-A and group-B showed lower risk (HR=0.087; 95%CI = 0.012 - 0.638; p=0.016) and better PFS compared to other TP53 mutations (p,log-rank=0.010).
Conclusions Clinically, group-A and group-B behave like group-C, having better prognosis. Therefore, these patients may escape adjuvant therapy despite their TP53-mutant status. The subset of cases who would benefit from this comprise 8.41% (group-A + group-B = 18/214*100) of the TP53-mutant cases or 3.39% (group-A + group-B = 18/530*100) as opposed to the repoetedly acclaimed 1.69% (group-C = 9/530*100) of total cases.
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