Proteogenomic study reveals insights into early-stage lung cancer

FROM CELL / Novel insights into the underlying genetic and molecular architecture of lung adenocarcinoma may aid the management of patients with early-stage disease, according to researchers.

A proteogenomic study revealed sex- and smoking-related differences, proteomic subtypes that may be associated with clinical outcomes, and potential biomarkers for therapeutic intervention.

Yi-Ju Chen, PhD, of Academia Sinica in Taipei, Taiwan, and colleagues reported these findings in Cell.

The researchers prospectively analyzed proteogenomic data from 103 treatment-naive lung cancer patients in Taiwan. Most patients (89%) had adenocarcinoma, and most (80%) had stage IA or IB disease. The patients’ median age was 63 years, 58% were female, and 83% were non-smokers.

RNA and whole-exome sequencing as well as proteomics analyses were performed for each tumor sample. ­Phosphoproteomics data were also collected and analyzed.

Among patients with adenocarcinoma (n = 91), 23,145 nonsynonymous somatic single nucleotide variants were detected. More than 10,000 unique proteins and 20,000 phosphosites were quantified, and a total of 30,155 RNAs were measured at the transcriptional level. 

Sex, smoking, and subtypes

The researchers found that, overall, the most commonly mutated genes were EGFR (85%), TP53 (33%), and RBM10 (20%). KRAS and APC were most frequently mutated in men, while EGFR-L858R and RBM10 mutations were more common in women (P < .05). KRAS and ATM mutations occurred more frequently among patients with smoking history (P < .01).

The researchers also divided patients into proteomic subtypes. Subtype 1 consisted largely of patients with stage II or higher tumors and tumors with visceral pleural invasion, TP53 mutations, and high mutational burden. Patients with subtype 2 had stage IA or IB tumors without EGFR-L858R mutations. And subtype 3 patients tended to have stage IA tumors lacking TP53 mutations.

Some early-stage tumors were clustered together with late-stage tumors in subtype 1, so the researchers further divided tumors into stage IA ‘‘late-like’’ and stage IB ‘‘late-like.’’

Stage IA late-like patients were more likely to be smokers and had a slightly higher mutational burden, when compared with non-late-like stage IA patients.

The stage IB late-like group included nearly all stage IB patients with visceral pleural invasion. The stage IB late-like group was also enriched for EGFR-L858R mutations and TP53 mutations, and all stage IB patients with dual EGFR-L858R/TP53 mutant tumors were in the late-like group.

An analysis of data from an independent cohort (n = 208) suggested these classifications can have clinical implications. Among stage IA patients, there was no difference in overall survival between those with EGFR-L858R and those with EGFR-Del19. However, among stage IB patients, those with EGFR-L858R had significantly worse overall survival (P = 0.028).

APOBEC and MMP11

The researchers found evidence to suggest the APOBEC signature may play a role in lung cancer development at an early age in female non-smokers, and the signature could potentially be used to predict response to immunotherapy.

“Our findings suggest that high APOBEC signature may help identify patients, such as young EGFR-[wild-type] female patients, [who] are anticipated to respond to immunotherapy,” the researchers wrote.

Finally, the team found evidence to support MMP11 as a therapeutic target. They found that MMP11 and related proteins were upregulated in the study cohort, most significantly in the late and late-like classes in subtype 1.

In an independent cohort of early-stage patients (n = 117), strong expression of MMP11 was significantly associated with poor overall survival.

Based on these and prior findings (Mol Ther Oncolytics. 2019 Apr 6;14:82–93), the researchers concluded that MMP11 may be “a biomarker for early detection and treatment” of non–small cell lung cancer.

“Genomic analysis has formed the basis for several targeted treatment strategies and has transformed the field [of lung cancer],” commented Philipp Lange, PhD, of the University of British Columbia in Vancouver, who was not involved in this study.

“It is to be expected that we will see an increase in proteogenomic-based guidance of therapy for patients with lung cancer and other malignancies,” he added.

This research was supported by the Next-Generation Pathway of Taiwan Cancer Precision Medicine Program, the Taiwan Protein Project at Academia Sinica, Ministry of Science and Technology, and National Taiwan University. The authors and Dr. Lange declared no conflicts of interests.

SOURCE: Chen YJ et al. Cell. 2020 Jul 9. doi: 10.1016/j.cell.2020.06.012.