420P - Combinatory genomic and transcriptomic sequencing of Chinese KRAS mutant non-small cell lung cancer revealed molecular and inflammatory heterogeneity in tumor microenvironment

Background

KRAS mutations define a molecular subgroup of non-small cell lung cancer (NSCLC). KRAS G12C mutations can be targeted by small molecule inhibitors. Further investigation of cellular and molecular components of KRASm NSCLC is warranted to understand the disease mechanisms and guide precise treatment.

Methods

Tumor specimens of KRASm NSCLC were histologically evaluated, DNA and RNA were extracted. Comprehensive genomic and transcriptomic profiling were detected by Illumina TruSight Oncology 500 kit and TruSeq RNA Exome kit. Correlation analysis included demographic and clinical data as well.

Results

Among 162 cases of KRASm NSCLC, there were 141 males and 21 females, 140 adenocarcinoma and 8 squamous cell carcinoma, 2 sarcoid carcinoma, 1 large cell carcinoma and 1 NOS, 121 smokers and 41 non-smokers. Using next-generation sequencing (NGS), C>T transition signatures were found most often, followed by C>A, T>C, C>G, T>G, and T>A. KRAS mutations included 68 G12Cs, 33 G12Ds, 32 G12Vs, 9 G12As, 6 G13Ds, 6 Q61H/Ls and others. Major co-altered genes included TP53, LRP1B, FAT1, STK11, ARID1B, PTPRD, SPTA1, NOTCH3, NOTCH1, MGA, KEAP1, ZFHX3, etc. The genes co-alterations with KRAS were TP53 (59, 35.1%), followed by STK11 (27, 16.1%), STK11/TP53 (20, 11.9%), CDKN2A/TP53 (7, 4.2%), CDKN2A/STK11 (4, 3.4%) and CDKN2A/STK11/TP53 (3, 1.8%). Using MDACC's report, four groups were established: KL, KP, KC, and K-only. Correlation of genotypes with clinical outcome after adjuvant therapies will be analysed. Compared with adjacent tissues, KRASm cancer tissues had differentially expressed genes (DEGs) enriched in pathways of cytokine receptor interaction, primary immunodeficiency, intestinal immune network for IgA production, and etc. All KRAS tumors can be categorized into low and high inflamed groups by StromalScore, ImmuneScore and ESTIMATEScore methods.

Conclusions

Chinese KRAS mutant lung cancers are highly heterogeneous in terms of both KRAS mutations and co-altered genes and varied in inflammatory status in tumor microenvironment as well. Molecular and immune characteristics in KRASm NSCLC may influence the clinical outcome of adjuvant therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The National Natural Science Foundation of China.

Disclosure

The author has declared no conflicts of interest.