Comprehensive molecular profiling of lung adenocarcinoma

Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma

“…PIK3CA mutation was detected in a large variety of human cancers. With a frequency of 2–7% in NSCLC, it is more frequent in lung squamous cell carcinoma than in lung adenocacinoma 12, 13, 14. PIK3CA mutation was found both in patients without EGFR‐TKIs dosing and those resistance to targeted therapy 14, 15.…”

Identification of novel cyclin gene fusion transcripts in endometrioid ovarian carcinomas

“…5 Taking all these results together, we see that all the mentioned genes were recurrently rearranged in ovarian cancer, admittedly at very low frequencies. Furthermore, 21 of the genes we found involved in fusions were previously reported in 35 different fusion transcripts in studies of breast cancer and 14 fusion transcripts were identified in lung cancer5, 31, 32 (Table 3), hinting that they may be generally relevant in carcinogenesis of different types.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…24 In order to explore the association of Tfh with neoantigen load, we analyzed a subset of tumours (n = 275) with characterized somatic mutational loads. 17 When stratified by Tfh levels, the number of non-silent somatic mutations per megabase increased significantly with Tfh signatures (Figure 3B). Since increased mutational load may identify tumours with specific mutational drivers, we assessed whether Tfh expression associated with KRAS or EGFR status, common driver mutations in NSCLC with heterogeneous immune infiltration patterns.…”

“…16 The expression profiles for the TCGA cohort were generated using the Agilent 244K custom gene expression G4502A_07_3 microarray, 17 while the profiling of the matched LUAD Stage I cohort used the Illumina HumanRef-8 v3.0 expression beadchip. 16 For all single gene expression comparisons, outliers were identified and removed via nonlinear regression followed by false discovery correction (FDR-BH p < 0.01).…”