Abstract
Lung cancer is the most common cause of cancer mortality worldwide, with an estimated 1.4 million deaths each year. Here we report whole-exome sequencing of nine tumor/normal tissue pairs from Chinese patients with non-small cell lung carcinoma (NSCLC). This allows us to identify a number of significantly mutated genes in NSCLC, which were highly enriched in DNA damage repair, NF-κB pathway, JAK/STAT signaling and chromatin modification. Notably, we identify a histone-lysine methyltransferase gene, namely, MLL2, as one of the most significantly mutated genes in our screen. In a following validation study, we identify deleterious mutations of MLL2 in 12 out of 105 (11.4%) NSCLC patients. Additionally, reduced or lost expression of MLL2 was commonly observed in tumor tissues as compared with paired adjacent non-tumor tissues regardless of mutation status. Together, our study defines the landscape of somatic mutations in Chinese NSCLC and supports the role of MLL2 mutation in the pathogenesis of the disease.
Highlights
We identified small insertions/deletions as well as copy number variations (CNVs) in these nine patients using different computational approaches
No somatic mutation was detected in any components of NF-kB complex, we found frequent mutations in a wide range of membrane receptors and their downstream effectors that might result in perturbed NF-kB function in six cases
In our validation screen for MLL2 somatic mutation, we identified a high proportion of nonsense mutations which result in truncated proteins of MLL2 lacking the SET domain (Figure 2A)
Summary
TTN is the most frequently mutated proteins in our study which contains 13 missense mutations in 6 out of 9 samples (67%) This is consistent with results from COSMIC that 244 out of the 467 (52%) lung cancer samples sequenced have somatic mutations in TTN. We performed pathway analysis to identify signaling cascades that contain a larger number of mutated genes than expected by chance (Supplementary table 8). We find that the most significantly affected module is involved in Tyrosin kinase activity of JAK-STAT cascade (Supplementary Figure 1B) This is in line with our pathway analysis and supports the roles of alternations in JAK-STAT module as driver mutations in NSCLC. All together we identified inactivating mutations or protein deficiency of MLL2 in 12 out of 105 (11.4%) individuals (Figure 2A, Table 3), which was similar to that reported in COSMIC database (64/431, 15%), indicating that MLL2 is frequently mutated in NSCLC. We found that MLL2 was frequently mutated and repressed in NSCLC, supporting its role as a critical tumor suppressor
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