KRAS Mutation in Rare Tumors: A Landscape Analysis of 3453 Chinese Patients

Abstract

KRAS is the most commonly mutated oncogene in human cancers. Targeted therapy and immunotherapy for this gene have made remarkable progress in recent years. However, comprehensive molecular landscape analysis of KRAS in rare tumors is lacking. Retrospective analysis was performed on clinical samples from patients with rare tumors collected between September 2015 and September 2021, using hybrid-capture-based next-generation sequencing for genomic profiling and immunohistochemistry assay for PD-L1. Of the 3,453 patients included in analysis, KRAS mutations were identified in 8.7% patients in overall; mutation rate and mutation subtypes varied widely across tumor systems and subtypes. KRAS mutations included 21 missense mutations, of which G12D (29.2%), G12V (24.6%), and G13D (10.8%) were most common. Interestingly, KRAS G12C was observed in 0.6% patients overall, and in 5.7% of sarcomatoid carcinoma of the lung and 5.4% of clear cell ovarian cancer tumors, but none in small-bowel cancer tumors. 31.8% KRAS mutations and 36.4% KRAS G12C mutations co-occurred with other targetable alterations. No significant correlation was observed between TMB-H, MSI-H, PD-L1 status, and KRAS mutation status, which may be related to the high proportion of G12D. This study is the first KRAS mutation landscape study in rare tumors of large sample size in China and worldwide. Our results suggest that targeted therapy and immunotherapy are both feasible, albeit complex, in these patients. This information may have significant impact on the operation of clinical trials for rare tumor patients with KRAS mutations in China.

Genetic testing and prognosis of sarcomatoid hepatocellular carcinoma patients

“…G12D (60%) is the dominant mutant subtype of KRAS in this study, and we still found that the numbers of patients who survived over one year in wild- type KRAS group were greater than those in the KRAS mutation (n=3 vs n=0). Evidence exists that KRAS- mutant cancers with the G12C subtype, instead of the G12D subtype, was associated with higher TMB and PD-L1 positivity rate compared with wild-type KRAS ( 32 ). Novel inhibitors targeting KRAS ( G12C ), such as AMG510 (sotorasib) and MRTX849 (adagrasib), have displayed promising results in preclinical and clinical trials, due to the covalent inhibition of cysteine and high GTPase activity of KRAS ( G12C ) ( 33 ).…”

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

“…Specifically in NSCLC, KRAS G12C is the most common mutant subtype, accounting for roughly 45% of all KRAS mutations, followed by G12V and G12D [ 18 ]. Apart from the common tumor types, the landscape of the KRAS mutation in rare tumors is investigated, with an overall mutation rate of 8.7%; and G12D and G12V, along with G13D, are the most common subtypes [ 19 ]. The KRAS mutation frequency and subtype proportion in common cancers are summarized in Table 1 .…”

Targeting rare tumors: new focus for clinical research in China

“…A previous study in Chinese NSCLC patients reported a prevalence of 10.7% and 4.6% in overall KRAS mutation and G12C, respectively. We depicted the first KRAS mutation landscape of rare tumors in a large Chinese rare tumor population and observed an overall prevalence of 8.7% of KRAS mutation, concentrated on G12D, G12V, and G13D (Wang et al , 2022a ). The G12C mutation was found in 0.6% of the population.…”

“…The G12C mutation was found in 0.6% of the population. However, a higher rate of G12C mutations was observed in sarcomatoid carcinoma of the lung (SARCL) and clear cell ovarian cancer (CCOV), with a prevalence of more than 5% (Wang et al , 2022a ).…”