KRAS mutations and their prognostic implications in appendiceal cancers.
Authors: Nutalapati Snigdha , Sadeghipour Negar , Xiu Joanne , Wu Sharon , Lenz Heinz-Josef , Schmocker Ryan , Oberley Matthew James , Reagan Anna , McDonald Hannah , Patel Reema Anil , Goel Sanjay , Pandalai Prakash , Kim Joseph 
Published: June 2024

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Background: Despite shared embryonic origin, appendiceal cancers (AC) have distinct clinical and molecular features compared to colorectal cancers (CRC). Detection of mutant KRAS has been associated with worse survival in CRC, whereas in AC the prognostic significance of mutant KRAS (55-65% prevalence) has yet to be characterized. Methods: AC tissues from 852 individual patients that underwent DNA (592, NextSeq, or whole exome sequencing) and whole transcriptome sequencing (NovaSeq) at Caris Life Sciences (Phoenix, AZ) were analyzed. Low-grade appendiceal mucinous neoplasms were excluded. Chi-square, Fishers-exact, and Mann Whitney U tests were used to determine statistical significance and were adjusted for multiple hypothesis testing (p< 0.05). Real-world overall survival (OS) was calculated using insurance claims of AC patients from time of sample collection to last contact. Hazard ratios (HRs) were calculated using the Cox proportional hazards model (log-rank test). Multivariate regression analysis was performed on age, sex, histology, site, comutations and KRASmut vs. KRASwt. Results: AC histological subtypes comprised mucinous adenocarcinoma (37.9%), goblet cell carcinoma (19.6%), signet ring cell carcinoma (12.1%), and adenocarcinoma- not otherwise specified (NOS, 30.4%). Among all AC specimens, KRAS was the most common mutation (49%). KRASmut vs. KRASwt tumors were more frequently associated with TP53mut (51.2% vs. 36.8%, respectively; p< 0.01) and GNASmut (41.1% vs. 5.7%, respectively; p < 0.00001). Most frequent co-mutant gene with KRAS was TP53 (61.2%) in adenocarcinoma-NOS, and GNAS (46.9%) in mucinous adenocarcinomas.Median OS among KRASmut vs. KRASwt was 33.3 vs. 25.1 months, respectively (HR 0.68, 95% CI: 0.58-0.80, p < 0.00001). KRASmut was associated with improved survival in mucinous adenocarcinomas (HR 0.71; 95% CI: 0.52-0.96, p = 0.028) and adenocarcinoma-NOS (HR 0.77; 95% CI: 0.62-0.97, p = 0.025), but not with signet ring cell (HR 1.92; 95% CI: 0.90-4.10, p = 0.087) or goblet cell carcinoma (HR 1.39; 95% CI: 0.50-3.91, p = 0.536). Multivariate analysis showed KRASmut was an independent prognostic factor for improved survival among all AC (HR 0.77, 95% CI: 0.64-0.93, p = 0.007) and mucinous adenocarcinoma (HR 0.60, 95% CI: 0.42-0.84, p<0.0001).Notably, GNASmut was associated with improved survival (HR 0.57, 95% CI: 0.47-0.70, p < 0.00001), while TP53mut was associated with poorer survival (HR 1.58, 95% CI: 1.35-1.86, p < 0.00001) among all AC. Conclusions: KRAS was one of most frequently mutated genes in ACs. In contrast to CRC, KRASmut was associated with significantly improved survival. This observed survival advantage remained consistent in the histologic subgroup of mucinous adenocarcinoma, but not in goblet and signet ring cell cancers. Further studies with population level data understanding the molecular profiles and their survival implications in histologically distinct AC are needed.