The prognostic significance of TP53 mutations in patients with right-sided and left-sided colorectal cancer.
Authors: Khushman Moh'd M. , Gandhi Nishant , Xiu Joanne , El-Rayes Bassel F. , Seeber Andreas , Williams Grant Richard , Outlaw Darryl Alan , Lou Emil , Shields Anthony Frank , Philip Philip Agop , El-Deiry Wafik S. , Marshall John , Jayachandran Priya , Lenz Heinz-Josef , Oberley Matthew James , Korn Wolfgang Michael , Manne Upender 
Published: June 2022

3589

Background: In patients with colorectal cancers (CRCs), prior studies have reported that various TP53 mutations have prognostic significance. The anatomic location of the primary CRC and the TP53 mutation subtype influence patient survival. In this study, we explored the prognostic significance of TP53 mutations (mTP53) classified as gain-of-function (GOF) or non-GOF in patients with right-sided (RCC) and left-sided CRCs (LCC). Methods: CRC specimens (6,248 RCCs and 14,215 LCCs) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing (NGS) of DNA (592-gene panel or whole- exome sequencing). R175H, R248W, R248Q, R249S, R273H, R273L, and R282W were defined as GOF mTP53 and all other mTP53 were defined as non-GOF mTP53. MSI-H/dMMR status was determined by immunohistochemistry (IHC) of MMR proteins and/or NGS. Real-world median overall survival (mOS) was obtained from insurance claims data and calculated from tissue collection to last contact using Kaplan-Meier estimates. Results: GOF mTP53 and non-GOF mTP53 were identified in 15% and 39% respectively, in RCC and 17% and 46% respectively, in LCC. In RCC, the mOS for patients with wild-type TP53 ( wtTP53) vs. GOF mTP53 was 34 months (m) vs. 23m (p < 0.00001), and the mOS for patients with wtTP53 vs. non-GOF mTP53 was 34m vs. 27m (p < 0.001). In LCC, the mOS for patients with wtTP53 vs. GOF mTP53 was 35m vs. 33m (p = 0.056), and the mOS for patients with wtTP53 vs. non-GOF mTP53 was 35m vs. 35m (p = 0.32). The mOS for patients with non-GOF mTP53 vs. GOF mTP53 in RCC and LCC was 28m vs. 24m (p = 0.096), and 35m vs. 34m (p = 0.175), respectively. The prognostic value of GOF mTP53 and non-GOF mTP53 was further explored in relation to MSI-H/dMMR, RAS, BRAF, and PIK3CA mutation status. The worse prognosis associated with mTP53 in RCC was seen in all comparisons, except in GOF mTP53/MSI-H/dMMR, and non-GOF mTP53/ wtKRAS subgroups. In patients with LCC, worse prognosis associated with GOF mTP53 and non-GOF mTP53 was only noticeable in KRAS and PIK3CA mutant subgroups. Conclusions: This is the largest study to explore TP53 mutations and their prognostic significance in patients with RCC and LCC. The prevalence of GOF mTP53 and non-GOF mTP53 was higher in LCC compared to RCC. However, both GOF mTP53 and non-GOF mTP53 were associated with worse mOS for patients with RCC, but not LCC. Our study validates the sidedness-dependent prognostic significance of TP53 mutations. It also shows that the worse prognosis of mTP53 is independent of the approach of collectively classifying TP53 mutations into GOF vs non-GOF. Given the sheer extent and diversity of TP53 mutations, a more nuanced approach towards re-classification of GOF mTP53 is warranted. Detailed information on p53 mutations will be crucial for the interpretation of future clinical trials and for the design of novel therapeutic strategies.