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. 2020 Jan;9(1):84-93.
doi: 10.1002/cam4.2682. Epub 2019 Nov 10.

The prevalence and prognostic value of KRAS co-mutation subtypes in Chinese advanced non-small cell lung cancer patients

Dongjing Cai  1   2 , Chengping Hu  1   2 , Li Li  1   2 , Shichao Deng  1   2 , Jing Yang  1   2 , Han Han-Zhang  3 , Min Li  1   2   4   5
Affiliations

The prevalence and prognostic value of KRAS co-mutation subtypes in Chinese advanced non-small cell lung cancer patients

Dongjing Cai et al. Cancer Med. 2020 Jan.

Abstract

Objective: KRAS mutation plays a critical role in the initiation and development of non-small cell lung cancer (NSCLC). KRAS-mutant patients exhibit diverse response to chemotherapy. KRAS co-mutation subtypes and their prognosis value in advanced Chinese NSCLC patients remain largely elusive.

Methods: A total of 1126 Chinese advanced NSCLC patients from Xiangya hospital were screened by capture-based ultra-deep sequencing for KRAS mutation between January 2015 and December 2016. Survival analyses were performed using Kaplan-Meier analysis.

Results: Among the patients screened, 84 cases were detected with KRAS mutation (7.5%). All of them were non-squamous NSCLC and received pemetrexed plus platinum as the first-line treatment. The most frequent KRAS co-mutation genes were TP53 (29%), TP53/LKB1 (19%), and LKB1 (14%). Our data revealed that patients with KRAS co-mutation had poorer prognosis in comparison with those harboring single KRAS mutation. Furthermore, patients with KPL (KRAS mutated with TP53 and LKB1) subtype, which was a novel subtype, had the shortest progression-free survival (PFS) in all types of KRAS co-mutation patients (P < .0001). The PFS and overall survival (OS) of patients with KRASG12D mutation were inferior than those with KRASG12C mutation or KRASG12V mutation. Patients in KRASG>T type had significantly longer survival than those in KRASG>C type or KRASG>A type.

Conclusion: Our study revealed that concurrent genomic alterations can further stratify KRAS-mutant lung adenocarcinoma patients into various subgroups with distinctive therapeutic responses and differential survival outcomes. The KPL is a novel and less responsive subtype among KRAS-mutated NSCLC, and further investigation of effective treatment for this subtype is warranted.

Keywords: KRAS; Chinese; co-mutation; heterogeneity; non-small cell lung cancer.

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Conflict of interest statement

None declared.

Figures

Figure 1
Figure 1
The prevalence and genotype distribution of KRAS co‐mutation in Chinese advanced non‐small cell lung cancer patients; A, KRAS co‐mutation subtypes in the cohort of 56‐genes panel; B, KRAS mutation sites in the cohort of 56‐genes panel; C, the concurrent mutations which occur with different KRAS mutations
Figure 2
Figure 2
The progression‐free survival of different KRAS co‐mutation subtypes in Chinese advanced non‐small cell lung cancer patients. A, the PFS among KP, KL, KPL, and KRAS types were analyzed using Kaplan‐Meier and log‐rank test; B, the type of KRAS co‐mutation has shorter PFS in contrast with the ones of single KRAS mutation which has non‐co‐mutation with other vital genes like TP53, CDKN2A, LKB1, KEAP1; C, patients with KP mutation have similar PFS as the patient with non‐KP mutation (non‐KP = KL + KPL + KK + KC); D, the PFS of patients with KL mutation are similar to the ones of non‐KL in statistic (non‐KL = KP + KPL + KK + KC); E, the PFS of patients with KPL mutation are worse than the ones of non‐KPL mutation (non‐KPL = KP + KL + KK + KC)
Figure 3
Figure 3
The overall survival of different KRAS co‐mutation subtypes in Chinese advanced non‐small cell lung cancer patients. A, the overall survival among KP, KL, KPL and KRAS were analyzed using Kaplan‐Meier and log‐rank test (Mantel‐Cox); B, KRAS co‐mutation subtypes has shorter overall survival in contrast with the ones of single KRAS mutation which has non co‐mutation with other vital genes like TP53, CDKN2A, LKB1, KEAP1; C, patients with KP mutation have similar overall survival as the patient with non‐KP mutation (non‐KP=KL+KPL+KK+KC); D, the overall survival of patients with KL mutation are similar to the ones of non‐KL in statistic (non‐KL = KP + KPL + KK + KC); E, the overall survival of patients with KPL mutation are resemblance with the ones of non‐KPL (non‐KPL = KP + KL + KK + KC)
Figure 4
Figure 4
The survival of different KRAS mutation subtypes in Chinese advanced non‐small cell lung cancer patients. A, the comparison of overall survival in different KRAS‐mutated sites containing KRASG12C, KRASG12D, KRASG12V, the statistical significance was analyzed by the means of Kaplan‐Meier and log‐rank test (Mantel‐Cox); B, the difference of PFS in KRAS mutation sites was analyzed by the means similar as A; C, at the level of amino acid substitution, the comparison of overall survival in various subtypes was presented; D, the PFS of amino acid substitution subtypes was analyzed
Figure 5
Figure 5
The overall survival and distinctive expression of immune‐maker genes among different KRAS co‐mutation types in TCGA cohort. A and B, the KPL type have poor OS Page 21 of 27 Cancer Medicine compared to other KRAS co‐mutation subtypes, the statistical significance was analyzed by the means of Kaplan‐Meier and log‐rank test (Mantel‐Cox). C, the heat map was built based on the expression of immune‐related genes in different KRAS subtypes. D‐I, with further details, except for CD274/PD‐L1 expression, the lower immune‐costimulatory and immune‐coinhibitory genes were expressing in KPL type compared to KP type. The statistical significance was analyzed by unpaired t tests
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